Combining Pembrolizumab and Palliative Radiotherapy in Gastroesophageal Cancer to Enhance Anti-Tumor T Cell Response and Augment the Abscopal Effect
Phase: PHASE2
Conditions: Gastric Adenocarcinoma, Gastric Squamous Cell Carcinoma, Gastroesophageal Junction Adenocarcinoma, Metastatic Malignant Neoplasm in the Stomach, Stage IV Esophageal Adenocarcinoma AJCC v7, Stage IV Esophageal Squamous Cell Carcinoma AJCC v7
Sponsor: City of Hope Medical Center

IRB# 16099 
 
10/16/2019 
Packet:  05 
 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:  
COMBINING PEMBROLIZUMAB AND PALLIATIVE RADIOTHERAPY IN 
GASTROESOPHAGEAL CANCER TO ENHANCE ANTI-TUMOR T CELL RESPONSE AND 
AUGMENT THE ABSCOPAL EFFECT 
 
CITY OF HOPE PROTOCOL NUMBER: 
16099 
Protocol Dated:  10/16/2019 
 
COH Initial Submission: 
 Protocol dated 04/08/2016 
 
 
 
Version: 00 
COH Amendment 01 
   Protocol dated 02/10/2017 
 
 
 
Version: 01 
COH Amendment 02 
   Protocol dated 07/26/2017 
 
 
 
Version: 02 
COH Amendment 03 
   Title Page dated 02/27/2018  
 
 
Version: 03 
COH Amendment 04 
 Protocol dated 10/16/2019 
 
 
 
Version: 04 
COH Amendment 05 at Cont.Protocol dated 10/16/2019(tp) 
 
 
Packet:  05 
 
DISEASE SITE: 
 
 
 
 
Esophageal, gastric, and gastroesophageal cancers 
STAGE (if applicable):  
 
 
 
IV 
MODALITY: 
 
 
 
 
Intravenous 
PHASE/TYPE: 
 
 
 
 
Phase II/Prospective biomarker analysis 
 
PRINCIPAL INVESTIGATOR: 
 
Joseph Chao, MD 
COLLABORATING INVESTIGATOR(S) 
 
Yi-Jen Chen, MD,  
 
PARTICIPATING CLINICIANS: 
 
Vincent Chung, MD, Marwan Fakih, MD, 
Daneng Li, MD, Dean Lim, MD 
 
DIAGNOSTIC RADIOLOGIST: 
. 
STUDY STATISTICIAN: 
Paul Frankel, PhD 
  EXTERNAL COLLABORATING INVESTIGATOR(S): 
Greg Caporaso, Ph.D.,  
Joanne Weidhaas, M.D., Ph.D.  
 
 
 
 
 

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IRB Protocol No. 16099 
 
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CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
TITLE:  COMBINING PEMBROLIZUMAB AND PALLIATIVE RADIOTHERAPY IN 
GASTROESOPHAGEAL CANCER TO ENHANCE ANTI-TUMOR T CELL 
RESPONSE AND AUGMENT THE ABSCOPAL EFFECT 
CITY OF HOPE PROTOCOL NUMBER: 
16099 
VERSION: 
04 
COH Initial Submission: 
Protocol dated 04/08/2016 
Version: 00 
COH Amendment 01 
Protocol dated 02/10/2017 
Version: 01 
COH Amendment 02 
Protocol dated 07/26/2017 
Version: 02 
COH Amendment 03 
Title Page dated 02/27/2018 
 
 
Version: 03 
COH Amendment 04 
Protocol dated 10/16/2019 
Version: 04 
 
SPONSOR/IND NUMBER: 131134  
DISEASE SITE: 
Esophageal, gastric, and gastroesophageal cancers 
STAGE (if applicable): IV 
MODALITY: 
Intravenous 
PHASE/TYPE: 
Phase II/Prospective biomarker analysis 
PRINCIPAL INVESTIGATOR: 
 
Joseph Chao, M.D. 
City of Hope 
COLLABORATING INVESTIGATOR(S)
 
 
Peter Lee, M.D. 
Yi-Jen Chen, MD., Ph.D. 
City of Hope 
 
PARTICIPATING CLINICIANS: 
 
Vincent Chung, M.D., Marwan 
Fakih, M.D., Daneng Li, M.D., Dean 
Lim, M.D., City of Hope 
STUDY STATISTICIAN: 
Paul Frankel, Ph.D. 
Department of Information Sciences 
PARTICIPATING SITES: 
EXTERNAL COLLABORATING 
INVESTIGATORS: 
City of Hope – Duarte 
Greg Caporaso, Ph.D. 
Northern Arizona University/TGen 
Joanne Weidhaas, M.D., Ph.D. 
UCLA 
STUDY SPONSOR AND MONITOR: 
City of Hope 
  
 

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IRB Protocol No. 16099 
 
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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 5 
2.0 
TRIAL DESIGN.......................................................................................................... 5 
2.1 
Trial Design ............................................................................................................. 5 
2.2 
Trial Diagram .......................................................................................................... 6 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 7 
3.1 
Primary Objective(s) & Hypothesis(es) ................................................................ 7 
3.2 
Secondary Objective(s) & Hypothesis(es)............................................................. 7 
3.3 
Exploratory Objective ............................................................................................ 7 
4.0 
BACKGROUND & RATIONALE ............................................................................ 8 
4.1 
Background ............................................................................................................. 8 
4.1.1 Pharmaceutical and Therapeutic Background ...................................................... 8 
4.1.2 Preclinical and Clinical Trial Data ........................................................................ 9 
4.2 
Rationale .................................................................................................................. 9 
4.2.1 Rationale for the Trial and Selected Subject Population ...................................... 9 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 10 
4.2.3 Rationale for Endpoints ...................................................................................... 12 
5.0 
METHODOLOGY ................................................................................................... 13 
5.1 
Entry Criteria ........................................................................................................ 13 
5.1.1 Inclusion Criteria ................................................................................................ 15 
5.1.2 Exclusion Criteria ............................................................................................... 17 
5.2 
Trial Treatments ................................................................................................... 19 
Table 1 Trial Treatment ................................................................................................... 19 
5.2.1 Dose Selection/Modification .............................................................................. 19 
Table 2: Dose Modification Guidelines for Drug-Related Adverse Event .................. 20 
5.2.2 Timing of Dose Administration .......................................................................... 21 
5.2.3 External Beam Radiotherapy .............................................................................. 21 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 23 
5.3.1 Acceptable Concomitant Medications ................................................................ 23 
5.3.2 Prohibited Concomitant Medications.................................................................. 23 
5.4 
Rescue Medications & Supportive Care ............................................................. 24 
5.4.1 Supportive Care Guidelines ................................................................................ 24 
Table 3 Infusion Reaction Treatment Guidelines .......................................................... 26 
5.5 
Diet/Activity/Other Considerations ..................................................................... 27 
5.5.1 Diet ...................................................................................................................... 27 
5.5.2 Contraception ...................................................................................................... 27 
5.5.3 Use in Pregnancy ................................................................................................ 28 
5.5.4 Use in Nursing Women ....................................................................................... 28 
5.6 
Subject Withdrawal/Discontinuation Criteria ................................................... 28 
5.6.1 Discontinuation of Study Therapy after CR ....................................................... 30 
5.7 
Clinical Criteria for Early Trial Termination ................................................... 30 
6.0 
STUDY CALENDAR ............................................................................................... 31 
6.1 
Initial Treatment Phase ........................................................................................ 31 
6.2 
Second Course Phase ............................................................................................ 34 

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7.0 
TRIAL PROCEDURES ........................................................................................... 36 
7.1 
Trial Procedures ................................................................................................... 36 
7.1.1 Administrative Procedures .................................................................................. 36 
7.1.2 Clinical Procedures/Assessments ........................................................................ 38 
Table 4  Imaging and Treatment after 1st radiologic evidence of progressive disease 
(PD) ........................................................................................................................ 40 
7.1.3 Laboratory Procedures/Assessments .................................................................. 46 
Table 5  Laboratory Tests ................................................................................................ 46 
7.1.4 Other Procedures ................................................................................................. 47 
7.1.5 Visit Requirements .............................................................................................. 47 
8.0 
DATA AND SAFETY MONITORING PLAN ...................................................... 50 
8.1 
Definition of Risk Level ........................................................................................ 50 
8.2 
Monitoring and Personnel Responsible for Monitoring ................................... 50 
8.3 
Adverse Events and Serious Adverse Events ..................................................... 50 
8.4 
Deviations and Unanticipated Problems ............................................................. 53 
8.5 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
Merck ..................................................................................................................... 54 
8.6 
Reporting of Pregnancy and Lactation to Merck .............................................. 54 
8.7 
Reporting of Adverse Events to Merck ............................................................... 54 
9.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 55 
9.1 
Primary Objective ................................................................................................. 55 
9.2 
Secondary Objectives ........................................................................................... 56 
10.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 57 
10.1 
Investigational Product ........................................................................................ 57 
Table 7  Product Descriptions .......................................................................................... 57 
10.2 
Packaging and Labeling Information ................................................................. 57 
10.3 
Clinical Supplies Disclosure ................................................................................. 57 
10.4 
Storage and Handling Requirements .................................................................. 57 
10.5 
Returns and Reconciliation .................................................................................. 57 
11.0 
DATA REPORTING ................................................................................................ 58 
11.1 
Data Reporting ...................................................................................................... 58 
11.1.1 Confidentiality and Storage of Records .............................................................. 58 
11.1.2 Subject Consent Form ......................................................................................... 58 
11.1.3 Data Collection Forms and Submission Schedule .............................................. 58 
12.0 
HUMAN SUBJECT ISSUES ................................................................................... 59 
12.1 
Institutional Review Board .................................................................................. 59 
12.2 
Recruitment of Subjects ....................................................................................... 59 
12.3 
Study location and Performance Sites ................................................................ 59 
12.4 
Confidentiality ....................................................................................................... 59 
12.5 
Financial Obligations and Compensation........................................................... 60 
12.6 
Informed Consent Processes ................................................................................ 61 
REFERENCES ...................................................................................................................... 62 
APPENDIX 1: ECOG Perfomance Status .......................................................................... 64 
APPENDIX 2: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 ............... 65 

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APPENDIX 3: Events of Clinical Interest Guidance Document ...................................... 66 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab and palliative radiotherapy in metastatic gastroesophageal 
cancer 
Trial Phase 
II 
Clinical Indication 
SCC and/or adenocarcinoma of the esophagus, GEJ, and stomach 
Trial Type 
Prospective; Biomarker analysis 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups 
All patients will be assigned to the same therapy of palliative radiotherapy 
of 30 Gy over 10 fractions for symptoms from their primary tumor or a 
single target metastatic site in combination with pembrolizumab at a fixed 
dose of 200 mg every 3 weeks. 
Number of trial subjects 
14 
Estimated enrollment period 
24 months 
Estimated duration of trial 
36 months from the first patient signing informed consent until the last 
patient’s last visit. 
Duration of Participation 
Patients will complete radiation therapy of 30 Gy in 10 fractions and will 
continue pembrolizumab until confirmed disease progression, or 
intolerable toxicity, or an initial 35 administrations (approximately 2 
years).  Patients who stop pembrolizumab with stable disease or better or 
35 administrations of therapy without progression may be eligible at the 
discretion of the investigator to receive up to an additional year of 
pembrolizumab therapy.  Patients with evidence of progressive disease 
(PD) on imaging and are clinically stable may continue to be treated at the 
discretion of the investigator.   
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single-arm, prospective, phase II, biomarker analysis trial of pembrolizumab in 
combination with palliative radiotherapy for patients with metastatic squamous cell or 
adenocarcinoma of the esophagus, stomach, or gastroesophageal junction (GEJ).  We will 
enroll 14 patients within our institution who are in need of palliative radiation for symptoms 
related to their primary tumor including pain, dysphagia, and bleeding.  Patients with a single 
metastatic site in need of palliative radiation (e.g., pain from a bony metastasis, enlarged lymph 
nodes, liver metastasis, etc.) will also be eligible provided they have other measurable 
metastatic sites outside of the radiation field.  The exception will be patients who require 
palliative radiation to a symptomatic central nervous system (CNS) metastasis.  The first dose 
of palliative radiation and first dose of pembrolizumab will commence on cycle 1, day 1. 
Participation in this trial will be dependent on patients having a metastatic site amenable to 
ultrasound and/or CT-guided biopsy, inclusive of patients with malignant ascites amenable to 
ultrasound-guided aspiration, and agreeing to provide pre- and post-treatment biopsies for the 

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biomarker analysis primary endpoint of the study.  Patients who are undergoing palliative 
radiation for a single target metastatic site, and only the primary tumor is amenable to biopsy 
are also eligible to participate if they consent to endoscopic pre- and post-treatment biopsies.
Treatment will continue until documented clinical PD, unacceptable AE(s), intercurrent illness 
that prevents further administration of treatment, investigator’s decision to withdraw
the patient, patient withdraws consent, pregnancy of the subject, noncompliance with trial
treatment or procedure requirements, completion of 35 administrations (approximately 2
years) of treatment with study medication or achievement of a complete response.
2.2
Trial Diagram
Start of RT
End of RT
Day +21 after end of RT
Pembrolizumab 200 mg every 3 weeks
CT every 6 weeks for 18 weeks then every 9 weeks
for RECIST1.1 assessment
Blood sampling for PBMC coll
of circulating T cells and serum
sequencing
Study Schema
Pre-treatment
Pro
Radiology-guided biopsy of metastatic sites 
and/or removal of malignant ascites

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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To establish that the combination of pembrolizumab and traditional external 
beam multifractionated RT to the primary tumor or a single target metastatic site of patients 
with metastatic gastric, esophageal, and/or GEJ cancers will lead to an increase in tumor 
infiltrating cytotoxic T-cells and circulating cytotoxic T cells and a reduction in 
immunosuppressive Tregs and MDSCs in metastatic sites. 
Hypothesis: The combination of pembrolizumab and traditional external beam 
multifractionated RT to the primary tumor or a single target metastatic site will lead to 
increased immune-mediated tumor cytoxicity via a demonstrable increase in tumor 
infiltrating and circulating cytotoxic T cells and a reduction in immunosuppressive Tregs 
and MDSCs within metastatic sites post-therapy. 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective: To establish that the combination of pembrolizumab and RT is feasible in this 
patient population and evaluate toxicities per NCI CTCAE ver.4.03. 
Hypothesis: The combination of pembrolizumab and RT will be feasible with an 
acceptable safety profile to warrant future studies. 
(2) Objective: To evaluate overall response rate (ORR) per RECIST1.1 and irRECIST in this 
treatment population and correlate with tumor T-cell response. 
Hypothesis: The combination of pembrolizumab and RT will demonstrate clinical efficacy 
with a promising response rate compared to historical controls to warrant future studies. 
(3) Objective: To evaluate progression-free (PFS) and overall survival (OS) in this treatment 
population. 
Hypothesis: The combination of pembrolizumab and RT will demonstrate promising PFS 
and OS to warrant future studies. 
3.3 
Exploratory Objectives 
(1) 
Objective: To measure changes in whole genome serum miRNA signatures before and 
after protocol therapy and correlate with tumor/immune/stromal cell miRNA expression 
profiling determined by deep sequencing. 
(2) 
Objective: To measure changes in fecal and oral microbiomic diversity and correlate 
with ORR, PFS, and OS. 
(3) 
Objective: To assess germline mutations in a panel of miRNA regulatory genes using 
the MiraDx assay as predictors of response and toxicity to pembrolizumab and RT.   

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4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (aka MK-3475). 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors .  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 

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of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Metastatic squamous cell carcinomas (SCC) and adenocarcinomas of the esophagus, stomach, 
and gastroesophageal junction (GEJ) account for a high proportion of worldwide cancer-
related mortality.  While some progress has been made for HER2 and VEGFR2 targeted 
therapies in adenocarcinomas,1,2 options for metastatic SCC remain dismal.  Evidence for 
cytotoxic agents in SCC typically stem from a small proportion of patients enrolled in large 
phase III trials predominated by patients with adenocarcinoma histologies.3  Novel targeted 
therapeutic approaches for both subtypes are desperately needed. 
Pembrolizumab has demonstrated encouraging preliminary evidence of activity in small 
cohorts of gastric and esophageal cancer patients within the KEYNOTE-012 and KEYNOTE-
028 trials, respectively.4,5  Both trials selected for patients with evidence of PD-L1 expression 
within tumor stroma and/or tumor cells.  KEYNOTE-012 reported a 22.2% overall response 
rate by central review, while KEYNOTE-028 noted a 30.4% overall response rate when 
assessed by investigator review.  The activity of pembrolizumab in gastroesophageal cancer 
patients without tumor PD-L1 expression remains unknown, though lack of PD-L1 expression 
does not necessarily translate to an absolute lack of response to immune checkpoint inhibitors 
in pooled analyses of patients with melanoma, NSCLC, and genitourinary malignancies.6  
Given the promising early evidence of clinical efficacy in gastroesophageal cancers, strategies 
should be further developed to enhance the potency of immune checkpoint inhibitors, even in 
patients whose tumors are currently not considered to have detectable PD-L1 expression. 
The abscopal effect is a rarely observed though well annotated clinical phenomenon in cancer 
radiotherapy (RT), in which non-irradiated metastatic lesions distant from the primary tumor 
site directly subjected to radiation are noted to regress.  This phenomenon has been attributed 
to immune-mediated effects in preclinical models,7 and provides rationale that immune 
checkpoint inhibition and RT could act synergistically.  In a recent preclinical study, PD-1 was 
reported to suppress RT antitumor response, though delivery of a PD-1 blocking antibody 

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enhanced antitumor response at the primary radiated site as well as non-irradiated metastatic 
lesions.8  Furthermore, radiation therapy has been shown to drive up the expression of PD-L1 
tumor expression in preclinical models.8,9,10  Mounting evidence also supports that mutational 
load in tumors correlate with clinical benefit from immune checkpoint inhibition.11  Results 
from The Cancer Genome Atlas (TCGA) have demonstrated both esophageal SCC and gastric 
adenocarcinomas demonstrate a high rate of somatic mutations.12,13  Furthermore, the 
development of esophageal SCC is commonly attributed to tobacco smoking, a risk factor 
shared with NSCLC in which anti-PD-1 strategies have been successful.  It is not uncommon 
for patients with metastatic disease to undergo palliative, traditional external beam 
multifractionated RT to their primary tumor for the treatment of dysphagia, pain, or 
gastrointestinal bleeding or a single metastatic site such as a bone metastasis for the treatment 
of pain.  The concordant delivery of pembrolizumab during palliative RT thus serves as an 
attractive window-of-opportunity trial to determine if the abscopal effect may be augmented 
with immune checkpoint blockade.   
We propose a prospective trial to assess pre- and post-treatment biopsies of patients’ metastatic 
sites with the hypothesis that tumor cytotoxic T cells will be increased with combining 
pembrolizumab and palliative RT with corresponding improvement in clinical activity.  As we 
will only be radiating a single target lesion in this study population, assessment of response 
among non-irradiated metastatic sites will serve as a true measure of the abscopal effect.  
Toxicities are not anticipated to be overlapping for these two modalities, though safety should 
still be assessed in this early cohort of patients to ensure immune-mediated or radiation-
induced toxicities are not exacerbated by the combination.   At City of Hope where patients 
will be solely recruited for this trial, we have extensive experience in the conduct of pre- and 
post-treatment biopsy studies having completed accrual to a pilot trial of the novel 
nanopharmaceutical CRLX101 in this disease subset (Clinicaltrials.gov, NCT01612546).  We 
also have a broad gastroesophageal cancer patient population evaluating more than 60 new 
cases per year due to our institution serving the diverse, multicultural population of the San 
Gabriel Valley in Los Angeles County.  Dr. Peter Lee, MD, Chair of the Department of 
Immuno-Oncology, will serve as a collaborating investigator on this study given his 
laboratory’s expertise in translational analyses of tumor/immune/stromal cell interactions. 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested 
in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to 
test for initial tumor activity.  Recent data from other clinical studies within the MK-3475 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
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PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed 
for other antibodies and would support both body weight normalized dosing or a fixed dose 
across all body weights.  MK-3475 has been found to have a wide therapeutic range based on 
the melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative 
to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 

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4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The clinical efficacy of combining pembrolizumab and palliative radiotherapy will be 
measured by assessing overall response rate by RECIST 1.1 and irRECIST.  To truly measure 
the abscopal effect, patients will be required to have metastatic disease sites outside the field 
of palliative radiation that are considered measurable by RECIST 1.1.   
4.2.3.2 Biomarker Research 
Analysis of pre- and post-treatment biopsies 
Radiology-guided biopsies will utilize 20-gauge core biopsy needles.  Biopsies obtained via 
an endoscopic approach will utilize standard endoscopic biopsy forceps in which specimens 
are typically 3-6 mm in diameter.  As such tissue samples will be composed of both tumor 
cells and associated tumor stroma.  Fresh tumor samples will be immediately delivered to the 
laboratory of Dr. Peter Lee for both ex vivo tumor/immune/stromal cell culture and expansion 
as well as histologic analyses.  Patients with fresh malignant ascites collected will also be 
immediately delivered to the lab for ex vivo tumor/immune/stromal cell culture and expansion 
alone. Dr. Lee’s lab will utilize quantitative spatial image analysis to examine changes in 
tumor cell-stromal interactions including CD4, CD8, Treg, and MDSC populations pre- and 
post-therapy.  
PD-L1 expression within the tumor, on cancer cells and stromal cells, will be analyzed by 
immunohistochemistry (IHC).  PD-1 expression on tumor infiltrating T cells and circulating 
peripheral blood mononuclear cell (PBMC) T cells will be analyzed by a combination of IHC 
and flow cytometry.  Immune cell populations will be further analyzed via high dimensional 
flow cytometry to measure levels of Tregs and MDSCs, which will allow us to calculate the 
ratio of effector T cells to Tregs and MDSCs, respectively.  Ex vivo isolated T cells will also 
be analyzed for proliferative capacity (CFSE dilution) and cytokine production (IFN-γ and 
IL-17) after stimulation with anti-CD3 and/or PMA and Ionomycin.  Furthermore, by use of 
multi-color IHC we will determine influences of pembrolizumab+RT treatment on the 
magnitude and proximity of CD8 T cells to cancer cells within the tumor.  Lastly, we will 
analyze changes in the diversity of T cell repertoire in both PD-1 positive and PD-1 negative 
T cell populations following pembrolizumab+RT treatment via deep sequencing of the TCR 
Vβ CDR3 region.  Such changes in T cell repertoire can be suggestive of potential epitope 
spreading for anti-tumor antigens and reversal of tumor antigen-specific T cell anergy. 
Genomic analyses utilizing City of Hope’s Integrative Genomics Core will also be performed 
on the corresponding cancer/stromal/immune cell populations via total RNA-seq for coding 
and non-coding RNAs (including miRNAs). 
Performance of these studies will require several highly developed techniques that have been 
routinely conducted in Dr. Peter Lee’s lab.  A prototype BD microfluidic FACS instrument 
allows for 12-color analysis of low cell numbers, thereby allowing maximal data acquisition 
out of small sample sizes. A powerful quantitative, spatial image analysis system will enable 

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us to analyze immune and cancer cells in tissues via 8-color histology.  Lastly, Dr. Lee’s lab 
has considerable expertise in TCR repertoire analysis via deep sequencing, which can yield 
information on T cell specificity to unknown antigens. 
Serum circulating miRNA sequencing 
10 mL of whole blood will be collected from each patient at prespecified time points and serum 
separated per standard procedures. Total RNA will be extracted using Trizol and sent to the 
Integrative Genomics Core at City of Hope for miRNA-seq. The Integrative Genomics Core 
is a shared resource at City of Hope and is equipped with all major state-of-the-art microarray 
and sequencing platforms for genomic studies, including Illumina’s Hiseq 2500 and Life 
Technology’s Ion Proton sequencers, Illumina’s Hiscan Beadchip system, Affymetrix’s 
GeneChip system, and Agilent’s microarray system. With a highly experienced team of 
bioinformaticians integrated within the core, efficient genomic data analysis services will be 
provided to convert high throughput data into biologically interpretable results. They have 
extensive expertise in utilizing both commercial and open-source software tools for sequencing 
data analysis including but not limited to R/Bioconductor, IGV, Bowtie, TopHat, Cufflinks, 
Novoalign, MACS, MEME, Transfac, BWA, GATK, Samtools, Gene Set Enrichment 
Analysis (GSEA), Ingenuity Pathway Analysis and DAVID.  
Sequence reads that match human miRNAs in Sanger mirBase will be calculated and analyzed. 
Circulating whole genome miRNA signatures will be compared to miRNAs sequenced from 
total RNA-seq from the corresponding tumor biopsy timepoints to aid in biomarker discovery 
of serum miRNAs that may predict for immunotherapy response or resistance. miR-23a will 
be of particular interest given its description as a gastric cancer oncomir and function as a 
repressor of T cell cytotoxicity in preclinical miRNA screens.14,15  miR-34a and miR-200 will 
be other miRNAs of interest to measure given reporting of their ability to suppress PD-L1 
expression in other experimental systems.16,17 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
will be done only after obtaining written informed consent. Studies or procedures that were for 
clinical indications (not exclusively to determine study eligibility) may be used for baseline 
values and/or to determine pre-eligibility, even if the studies were done before informed 
consent was obtained.  The informed consent process is to be fully documented, and the 
prospective participant must receive a copy of the signed informed consent document.  All 
screening procedures and their respective windows are detailed in the Study Activity Calendar. 

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Participant Enrollment 
COH DCC Availability and Contact Information 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center 
(DCC) at City of Hope.   
DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through 
Friday (except holidays). DCC contact information is as follows:  
o Phone: (626) 256-4673 ext. 83968 
o E-mail: DCC@coh.org 
 
Eligible subjects must be registered prior to start of protocol therapy. Issues that would cause 
treatment delays should be discussed with the Principal Investigator. If a subject does not 
receive protocol therapy following registration, the subject’s registration on the study may be 
canceled after discussion with the PI. The Data Coordinating Center should be notified of 
cancellations as soon as possible. 
Registration Process  
To register a participant the subsequent procedure is to be followed: 
1. The study team should contact the DCC via telephone or email to provide notification 
regarding the pending registration and communicate desired timeline of the 
registration, especially if it must be completed promptly to meet the registration 
window.  
2. The protocol nurse or CRC will email a copy of the following documents to the DCC: 
o Completed eligibility checklist (printed from Section 5.1 of the protocol)  
o Signed Informed Consent  
o Signed subject’s bill of Rights  
o Signed HIPAA authorization form and  
o Provide copies of source documentation only if not readily available as a 
finalized record in the COH Electronic Medical Record (EMR).  
3. After having received all transferred documentation, the DCC will complete the review 
the documents to verify eligibility, working with the study team as needed to resolve 
any missing required source elements. A participant failing to meet all protocol 
eligibility requirements will not be registered. 
4. Once eligibility has been confirmed, DCC staff will register the participant by: 
assigning a subject accession number, register the subject on study centrally into a COH 
clinical trials management system (e.g. MIDAS), and enter the subject into the eCRF 
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5. Once registration has been completed, DCC staff will send a Confirmation of 
Registration Form within 24 hours, including the participant study number to:  
o The site study team: Principal Investigator, treating physician, protocol 
statistician, protocol nurse, CRC and COH IDS Pharmacy. 
o the COH sponsor team designees 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
The DCC is to be notified of all participants who sign consent but do not meet eligibility criteria 
or do not initiate protocol therapy.  
5.1.1 Inclusion Criteria 
Participants must meet all of the following criteria on screening examination to be eligible to 
participate in the study:  
Patient MRN: 
Patient Initials:  (F,M,L): 
Informed Consent and Willingness to Participate 
___ 1. 
Documented informed consent of the participant 
___ 2. 
Willing to provide tumor tissue amenable to ultrasound or CT-guided 
biopsy for biomarker analyses.   
 Patients with malignant ascites are permitted to participate and provide 
ascites samples for biomarker analyses.   
 Patients receiving radiation to a single metastatic site in which only the 
primary tumor is accessible for biopsy by endoscopy will also be 
eligible. 
Age Criteria, Performance Status and Life Expectancy 
___ 3. 
Age: t 18 years  
___ 4. 
ECOG performance status of ≤ 1  
___ 5. 
Life expectancy of ≥ 3 months  
Nature of Illness and Treatment History 
___ 6. 
Diagnosis 
of 
metastatic 
squamous 
cell 
carcinoma 
and/or 
adenocarcinoma of the esophagus, gastroesophageal junction, or stomach in 
need of palliative radiotherapy to the primary tumor or a single metastatic site 
for symptoms such as pain, dysphagia, and/or gastrointestinal bleeding.   
 Patients with adenocarcinoma histology and known HER2-
overexpressing disease are permitted to participate if they progressed or 
are intolerant of prior trastuzumab-containing therapy. 

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___ 7. 
Measurable metastatic sites of disease outside of the target lesion 
undergoing palliative radiation based on RECIST 1.1 as assessed by the 
investigator.   
___ 8. 
Have no limits on prior lines of therapy or may be treatment-naïve if in 
need of palliative RT provided the patient has not received prior anti-PD-1, 
anti-PD-L1, or anti-PD-L2 therapy. 
Laboratory Criteria (within 10 days of treatment initiation unless indicated otherwise) 
___ 9. 
ANC ≥ 1,500/mm3  
ANC: 
Date: 
___ 10. Platelets ≥ 100,000/mm3  
Plts: 
 
Date: 
___ 11. Hemoglobin ≥ 9 g/dL  
Hgb: 
Date: 
 May receive transfusion to meet this goal as it is anticipated a subset of 
patient will require palliative radiation to a bleeding primary tumor 
___ 12. Total serum bilirubin ≤ 1.5 x ULN 
OR Direct bilirubin ≤ ULN if total 
bilirubin levels > 1.5 x ULN 
ULN: 
Bil: 
 
Direct Bil: 
 
Date: 
___ 13. Albumin ≥ 2.5 mg/dL 
Albumin: 
Date: 
___ 14. AST and ALT ≤ 2.5 x ULN OR ≤ 
5.0 x ULN if liver metastases present 
ULN: 
ALT: 
Date: 
ULN: 
AST: 
Date: 
___ 15. Serum creatinine ≤ 1.5 x ULN OR 
Creatinine clearancea ≥ 60 mL/min if 
creatinine levels > 1.5 x ULN 
 GFR can also be used in place of 
creatinine or CrCl 
a If measured or calculated per institutional standard 
ULN: 
 
Serum Cr: 
 
Cr Cl: 
 
Date: 
___ 16. If not receiving anticoagulants: 
International Normalized Ratio (INR) 
OR Prothrombin (PT) ≤ 1.5 x ULN 
ULN: 
INR: 
PT: 
 
Date: 
If on anticoagulant therapy:  PT must 
be within therapeutic range of intended 
use of anticoagulants 
___ 17. If not receiving anticoagulants: 
Activated Partial Thromboplastin Time 
(aPTT) ≤ 1.5 x ULN 
If on anticoagulant therapy: aPTT 
must be within therapeutic range of 
intended use of anticoagulants 
ULN: 
aPTT: 
Date: 

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___ 18. Negative urine or serum pregnancy 
test (female of childbearing potential 
only)  
 If the urine test is positive or cannot 
be confirmed as negative, a serum 
pregnancy test will be required 
Urine test: 
 
Serum test: 
Date: 
Contraception 
___ 19. Female of childbearing potential: willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication.   
 Childbearing potential defined as not being surgically sterilized or have 
not been free from menses for > 1 year.  
___ 20. Male: Use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy. 
5.1.2 Exclusion Criteria 
Prior Therapy 
___ 1. 
Anti-PD-1, anti-PD-L1, or anti-PD-L2 agents 
___ 2. 
Prior radiation therapy within the field of the target lesion that in the 
opinion of the treating radiation oncologist would preclude further palliative 
radiation to a dose of 30 Gy. 
___ 3. 
Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 
___ 4. 
Chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 
1 or at baseline) from adverse events due to a previously administered agent. 
 Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. 
 Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy.   
___ 5. 
Live vaccine within 30 days of planned start of study therapy. 
 Note:  Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are allowed; however intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not 
allowed. 
___ 6. 
Immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 

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___ 7. 
Investigational device within 4 weeks of the first dose of treatment  
Concomitant Therapy 
___ 8. 
Currently receiving an investigational agent 
___ 9. 
About to undergo palliative radiation for a symptomatic CNS metastasis 
___ 10. Systemic steroid therapy 
Other Illnesses and Conditions 
___ 11. Hypersensitivity to pembrolizumab or any of its excipients  
___ 12. Diagnosis of immunodeficiency  
___ 13. Active autoimmune disease that has required systemic treatment in the 
past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).  
 Replacement therapy (e.g. thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
___ 14. Known history of, or any evidence of active, non-infectious 
pneumonitis. 
___ 15. Current active infection requiring systemic therapy  
___ 16. Known history of active TB, HIV 1/2, Hepatitis B or Hepatitis C 
___ 17. Known additional malignancy that is progressing or requires active 
treatment.   
 Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or 
in situ cervical cancer. 
___ 18. Known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.   
 Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first dose of trial treatment and any 
neurologic symptoms have returned to baseline), have no evidence of 
new or enlarging brain metastases, and are not using steroids for at least 
7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical 
stability.   
___ 19. History or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best 
interest of the subject to participate, in the opinion of the treating investigator.   

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___ 20. Known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
___ 21. Pregnant or breastfeeding (female only). 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 1. 
Table 1 Trial Treatment 
Drug 
Dose/Potenc
y 
Dose 
Frequenc
y 
Route of 
Administratio
n 
Regimen/Treatmen
t Period 
Use 
Pembrolizuma
b 
200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimenta
l 
Radiotherapy 
3 Gy 
Daily 
External 
Beam 
Daily except 
weekends and 
holidays for 10 
fractions 
Standard of 
care and 
combination 
agent 
 
Trial treatment should begin as close as possible to the date on which treatment is 
allocated/assigned.  The first dose of pembrolizumab on cycle 1, day 1 should occur on the 
same day after the first fraction of radiation therapy. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of the dose to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (aka MK-3475) are provided in 
the Pharmacy Manual.   
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment.  Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 2 below.  See Section 5.4.1 
and Events of Clinical Interest Guidance Document for supportive care guidelines, including 
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Table 2: Dose Modification Guidelines for Drug-Related Adverse Event 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor.  The reason for 
interruption should be documented in the patient's study record.  Dose reductions of 
pembrolizumab are not permitted. 

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5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Study Calendar (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All pembrolizumab treatment will be administered on an outpatient basis.  Palliative 
radiotherapy is permitted to be delivered as an inpatient if in line with patient standard-of-care 
and after discussion with the study PI. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.3 External Beam Radiotherapy 
5.2.3.1 General Radiotherapy Information 
The intent of treatment is to deliver a palliative course of radiotherapy to a total dose of 30 Gy 
in 10 fractions to the symptomatic primary disease sites in the esophageal, GE junction, or 
gastric areas or one of the metastases.  Both 3D conformal radiotherapy and IMRT are allowed. 
Megavoltage equipment with effective photon energies ≥6MV is required. 
Technique: 3D conformal using opposed AP-PA portals or multifield techniques, such as AP, 
PA and opposed lateral fields or IMRT are recommended. ICRU-50 and ICRU-62 prescription 
methods and nomenclature shall be used in this trial. Tightly contoured targets should be used 
to spare as much bone marrow, small bowel, liver, heart, lung and kidney as possible. 
The prescription volume is the planning target volume (PTV). The total dose is 30 Gy in 10 
fractions. A minimum of 90% of the PTV will receive 30 Gy. No more than 10% of the PTV 
shall receive greater than 35 Gy. 
5.2.3.2 Localization, Simulation, and Immobilization 
Prior to the simulation, all pertinent radiographs, operative notes, and other diagnostic 
procedures such as endoscopic findings should be reviewed. This will allow an informed 
determination of target volume and treatment field borders.  
Simulation is required for all patients and should be performed with the patient positioned in 
an individualized immobilization device in the treatment position on a flat hard table and it is 
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therapy simulator, which reproduces the geometry of the treatment machine.  Oral contrast can 
be used to help outlining the target volume in the esophageal/GE junction/gastric areas.  CT-
based treatment planning is required for this study.  The planning CT should encompass the 
entire thoracic cavity for esophageal/GE junction cancer and the abdominal to a level below 
the bottom of the kidneys for gastric cancer.  A maximum slice thickness of 3-5 mm is required 
through regions of the gross tumor volume (GTV). 
5.2.3.3 Treatment Planning and Target Volumes 
Gross Target Volume (GTV): The GTV is defined as the primary tumor in the esophageal/GE 
junction/gastric areas, the grossly enlarged lymph nodes, or the gross metastatic sites requiring 
a palliative course of radiotherapy. 
Clinical Target Volume (CTV): Since the intent of radiotherapy is for palliation, there is no 
need to define a CTV for treatment. 
Planning Target Volume (PTV): Margins shall be added to the GTV for set up error and 
movement as PTV.  This expansion could be 0.5 to 2 cm and does not need to be uniform in 
all dimensions.  4DCT scan is allowed to customize PTV expansion. 
3D conformal radiotherapy or IMRT should be planned to optimize the PTV coverage and a 
minimum of 90% of the PTV shall receive 30 Gy. No more than 10% of the PTV shall receive 
greater than 35 Gy. IMRT can be delivered by tomotherapy or TrueBeam using RapidArc 
technique. 
5.2.3.4 Critical Structures and Compliance Criteria 
Organs at risk including lungs, liver, heart, kidneys and spinal cord shall be contoured.  Dose 
constraints must follow the standard guidelines.  The treating physician must carefully consider 
the tolerance dose/volume to each critical normal structure.  It is recommended to reduce doses 
to lung and heart as much as possible.  
x Lung: mean dose ≤ 20 Gy, V30 ≤ 20%, V20 ≤ 25%, V10 ≤ 40% and V5 ≤ 50% 
x Heart: mean dose ≤ 25 Gy, V30 ≤ 30% 
x Kidney: V20 ≤ 30% 
x Liver: mean dose ≤ 20 Gy, V30 ≤ 30% 
5.2.3.5 Radiotherapy Adverse Events 
Adverse effects related to radiation therapy will be recorded. These include nausea/vomiting, 
diarrhea, poor appetite, weight loss, fatigue, skin erythema, esophagitis, carditis, pneumonitis, 
myelosuppression, myelitis, late pulmonary fibrosis, and esophageal stricture. 

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5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 8.0. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
x Antineoplastic systemic chemotherapy or biological therapy  
x Immunotherapy not specified in this protocol 
x Chemotherapy not specified in this protocol 
x Investigational agents other than pembrolizumab 
x Radiation therapy outside of the clinical target volume of the index target lesion 
o Note:  Radiation therapy to a symptomatic lesion other than the index target 
lesion or to the brain may be allowed at the investigator’s discretion if the 
radiation course occurs after radiation has completed to the index target lesion.   
x Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  

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x Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.   Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
x Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 

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x Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
x Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
x Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
x Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 

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

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
prophylactic medications indicated for 
< =24 hrs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Diphenhydramine 50 mg po or IV 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.5.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 

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methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 8.6-Reporting of Pregnancy 
and Lactation to Merck.  If there is any question that a subject will not reliably comply with 
the requirements for contraception, that subject should not be entered into the study. 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 8.6. 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 

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A subject must be discontinued from the trial for any of the following reasons: 
x The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
x Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.6.2 
x Unacceptable adverse experiences as described in Section 5.2.1.2 
x Intercurrent illness that prevents further administration of treatment 
x Investigator’s decision to withdraw the subject 
x The subject has a confirmed positive serum pregnancy test 
x Noncompliance with trial treatment or procedure requirements 
x The subject is lost to follow-up 
x Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.5.5 
x Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (Study Calendar) 
and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment as described in Section 8.0).  Subjects who discontinue for 
reasons other than progressive disease will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression each subject will be 
followed by telephone for overall survival until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 

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5.6.1 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 pembrolizumab and had at least two 
treatments with pembrolizumab 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 Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.5.5. 
5.7 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 

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6.0 STUDY CALENDAR 
6.1 
Initial Treatment Phase 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treat
ment 
Post-Treatment 
Treatment Cycle: 
Main Study 
Screening  
 C1/D1 
C1/D8  C1/D15 C2D1 
 
C3D1 
C4D1 
C5D1 
C6+D1a 
Last 
Dose 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upc 
Scheduling Window (Days): 
-21 to -1 
 
± 1 
± 1 
± 3 
± 3 
± 3 
± 3 
± 3 
At time 
of 
Discon 
30 days 
post 
discon 
Every 6 
weeks 
post 
discon 
Every 
12 
weeks  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Statusd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Trial Treatment Administration 
Pembrolizumab 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Palliative Radiotherapye 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 

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Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treat
ment 
Post-Treatment 
Treatment Cycle: 
Main Study 
Screening  
 C1/D1 
C1/D8  C1/D15 C2D1 
 
C3D1 
C4D1 
C5D1 
C6+D1a 
Last 
Dose 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upc 
Scheduling Window (Days): 
-21 to -1 
 
± 1 
± 1 
± 3 
± 3 
± 3 
± 3 
± 3 
At time 
of 
Discon 
30 days 
post 
discon 
Every 6 
weeks 
post 
discon 
Every 
12 
weeks  
Pregnancy Test – Urine or Serum E-HCGf 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
PT/INR and aPTTd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differentiald 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry Paneld 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysisd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSHd,g 
X 
 
 
 
X 
 
X 
 
Xg 
 
X 
 
 
Serum carcinoembryonic antigen (CEA)h 
X 
 
 
 
 
X 
 
X 
Xh 
 
 
 
 
12-Lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imagingi 
X 
 
 
 
 
X 
 
X 
Xi 
 
 
X 
 
Tumor Biopsies/Correlative Studies Blood 
Tumor Biopsiesj 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Correlative Studies Blood/Stool/Oral 
Swab Collectionk 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 

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Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treat
ment 
Post-Treatment 
Treatment Cycle: 
Main Study 
Screening  
 C1/D1 
C1/D8  C1/D15 C2D1 
 
C3D1 
C4D1 
C5D1 
C6+D1a 
Last 
Dose 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upc 
Scheduling Window (Days): 
-21 to -1 
 
± 1 
± 1 
± 3 
± 3 
± 3 
± 3 
± 3 
At time 
of 
Discon 
30 days 
post 
discon 
Every 6 
weeks 
post 
discon 
Every 
12 
weeks  
a. 
Patients will continue pembrolizumab for a maximum of 35 cycles for first course of therapy if no evidence of disease progression or intolerable toxicity. 
b. 
In patients who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring disease status by radiologic imaging 
every 6 weeks (± 7 days) until 1) the start of new anti-cancer treatment, 2) disease progression on imaging, 3) death, or 4) the end of the study, whichever occurs first. 
c. 
After the start of new anti-cancer treatment or documented disease progression by imaging, the patient should be contacted by telephone every 12 weeks to assess for survival 
status. 
d. 
Laboratory tests and ECOG PS are to be performed within 10 days prior to the first dose of trial treatment. 
e. 
Palliative radiotherapy to a total dose of 30 Gy to the primary tumor will be delivered in 3 Gy fractions daily with the exception of weekends and holidays.  The first fraction 
of radiation should be given on C1D1 prior to administration of pembrolizumab.  Radiation may continue into cycle 2 if delayed for management of toxicity or administrative 
reasons. 
f. 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first dose of trial treatment.  A serum test may be considered if 
urine test is not appropriate or inconclusive. 
g. 
Thyroid function tests should be collected at screening and every 6 weeks in concordance with day 1 of even-numbered cycles. 
h. 
Serum CEA should be collected at screening and every 6 weeks in concordance with day 1 of odd-numbered cycles. 
i. 
Tumor imaging should be performed every 6 weeks through the first 6 cycles, then subsequently performed every 9 weeks thereafter. For patients who complete 35 cycles of 
therapy or 2 years of follow up without evidence of progression, scans can be spaced out to every 12-24 weeks at the discretion of the treating physician. The exception will 
be patients who demonstrate PD, PR, or CR by RECIST 1.1, in which event the next imaging will be performed at 6 weeks for confirmation.  Refer to Section 7.1.2.6.2 for 
details. 
j. 
Tumor biopsies will be performed prior to cycle 1/day 1, and at 21 days (± 3 days) after completion of palliative radiotherapy.  Biopsies will be performed of metastatic sites 
amenable to access by CT or ultrasound-guidance.  Malignant ascites accessible by ultrasound guidance will also be eligible as tumor biopsy specimens.  For patients receiving 
RT to a metastatic site and only the primary tumor is accessible to biopsy, these will be obtained by endoscopy. 
k. 
Blood/stool/oral swab collection for correlative studies will be collected at screening assessment, at 21 days (± 3 days) after completion of palliative radiotherapy, at timepoint 
of first progression by RECIST (if applicable and continued on protocol therapy), and at end of treatment.   
 
 
 

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6.2 
Second Course Phase 
Trial Period: 
Treatment Cycles 
End of 
Treat
ment 
Post-Treatment 
Treatment Cycle: 
 C1/D1 
C2/D1  
C3/D1 
C4D1 
 
C5D1 
C6+D1a 
Last 
Dose 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upc 
Scheduling Window (Days): 
 
± 3 
± 3 
± 3 
± 3 
± 3 
At time 
of 
Discon 
30 days 
post 
discon 
Every 6 
weeks 
post 
discon 
Every 
12 
weeks  
Administrative Procedures 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
 
 
 
 
 
X 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
 
X 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pembrolizumab 
X 
X 
X 
X 
X 
X 
 
 
 
 
Laboratory Procedures/Assessments 
Pregnancy Test – Urine or Serum E-HCG 
X 
 
 
 
 
 
 
X 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Trial Period: 
Treatment Cycles 
End of 
Treat
ment 
Post-Treatment 
Treatment Cycle: 
 C1/D1 
C2/D1  
C3/D1 
C4D1 
 
C5D1 
C6+D1a 
Last 
Dose 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upc 
Scheduling Window (Days): 
 
± 3 
± 3 
± 3 
± 3 
± 3 
At time 
of 
Discon 
30 days 
post 
discon 
Every 6 
weeks 
post 
discon 
Every 
12 
weeks  
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSHd 
X 
 
X 
 
X 
Xd 
 
X 
 
 
Serum carcinoembryonic antigen (CEA)e 
X 
 
X 
 
X 
Xe 
 
 
 
 
Efficacy Measurements 
Tumor Imagingf 
 
 
X 
 
X 
Xf 
 
 
 
 
a. 
Patients will continue pembrolizumab for a maximum of 17 cycles for second course of therapy if no evidence of disease progression or intolerable toxicity. 
b. 
In patients who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring disease status by 
radiologic imaging every 6 weeks (± 7 days) until 1) the start of new anti-cancer treatment, 2) disease progression on imaging, 3) death, or 4) the end of the 
study, whichever occurs first. 
c. 
After the start of new anti-cancer treatment or documented disease progression by imaging, the patient should be contacted by telephone every 12 weeks to 
assess for survival status. 
d. 
Thyroid function tests should be collected at C1/D1 and every 6 weeks in concordance with day 1 of odd-numbered cycles. 
e. 
Serum CEA should be collected at C1D1 and every 6 weeks in concordance with day 1 of odd-numbered cycles. 
f. 
Tumor imaging should be performed every 6 weeks through the first 6 cycles, then subsequently performed every 9 weeks thereafter.  For patients who 
complete 35 cycles of second course therapy or 2 years of follow up without evidence of progression, scans can be spaced out to every 12-24 weeks at the 
discretion of the treating physician. The exception will be patients who demonstrate PD, PR, or CR by RECIST 1.1, in which event the next imaging will be 
performed at 6 weeks for confirmation.  Refer to Section 7.1.2.6.2 for details. 

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

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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 8.0. 
7.1.1.5 Disease Details and Treatments 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 

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first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
7.1.1.6 Assignment of Screening Number 
All consented subjects will be given a unique City of Hope screening number that will be used 
to identify the subject for all procedures that occur prior to treatment allocation. Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects. 
 
Any subject who is screened multiple times will retain the original screening number assigned 
at the initial screening visit. 
 
7.1.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment for greater than 12 weeks between 
treatments require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on subject management. 
 
Administration of trial medication will be witnessed by the investigator and/or trial staff.  The 
total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered.  The instructions for 
preparing and administering pembrolizumab are provided in the Pharmacy Manual. 
 
Treatment with standard of care palliative radiotherapy will be prepared and administered as 
per the approved Department of Radiation Oncology and institutional guidelines. 
 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Study Calendar and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0.  Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs); see the separate ECI guidance document in the Appendix regarding the 
identification, evaluation and management of potential irAEs.   

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Please refer to Section 8.0 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Study Calendar, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Study Calendar (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Study Calendar.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor imaging may be performed by computed tomography (CT; preferred) or magnetic 
resonance imaging (MRI), but the same imaging technique should be used in a subject 
throughout the trial.  CT scan is the more commonly used modality and is preferred for the 
majority of patients.  An MRI can be utilized if clinically appropriate. 
7.1.2.6.1 Initial Tumor Imaging 
To meet screening criteria, initial tumor imaging must be performed within 21 days prior to 
start of cycle 1, day 1.  This scan will be considered the baseline assessment for the study. The 
site study team must review pre-trial images to confirm the subject has at least one target lesion 
(i.e. meets measurability requirements) per RECIST 1.1. 
 
Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality, include all required anatomy, and performed within 21 
days prior to start of treatment. 

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7.1.2.6.2 Tumor Imaging on Study per Immune-related RECIST (irRECIST) 
The first on-study imaging assessment should be performed at 6 weeks (42 days ± 7 days) 
after the first dose of trial treatment.  Subsequent imaging should be performed every 6 weeks 
(42 days ± 7 days) through the first 6 cycles.  After 6 cycles, imaging will be pursued every 9 
weeks (63 days ± 7 days) until demonstration of PD, PR, or CR, in which event imaging will 
be performed in 6 weeks for confirmation.   
 
RECIST 1.1 may not provide an accurate assessment of immunotherapeutic agents such as 
pembrolizumab.  Immune-related RECIST (irRECIST) is RECIST 1.1 adapted as described 
below to account for the unique tumor response seen with immunotherapeutics.   
 
Patients with 1st radiologic assessment of PD by RECIST 1.1 may continue treatment if 
clinically stable as per Table 4.  If the repeat scan confirms PD, patients will be discontinued 
from treatment.  Exception can be made if the Investigator feels the patient is deriving benefit 
from treatment and after discussion with the study PI and Sponsor.  Subsequent imaging should 
be pursued every 6 weeks until demonstration of confirmed PR or CR in which event imaging 
will then be conducted every 9 weeks if a patients has completed at least 6 cycles of 
pembrolizumab.  Imaging may be more frequent if clinically indicated. 
 
Clinically stable is defined by the following criteria: 
x Absence of signs and symptoms indicating disease progression 
x No decline in ECOG performance status 
x Absence of rapid progression of disease 
x Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
Table 4  Imaging and Treatment after 1st radiologic evidence of progressive disease (PD)  
 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
per RECIST 1.1 
Repeat imaging 
at 6 weeks to 
confirm PD 
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory 
scan 
Repeat imaging 
at ≥ 4 weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
(exception is 
possible after 
discussion with 
No additional 
imaging required 
N/A 

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the PI and 
Sponsor) 
Repeat scan 
shows SD, PR, or 
CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 6-9 weeks 
dependent on 
cycle of therapy 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 6-9 weeks 
dependent on 
cycle of therapy 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion 
 
 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood/Stool/Oral Swab 
Sampling 
7.1.2.7.1  Analysis of pre- and post-treatment tumor biopsies 
Tumor biopsies will be performed during the Screening Phase and 21 days after completion 
of palliative radiotherapy.  CT or ultrasound-guided biopsies will utilize 20-gauge core biopsy 
needles.  As such tissue samples will be composed of both tumor cells and associated tumor 
stroma.  Fresh tumor samples will be immediately delivered to the laboratory of Dr. Peter Lee 
for both ex vivo tumor/immune/stromal cell culture and expansion as well as histologic 
analyses.  Patients with fresh malignant ascites collected by ultrasound guidance will also be 
immediately delivered to the lab for ex vivo tumor/immune/stromal cell culture and expansion 
alone.  
Dr. Lee’s lab will utilize quantitative spatial image analysis to examine changes in tumor cell-
stromal interactions including CD4, CD8, Treg, and MDSC populations pre- and post-
therapy.  
PD-L1 expression within the tumor, on cancer cells and stromal cells, will be analyzed by 
immunohistochemistry (IHC) locally in Dr. Lee’s lab, as well as centrally through QualTek 
Laboratories.  PD-1 expression on tumor infiltrating T cells will be analyzed by a combination 
of IHC and flow cytometry.  Immune cell populations will be further analyzed via high 
dimensional flow cytometry to measure levels of Tregs and MDSCs.  Dr. Lee’s lab will also 
pursue multi-color IHC to determine influences of pembrolizumab+RT treatment on the 
magnitude and proximity of CD8 T cells to cancer cells within the tumor.  Changes in the 
diversity of the T cell repertoire in both PD-1 positive and PD-1 negative T cell populations 
following pembrolizumab+RT treatment will be analyzed via deep sequencing of the TCR 
Vβ CDR3 region.  Such changes in T cell repertoire can be suggestive of potential epitope 
spreading for anti-tumor antigens and reversal of tumor antigen-specific T cell anergy. 
Genomic analyses utilizing City of Hope’s Integrative Genomics Core will also be performed 
on the corresponding cancer/stromal/immune cell populations via total RNA-seq for coding 
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Performance of these studies will require several highly developed techniques that have been 
routinely conducted in Dr. Peter Lee’s lab. A prototype BD microfluidic FACS instrument 
allows for 12-color analysis of low cell numbers, thereby allowing maximal data acquisition 
out of small sample sizes.  A powerful quantitative, spatial image analysis system will enable 
analysis of immune and cancer cells in tissues via 8-color histology. Lastly, Dr. Lee’s lab has 
considerable expertise in TCR repertoire analysis via deep sequencing, which can yield 
information on T cell specificity to unknown antigens. 
7.1.2.7.2 Correlative Studies Blood Sampling 
Circulating T cell, Tregs, and MDSC Isolation and Characterization 
Blood Sample Collection 
Blood samples will be collected from an indwelling venous catheter or by venipuncture into 
three 7 mL green-top tubes (sodium or lithium heparin) at three timepoints: (1) Screening visit, 
(2) 21 days after completion of palliative radiotherapy, and (3) at the time of first progression 
by traditional RECIST1.1 (to capture potential pseudoprogression and only applicable for 
patients continued on treatment beyond progression), and at end of treatment.  To prevent 
blood clotting, tubes will be inverted several times and then immediately placed on ice for 
transportation to the CICSL (Clinical Immunobiology Correlative Studies) processing 
laboratory. The whole blood should be processed within 4 hours of collection. While awaiting 
processing, the blood should be kept on a rocker set at low speed to mimic circulation and 
avoid clot formation.   
Sample Processing in CICSL 
Plasma 
x For plasma preparation, anti-coagulated whole blood (two 7 mL green-top tubes) will 
be processed by centrifugation for 10 minutes at 1000 x g at 4OC. The resulting upper 
plasma layer from each tube will be drawn up sequentially into a sterile 5 mL syringe 
and pushed through a sterile 0.2/0.8 micron disposable filter (PALL Acrodisc PF, Cat. 
4658). The filtered plasma will then be transferred in 500 μL aliquots into multiple 
appropriately-labeled Starstedt microfuge tubes (Starstedt Cat 72.692.005). To one 
aliquot, add 0.5 mL glycerol/0.02% sodium azide solution to dilute the plasma 50/50 
v/v. Keep the diluted plasma sample at -20˚C and do not freeze. All the remaining 
plasma aliquots will be stored frozen at -80˚C until ready for testing. 
 
 
PBMCs 
x Any blood remaining in the two 7 mL green-top tubes used to prepare plasma above 
will be diluted 1:1 with Hank’s Balanced Salt Solution (“HBSS”, Irvine Scientific, Cat. 
9228 or equivalent)  and combined with the whole blood from the unused green-top 
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(PBMC) will then be isolated from the combined whole blood sample by Ficoll-
gradient separation as described below; 
o Allow Accuspin-Histopaque tubes (“Accuspin”, Sigma Cat. A6929 or A0561, 
for 12 or 100 tubes, respectively) and HBSS to warm to room temperature. 
Place a Mr. Frosty container in the refrigerator and prepare the freezing media 
by adding 10% DMSO to fetal calf serum and chill at 4˚C or on ice.  
o Prepare Accuspin tubes by centrifuging at 1000 x g for 1 minute at room 
temperature (RT) with brakes on. Each tube can process up to 20 mLs of whole 
blood; prepare the appropriate amount of tubes necessary. After centrifugation, 
the Histopaque reagent should be below the barrier of the tube. Add 5 mLs of 
HBSS to the Accuspin tube. Add up to 20 mls of whole blood to each Accuspin 
tube until all the blood has been distributed.  
o Centrifuge the blood sample at 800 x g for 15 minutes at RT with brakes on 
LOW. After centrifugation, three layers should be visible above the barrier of 
the tube: the plasma layer at the top, a cloudy layer in the middle where the 
PBMC are, and a clear Histopaque reagent layer right below. Using a pipette, 
remove the upper plasma layer to within 2 cm of the cloudy interphase. 
Carefully pipette the cloudy PBMC interphase and transfer to a sterile 50 mL 
centrifuge tube.  
o Add HBSS up to the 45 mL mark in the centrifuge tube with the PBMC and 
spin at 400 x g for 10 minutes at RT with brakes on. Decant the supernatant and 
loosen the cell pellet before adding HBSS to the 45-mL mark again for a second 
wash. Centrifuge at 300 x g for 10 minutes at RT with brakes on. Decant the 
supernatant, loosen the cell pellet and then add a known volume of HBSS to 
resuspend the cells for counting. Mix the cell suspension up and down with a 
pipette several times before removing a small aliquot for cell count. 
Centrifuge the cell suspension one final time at 300 x g for 10 minutes at RT with brakes on. 
PBMC should be frozen down at 0.5 – 1 x 107 cells/vial. Determine the volume of freezing 
media (fetal calf serum with 10% DMSO) needed to give a 1 x 107 cell/mL suspension. After 
the last centrifugation is complete, discard supernatant and loosen the cell pellet before adding 
freezing media slowly, a small volume at a time with mixing in between (vortex at low speed). 
Aliquot 0.5 - 1 mL of the final cell suspension into individually labeled cryovials. Transfer the 
cryovials into Mr. Frosty and store at -80˚C. Twenty four hours later, cryovials will be 
transferred to liquid nitrogen tanks for long-term storage.   
Circulating T cell Characterization 
PD-1 expression on circulating PBMC T cells will be analyzed by flow cytometry. Immune 
cell populations will be further analyzed via high dimensional flow cytometry to measure 
levels of Tregs and MDSCs, which will allow for calculating the ratio of effector T cells to 
Tregs and MDSCs, respectively. Ex vivo isolated T cells will also be analyzed for proliferative 

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capacity (CFSE dilution) and cytokine production (IFN-γ and IL-17) after stimulation with 
anti-CD3 and/or PMA and Ionomycin.   
Serum Circulating miRNA Profiling 
20 mL of whole blood will be collected from each patient into 2 Vacutainer red top tubes (no 
additive) at three timepoints: (1) Screening visit, (2) 21 days after completion of palliative 
radiotherapy, and (3) at the time of first progression by traditional RECIST1.1 (to capture 
potential pseudoprogression and only applicable for patients continued on treatment beyond 
progression), and at end of treatment.  Blood will be allowed to clot on ice for 15-20 min, and 
then centrifuged at 1900g (3000 rpm) for 10 minutes at 4oC using a swinging bucket rotor.  
The upper (yellow) serum phase will then be transferred to four separate labeled cryovials 
without disturbing the intermediate buffy coat layer.  The cryovials will be placed on ice, and 
then delivered immediately for storage in the Fox North Building, Room N2002, freezer 
EFRU385.  Serum samples will be stored frozen at -80 oC until time of analysis. 
Total RNA will be extracted using Trizol within the Integrative Genomics Core at City of Hope 
for miRNA-seq.  Sequence reads that match human miRNAs in Sanger mirBase will be 
calculated and analyzed.  Circulating whole genome miRNA signatures will be compared to 
miRNAs sequenced from total RNA-seq from the corresponding tumor biopsy timepoints to 
aid in biomarker discovery of serum miRNAs that may predict for immunotherapy response 
or resistance.  miR-23a will be of particular interest given its description as a gastric cancer 
oncomir and function as a repressor of T cell cytotoxicity in preclinical miRNA screens.14,15  
miR-34a and miR-200 will be other miRNAs of interest to measure given reporting of their 
ability to suppress PD-L1 expression in other experimental systems.16,17 
Germline miRNA biomarker analysis 
Weidhass et al recently discovered that a new class of miRNA regulatory network disrupting 
germline mutations can act as biomarkers of response and toxicity to anti-PD-1 and anti-PD-
L1 therapy.18  Specifically a panel of germline mutations in 3’ untranslated regions (3’-UTR) 
and miRNA promoter regions provided 89% specificity for response and 76% specificity for 
toxicity in a population of 85 patients with melanoma and non-small cell lung cancer treated 
with anti-PD-1 or anti-PD-L1 agents.   
Leftover banked PBMC samples from any timepoint will be shipped batched via overnight 
courier on dry ice to: 
 
MiraDx 
Contact: Joanne Weidhaas, M.D., Ph.D  
11600 Wilshire Blvd. 
Los Angeles, CA 90025 
 

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DNA extraction from PBMCs will be performed at MiraDx and targeted sequencing will be 
performed for the panel of miRNA germline mutation biomarkers.  Results will be correlated 
with RECIST1.1 and irRECIST responses as well as toxicities recorded per NCI CTCAE. 
  
7.1.2.7.3 Correlative Studies Stool and Oral Swab Sampling 
Stool Sampling 
Patients will be provided a biospecimen bag and 
sterile swab (BD BBLTM CultureSwabTM 
Sterile, Media-free Swabs) and instructed on 
proper collection from a used toilet tissue paper 
the required stool sample.  Patients will be contacted and reminded by the clinical research 
coordinator 48-24 hours in advance of the specified protocol visit to perform the stool 
collection and will be advised to leave the specimen at room temperature until the day of their 
visit.  Patients will also have the option of swabbing and submitting the stool specimen during 
their protocol visit provided they are reporting daily regular bowel movements.  Samples 
submitted to the clinical research coordinator will be stored promptly and banked at -20 OC 
until analysis.  Samples will be labeled as “stool” and with the patient’s deidentified protocol 
ID number and date of collection. 
Oral Sampling 
At the prespecified timepoints, patients will be asked during their protocol visit in clinic to 
perform an oral swab of both inner cheeks and tongue using a provided sterile swab (BD 
BBLTM CultureSwabTM Sterile, Media-free Swabs).  These samples will also be collected by 
the clinical research coordinator and will be stored promptly and banked at -20 OC until 
analysis.  Samples will be labeled as “oral swab” and with the patient’s deidentified protocol 
ID number and date of collection. 
Microbiomic Profiling 
Banked stool and oral swab specimens at the time of planned analysis will be shipped via 
courier overnight on dry ice to the lab of Dr. Greg Caporaso of Northern Arizona 
University/TGen: 
J. Gregory Caporaso, Ph.D. 
Northern Arizona University 
1350 S Knoles Drive 
Flagstaff, AZ 86011, USA 
 
Microbial DNA will be extracted from swab samples using the PowerSoil® DNA Isolation Kit 
(Mobio Carlsbard, CA). A 16S rRNA library for the MiSeq Illumina platform will be prepared 
according 
to 
the 
protocol 
from 
the 
Earth 
Microbiome 
Project 
(http://www.earthmicrobiome.org/emp-standard-protocols/). Microbiome sequencing data to 
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Microbial Ecology (QIIME) 1.9.1, biom-format version 2.1.5, VSEARCH version 1.7.0 
(https://github.com/torognes/vsearch), SSU-ALIGN 0.1, and FastTree, as well as custom 
analytic software (source code at https://github.com/caporaso-lab/autism-fmt1) being prepared 
for release in QIIME 2. 
 
7.1.3 Laboratory Procedures/Assessments 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   
Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and 
differential) 
Aspartate 
aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase 
(LDH) 
Microscopic exam (If 
abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil 
Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte 
Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone 
(TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated above 
the upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required.   
‡ If considered standard of care in your region. 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 8.0 – Data and Safety 
Monitoring Plan.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.5.5.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4). 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 – Study Calendar.  Specific procedure-related 
details are provided in Section 7.1 – Trial Procedures. 
 
7.1.5.1 Screening 
Within 21 days prior to start of treatment, potential subjects will be evaluated to determine that 
they fulfill the entry requirements as set forth in Section 5.1.  Screening procedures may be 
repeated after consultation with the Sponsor. 
 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.  Screening procedures are to be completed within 21 days prior to the first dose trial 
treatment except for the following: 
 
Laboratory tests and ECOG PS are to be performed within 10 days prior to the first dose of 
trial treatment. 
 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours 
prior to the first dose of trial treatment.  A serum test may be considered if urine test is not 
appropriate or inconclusive. 
 

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Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.  Subjects who are rescreened will retain their original 
screening number. 
7.1.5.2 Treatment Period 
Visit requirements are outlined in Section 6.0 – Study Calendar.  Specific procedure-related 
details are provided in Section 7.1 – Trial Procedures. 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1 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 beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 7.1.5.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 9 
weeks (± 7 days). 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 begins retreatment with pembrolizumab as detailed in Section 7.1.5.5.  Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Second Course Phase.    
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival 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.  

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7.1.5.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  A repeat 
course of palliative radiotherapy to the primary tumor will not be given during this time.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
x Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
x Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
x Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
x Has a performance status of 0 or 1 on the ECOG Performance Scale 
x Demonstrates adequate organ function as detailed in Section 5.1.1 
x Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
x Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.5.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  

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x Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
x 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 in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Patients will not receive another course of palliative 
radiotherapy to their primary tumor.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.2 – Second Course Phase. 
8.0 DATA AND SAFETY MONITORING PLAN 
8.1 
Definition of Risk Level 
This is a Risk Level 4 study as defined in the City of Hope Institutional Data and Safety 
Monitoring Plan [policy dated 07/09/2014].  This determination was made because the study 
is an investigator-initiated phase II trial and involves a COH IND. 
8.2 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) is responsible for monitoring the data and safety of 
this study.  The PMT consists of the Principal Investigator (PI), Biostatistician, Research 
Protocol Nurse, and Clinical Research Coordinator. 
 
The PMT is required to submit periodic status reports (i.e., the PMT Report) according to the 
frequency prescribed in the City of Hope Institutional Data and Safety Monitoring Plan 
[policy dated 07/09/2014].  Important decisions made during PMT meetings (i.e., dose 
escalation, de-escalation, etc.) only need to be noted in the PMT Report submitted to the Data 
and Safety Monitoring Committee (DSMC). 
 
8.3 
Adverse Events and Serious Adverse Events 
The PI will be responsible for determining the event name, assessing the severity (i.e., grade), 
expectedness, and attribution of all adverse events. 
Adverse Event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  

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Reporting Non-serious Adverse Events – Adverse events will be collected after the patient 
is given the study treatment or any study related procedures.  Adverse events will be monitored 
by the PMT.  Adverse events that do not meet the criteria of serious OR are not unanticipated 
problems will be reported only in the PMT Report. 
Serious Adverse Event (SAE) [Modified from the definition of unexpected adverse drug 
experience in 21 CFR 312.32] - defined as any expected or unexpected adverse events that 
result in any of the following outcomes: 
x Death 
x Is life-threatening experience (places the subject at immediate risk of death from the 
event as it occurred) 
x Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
x A persistent or significant disability/incapacity 
x A congenital anomaly/birth defect 
x Secondary malignancy 
x Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, blood 
dyscrasias of convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse). 
 
Reporting Serious Adverse Events - begins after study treatment or any study related 
procedures.  All SAEs occurring during this study, whether observed by the physician, nurse, 
or reported by the patient, will be reported according to the approved City of Hope’s 
Institutional policy [policy effective date:  05/14/14].  Serious Adverse Events that require 
expedited reporting will be submitted electronically using iRIS. 
Adverse Event Name and Severity 
The PI will determine the adverse event name and severity (grade) by using the CTCAE 
version 4.0. 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event, 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event. 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if it is not 
listed in the investigator’s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in the 
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disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the event to 
the study agent or study procedure. 
Definite - The AE is clearly related to the investigational agent or study procedure and 
unrelated to any other cause. 
Probable - The AE is likely related to the investigational agent or study procedure and 
unlikely related to other cause(s). 
Possible -The AE may be related to the investigational agent or study procedure and may 
be related to another cause(s). 
Unlikely -The AE is doubtfully related to the investigational agent or study procedure and 
likely related to another cause(s). 
Unrelated -The AE is clearly not related to the investigational agent or study procedure 
and is attributable to another cause(s). 
COH Held IND 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report 
using the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the Medwatch 3500A are: 
x Any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of 
the information [21 CFR 312.32(c)(2)] 
x Any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of 
the information [21 CFR 312.32(c)(1)] 
x Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
 
The PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  
OIDRA will assist the PI with the preparation of the report and submit the report to the FDA 

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in accordance with the approved City of Hope’s Institutional policy [policy effective date:  
05/14/14]. 
 
8.4 
Deviations and Unanticipated Problems 
Deviation - A deviation is a divergence from a specific element of a protocol that occurred 
without prior IRB approval.  Investigators may deviate from the protocol to eliminate 
immediate hazard(s) for the protection, safety, and well-being of the study subjects without 
prior IRB approval.  For any such deviation, the PI will notify the COH DSMC and IRB 
within 5 calendar days of its occurrence via iRIS in accordance with the Clinical Research 
Protocol Deviation policy [policy effective date:  11/07/11].   
 
Single Subject Exception (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific 
procedures called for in a protocol are not in the best interests of a specific patient.  It is a 
deviation that is anticipated and receives prior approval by the PI and the IRB.  The SSE must 
be submitted as a “Single Subject Exception Amendment Request” via iRIS in accordance with 
IRB guidelines and the Clinical Research Protocol Deviation policy [policy effective date:  
11/07/11].  An IRB approved SSE does not need to be submitted as a deviation to the DSMC. 
Unanticipated Problem (UP) – Any incident, experience, or outcome that meets all three of 
the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure (IB); 
and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcomes may have been 
caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or 
recognized. 
 
Any UP that occurs during study conduct will be reported to the DSMC and IRB in accordance 
with the City of Hope’s Institutional policy [policy effective date:  05/14/14] using iRIS.   
 

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8.5 
Definition of an Overdose for This Protocol and Reporting of Overdose to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 2 working 
days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
8.6 
Reporting of Pregnancy and Lactation to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
8.7 
Reporting of Adverse Events to Merck 
8.7.1.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 

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x Results in death; 
x Is life threatening; 
x Results in persistent or significant disability/incapacity; 
x Results in or prolongs an existing inpatient hospitalization; 
x Is a congenital anomaly/birth defect; 
x Is a new cancer (that is not a condition of the study); 
x Is associated with an overdose; 
x Is another important medical event  
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to 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 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
9.0 STATISTICAL ANALYSIS PLAN 
9.1 
Primary Objective 
The primary objective of this study is to establish that the combination of pembrolizumab and 
a palliative course of traditional external beam multifractionated RT in patients with metastatic 
gastric, esophageal, and/or GEJ cancers will lead to an increase in tumor infiltrating cytotoxic 
T-cells and circulating cytotoxic T cells and a reduction in immunosuppressive Tregs and 
MDSCs in non-irradiated sites. 

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Each patient will serve as their own control, and tumor cytotoxic T cell infiltration and 
immunosuppressive Tregs will be compared pre- and post-treatment. As variability of the 
difference in the T cell populations pre- and post-treatment is unknown and still being 
established, the power calculation is based on the concept of “effect size” in this biomarker 
analysis study.  Specifically, a sample-size of 14 patients will have 80% power to detect an 
effect size of 0.71 using a paired t-test with a 0.05 one-sided significance level.  The effect size 
is the mean difference divided by the standard deviation of the difference. 
A positive biological signal combined with acceptable secondary endpoints (response and 
toxicity) are sought for a clear indication of promise of this combination.  
9.2 
Secondary Objectives 
Secondary objectives such as ORR per RECIST 1.1 and irRECIST, PFS, and OS are 
exploratory, though will also be documented, along with toxicity.  All patients who receive at 
least one dose of pembrolizumab will be included in the safety analysis.  Stool/oral 
microbiomic profiling and germline miRNA biomarker panel analyses will also be correlated 
with secondary outcome measures of ORR and toxicities. 
While overlapping toxicities are not anticipated with the combination of pembrolizumab and 
RT, the initial treatment of patients within this trial warrants a careful review of toxicity: 
x Toxicity-based Interim Analysis: A study hold will be placed for re-evaluation at the 
proposed starting dose as accrual proceeds on this phase II study according to the 
following rule: The study will hold pending an amendment if 3 patients discontinue 
therapy after cycle 1 due to treatment-related toxicity.  This rule has a 97% chance of 
holding the study if the true discontinuation rate due to toxicity on cycle 1 is 50%. It 
has a 15% chance of holding if the true discontinuation rate on cycle 1 is 15%.  
x Treatment-related mortality stopping rule: Any treatment-related death will hold the 
study accrual pending review by the PI, Sponsor, and DSMB/IRB. 
 
 
With 14 patients, there is 96% power to detect at least one responder if the true response rate 
is 21% or higher, which is in the range of 22% in the phase I trial of pembrolizumab among 
gastric cancer patients with PD-L1 overexpression.  As a result, failure to observe any response 
in the 14 patients would result in lack of enthusiasm for the combination of pembrolizumab 
and RT in this patient population.  PFS and OS will be determined using the Kaplan-Meier 
method. 

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10.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
10.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
10.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
10.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
10.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
10.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to subjects, and the amount remaining at the 
conclusion of the trial.  

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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
11.0 DATA REPORTING 
11.1 Data Reporting 
11.1.1 Confidentiality and Storage of Records 
The original data collection forms will be sent to the CTO and stored in a locked area.  This 
protocol uses Electronic Data Collection per institutional policy for investigator-initiated trials, 
and the data will be stored in encrypted, password protected, secure computers that meet all 
HIPAA requirements.  When results of this study are reported in medical journals or at 
meetings, identification of those taking part will not be disclosed.  Medical records of subjects 
will be securely maintained in the strictest confidence, according to current legal requirements.  
They will be made available for review, as required by the FDA, HHS, or other authorized 
users such as the NCI, under the guidelines established by the Federal Privacy Act and rules 
for the protection of human subjects. 
11.1.2 Subject Consent Form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA 
research authorization form, and the California Experimental Subject’s Bill of Rights (for the 
medical record) and three copies (for the subject, the research record, and the Coordinating 
Center) must be available.  All Institutional, NCI, Federal, and State of California requirements 
will be fulfilled. 
11.1.3 Data Collection Forms and Submission Schedule  
All data will be collected 2 weeks prior using MediData Rave.  Data will be sent to the location 
identified in Section 11.1.1 and stored in a secure location. 
11.1.3.1 Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research associate 
and signed by an authorized investigator prior to registering the subject. 
11.1.3.2 Prior Therapy Forms and On-Study Forms 
Within 2 weeks of registration, the clinical research associate will submit data in regards to 
prior therapies the patient has received, if applicable. 

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12.0 HUMAN SUBJECT ISSUES 
12.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies 
with the federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health 
and Safety code, Title 17,  must review and approve this protocol and the informed consent 
form prior to initiation of the study.  All institutional, NCI, Federal, and State of California 
regulations must be fulfilled. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB.  The IRB’s written unconditional approval of the study protocol and the 
informed consent document will be in the possession of the investigator before the study is 
initiated. 
The IRB will be informed of revisions to other documents originally submitted for review; 
serious unexpected or unanticipated adverse experiences occurring during the study, and any 
additional adverse experiences in accordance with the standard operating procedures and 
policies of the IRB; new information that may affect adversely the safety of the patients of the 
conduct of the study; an annual update and/or request for re-approval; and when the study has 
been completed. 
Any amendment to the protocol document and accompanying informed consent 
document/template, as developed and provided by the PI, will require review and approval by 
the COH IRB before the changes are implemented in the study. 
12.2 Recruitment of Subjects 
The Gastrointestinal Medical Oncology Division will identify patients undergoing treatment 
for metastatic gastroesophageal cancer at City of Hope.   
12.3 Study location and Performance Sites 
This study will be performed at COH. 
12.4 Confidentiality  
Participant confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to any study information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to 
protected health information (PHI), including the requirements of the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed 
participant authorization informing the participant of the nature of the PHI to be collected, who 
will have access to that information and why, who will use or disclose that information, ant the 

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rights of a research participant to revoke their authorization for use of their PHI. In the event 
that a participant revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of participant 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the participant is 
alive) at the end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508. When results of this 
study are reported in medical journals or at meetings, identification of those taking part will 
not be disclosed and no identifiers will be used. 
Medical records of participants will be securely maintained in the strictest confidence, 
according to current legal requirements.  Data will be entered, analyzed and stored in 
encrypted, password protected, secure computers that meet all HIPAA requirements.   All data 
capture records, drug accountability records, study reports and communications will identify 
the patient by initials and the assigned patient number. Source documents provided to 
coordinating center for the purpose of auditing or monitoring will be de-identified and labeled 
with the study number, participant ID, and participant initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist 
of trial-related monitoring/ auditing, IRB reviews, and FDA/regulatory authority inspections. 
The participant’s confidentiality will be maintained and will not be made publicly available to 
the extent permitted by the applicable laws and regulations.   
12.5 Financial Obligations and Compensation 
The investigational drug, pembrolizumab, will be provided free of charge by City of Hope and 
Merck.  Should this drug or device become commercially available during the course of 
treatment, the research participant and/or the insurance carrier may be asked to pay for the costs 
of the drug. 
The standard of care drug(s) and procedures provided will be the responsibility of the research 
participant and/or the insurance carrier.  The research participant will be responsible for all 
copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by 
the insurance carrier.  The research participant and/or the insurance carrier will be billed for 
the costs of treatment and diagnostic procedures in the same way as if the research participant 
were not in a research study.  However, neither the research participant nor the insurance carrier 
will be responsible for the research procedures related to this study. 
In the event of physical injury to a research participant, resulting from research procedures, 
appropriate medical treatment will be available at the City of Hope to the injured research 
participant, however, financial compensation will not be available. 
The research participant will not be paid for taking part in this study. 

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12.6 Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, 
purpose of the study, potential risks, alternatives and potential benefits, and all other 
information contained in the informed consent document.  In addition, they will review the 
experimental subject’s bill of rights and the HIPAA research authorization form.  Prospective 
participants will be informed that they may withdraw from the study at any time and for any 
reason without prejudice, including as applicable, their current or future care or employment 
at City of Hope or any relationship they have with City of Hope.  Prospective participants will 
be afforded sufficient time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either 
the prospective participant or his/her guardian or legal representative before study 
participation. The method of obtaining and documenting the informed consent and the contents 
of the consent must comply with the ICH-GCP and all applicable regulatory requirements. 
Before implementing any study procedure, informed consent shall be documented by the use 
of a written consent form approved by the IRB and signed and dated by the prospective 
participant or his/her legally authorized representative at the time of consent.  A copy of the 
signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the investigator and 
available for inspection sponsor designated representatives, or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in 
the study and continues throughout study participation.  
  
 
 
 
 

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REFERENCES 
1. 
Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or 
gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 
Lancet 2010;376:687-97. 
2. 
Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo 
plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal 
junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. The Lancet 
Oncology 2014;15:1224-35. 
3. 
Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced 
esophagogastric cancer. N Engl J Med 2008;358:36-46. 
4. 
Muro K, Bang Y-J, Shankaran V, et al. Relationship between PD-L1 expression and 
clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 
monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012. ASCO 
Meeting Abstracts 2015;33:3. 
5. 
Doi T, Piha-Paul SA, Jalal SI, et al. Pembrolizumab (MK-3475) for patients (pts) with 
advanced esophageal carcinoma: Preliminary results from KEYNOTE-028. ASCO Meeting 
Abstracts 2015;33:4010. 
6. 
Carbognin L, Pilotto S, Milella M, et al. Differential Activity of Nivolumab, 
Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-
Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary 
Cancers. PLoS ONE 2015;10:e0130142. 
7. 
Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated 
tumors (abscopal effect) is immune mediated. International journal of radiation oncology, 
biology, physics 2004;58:862-70. 
8. 
Park SS, Dong H, Liu X, et al. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. 
Cancer Immunol Res 2015. 
9. 
Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired Resistance to Fractionated 
Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade. Cancer Research 
2014;74:5458-68. 
10. 
Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint 
blockade activate non-redundant immune mechanisms in cancer. Nature 2015;520:373-7. 
11. 
Snyder A, Makarov V, Merghoub T, et al. Genetic Basis for Clinical Response to 
CTLA-4 Blockade in Melanoma. New England Journal of Medicine 2014;371:2189-99. 
12. 
Lin D-C, Hao J-J, Nagata Y, et al. Genomic and molecular characterization of 
esophageal squamous cell carcinoma. Nat Genet 2014;46:467-73. 
13. 
The Cancer Genome Atlas Research N. Comprehensive molecular characterization of 
gastric adenocarcinoma. Nature 2014;513:202-9. 
14. 
Ma G, Dai W, Sang A, Yang X, Gao C. Upregulation of microRNA-23a/b promotes 
tumor progression and confers poor prognosis in patients with gastric cancer. International 
journal of clinical and experimental pathology 2014;7:8833-40. 

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15. 
Lin R, Chen L, Chen G, et al. Targeting miR-23a in CD8+ cytotoxic T lymphocytes 
prevents tumor-dependent immunosuppression. The Journal of clinical investigation 
2014;124:5352-67. 
16. 
Wang X, Li J, Dong K, et al. Tumor suppressor miR-34a targets PD-L1 and functions 
as a potential immunotherapeutic target in acute myeloid leukemia. Cellular Signalling 
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17. 
Chen L, Gibbons DL, Goswami S, et al. Metastasis is regulated via microRNA-
200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. 
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Weidhaas JB, Telesca D, Kalbasi A, Salzman D, Ribas A. Germ-line biomarkers 
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anti-PD-L1 therapies. Journal of Clinical Oncology 2017;35:3040-. 
 
 

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APPENDIX 1: ECOG PERFOMANCE STATUS 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 

Page 65 of 66 
 
 
 
 
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Version Date:  10/16/2019 
Version:  04 
 
 
APPENDIX 2: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) 1.1 AND IMMUNE RECIST (IR-RECIST) 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
irRECIST** will be utilized to account for the unique tumor responses associated with 
immunotherapeutics.  
**As published in Clinical Cancer Research: 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-related 
response criteria using unidimensional measurements. Clin Cancer Res. 2013 Jul 
15;19(14):3936-43. Epub 2013 Jun 6. 

Page 66 of 66 
 
 
 
 
IRB Protocol No. 16099 
 
Version Date:  10/16/2019 
Version:  04 
 
 
APPENDIX 3: EVENTS OF CLINICAL INTEREST GUIDANCE DOCUMENT 
The most recent version (5.0, 12/18/2014) of the Events of Clinical Interest (ECI) Guidance 
Document provides study sites with further guidance on the identification and management of 
ECI for the pembrolizumab program and reporting guidelines to Merck. 
 

Page 64 of 66 
 
 
 
 
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Version Date:  10/16/2019 
Version:  04 
 
 
APPENDIX 1: ECOG PERFOMANCE STATUS 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 

Page 65 of 66 
 
 
 
 
IRB Protocol No. 16099 
 
Version Date:  10/16/2019 
Version:  04 
 
 
APPENDIX 2: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) 1.1 AND IMMUNE RECIST (IR-RECIST) 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
irRECIST** will be utilized to account for the unique tumor responses associated with 
immunotherapeutics.  
**As published in Clinical Cancer Research: 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-related 
response criteria using unidimensional measurements. Clin Cancer Res. 2013 Jul 
15;19(14):3936-43. Epub 2013 Jun 6. 

Page 66 of 66 
 
 
 
 
IRB Protocol No. 16099 
 
Version Date:  10/16/2019 
Version:  04 
 
 
APPENDIX 3: EVENTS OF CLINICAL INTEREST GUIDANCE DOCUMENT 
The most recent version (5.0, 12/18/2014) of the Events of Clinical Interest (ECI) Guidance 
Document provides study sites with further guidance on the identification and management of 
ECI for the pembrolizumab program and reporting guidelines to Merck.