Randomized, Multicenter Phase II Study of Pembrolizumab in Combination With Chemotherapy and Chemoradiation in Locally Advanced Esophageal Adenocarcinoma
Phase: PHASE2
Conditions: Esophageal Adenocarcinoma
Sponsor: Weill Medical College of Cornell University

Protocol Cover Page 
“Multicenter, Randomized Phase II study evaluating 
Pembrolizumab in combination with chemotherapy and 
chemoradiation in locally advanced esophageal” 
NCT02998268 
October 14, 2022 

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Multicenter, Randomized Phase II study evaluating Pembrolizumab in combination with 
chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma 
 
IRB Protocol #: 1602016966 
IND # (if applicable): 131424 
Version 10.0, Dated: October 14, 2022 
 
Principal Investigators: 
Manish A. Shah, MD 
Professor of Medicine 
Weill Cornell Medical College 
1305 York Avenue, 12th Floor 
New York, NY 10065 
Tel: 646-962-6200, option 3 
Fax: 646-962-1607 
Email: mas9313@med.cornell.edu 
 
Nasser Altorki, MD 
Professor and Chief, Thoracic Surgery 
Weill Cornell Medical College 
525 E 68th St, Greenberg 4th Floor 
New York, NY 10065 
Tel: 212-746-5156 
Fax: 646-962-0203 
Email: nkaltork@med.cornell.edu 
 
 
Co-Investigators: 
Allyson Ocean, MD 
ajo9001@med.cornell.edu 
Medical Oncology 
Elizabeta Popa, MD 
ecp2002@med.cornell.edu 
Medical Oncology 
Doru Paul, MD 
dop9054@med.cornell.edu 
Medical Oncology 
Jeffrey Port, MD 
jlp2002@med.cornell.edu 
Thoracic Surgery 
Nicolas Sanfilippo, MD 
nis9129@med.cornell.edu 
Radiation Oncology 
Rhonda Y. Yantiss, MD 
rhy2001@med.cornell.edu 
Pathology 
Erika Hissong, MD 
emh9016@med.cornell.edu 
Pathology 
 
 
 
 
 
 
 
Statistician: 
Paul Christos, Dr.P.H., M.S. 
402 E. 67th Street, Room 34 
New York, NY 10065 
Tel: 646-962-8018 
Fax: 646-962-0281 
Email: pac2001@med.cornell.edu 

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PARTICIPATING SITES 
 
Bryan J. Schneider, MD 
Associate Professor of Medicine 
University of Michigan 
Department of Internal Medicine 
Hematology/ Oncology 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109-5848 
Email: bryansh@med.umich.edu 
 
Syma Iqbal, MD, FACP 
Associate Professor of Clinical Medicine 
USC Keck School of Medicine, Norris Cancer Center 
Division of Medical Oncology 
1441 Eastlake Avenue, Ste 3454 
Los Angeles, CA 90033 
Email: Iqbal_s@med.usc.edu 
 
Khaldoun Almhanna, MD, MPH 
Department of Oncology 
Rhode Island Hospital 
593 Eddy Rd. George Bldg 
Providence, RI 02903 
Email: Kalmhanna@lifespan.org 

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INVESTIGATOR AGREEMENT 
 
Protocol Version 10.0 Dated: October 10, 2022 
 
I have read the protocol entitled “Multicenter, Randomized Phase II study 
of Pembrolizumab in combination with chemotherapy or chemoradiation in locally 
advanced esophageal adenocarcinoma” 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for 
Good Clinical Practice and applicable regulatory requirements and to inform all who assist 
me in the conduct of this study of their responsibilities and obligations. 
 
 
 
 
 
Principal investigator printed name 
 
 
 
 
 
Principal investigator signature 
Date 
 
 
 
 
 
 
 
 
Investigational site or name of institution and 
location (printed) 

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Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCMC. 

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List of Abbreviations 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
ECI 
FDA 
Events of Clinical Interest 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBAF 
Human Research Billing Analysis Form 
ICF 
IND 
IRB 
PHI 
PI 
REDCap 
SAE 
SUSAR 
UAP 
WCMC 
Informed Consent Form 
Investigational New Drug 
Institutional Review Board 
Protected Health Information 
Principal Investigator 
Research Electronic Data Capture 
Serious Adverse Event 
Suspected Unexpected Serious AdverseReaction 
Unanticipated Problem 
Weill Cornell Medical College 

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Protocol Summary 
Full Title: 
Multicenter, Randomized Phase II study of Pembrolizumab in 
combination with chemotherapy and chemoradiation in locally 
advanced esophageal adenocarcinoma 
Short Title: 
Phase II study of Pembrolizumab in locally advanced esophageal 
adenocarcinoma 
Clinical Phase: 
II 
Principal Investigator: 
Manish A. Shah 
Sample Size: 
N= 42 patients 
Accrual Ceiling: 
This study will enroll 42 patients and screen up to 80 patients 
Study Population: 
locally advanced esophageal adenocarcinoma 
Accrual Period: 
3.5 years 
Study Design: 
multicenter, random assignment study 
Study Duration: 
4.5 years (projected end date July 2021). 
Study Agent/ 
Intervention Description: 
Pembrolizumab 
 
Primary Objective: 
To examine the safety and efficacy of the combination of 
pembrolizumab with chemotherapy and chemoradiation in locally 
advanced esophageal adenocarcinoma as assessed by the major 
pathologic response rate (defined as complete response or near 
complete response). 
 
Secondary Objectives: 1) To examine other measures of efficacy of pre-operative therapy 
in combination with pembrolizumab, including the pathologic 
complete (or near complete) response rate, R0 resection rate, and 
median and 1-year disease free and overall survival rates. 
2) To explore the effect of the combination of pembrolizumab with 
chemotherapy as assessed by the local immune infiltration and 
clinical response in each treatment group. 
 
Exploratory Objectives: 
1) To examine whether anti PD1 therapy is associated with 
a transcriptomic signature of intra-tumoral immune activation 
predictive of response and 1-year survival. 
2) To examine whether chemotherapy is associated with induction 
of PD-L1 expression in tumors. 
3) To examine whether anti PD1 therapy is associated with 
increased intra-tumoral immune cell infiltration 
 
Endpoints: 
Major pathologic response rate, 1yr disease free and overall survival rate 

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SCHEMA 
 
 
 
 
 
COHORT 1 
 
 
 
 
 
 
 
 
 
 
 
 
1:1 
N=46 
 
 
 
 
 
COHORT 2 
 
= Correlative studies 
chemo = taxol/ carboplatin 
 
 
 
 
 
Cohort 1 
1. Induction chemotherapy with taxol/carboplatin (q 3 week) 
2. Chemoradiation – taxol/carboplatin weekly, with Pembrolizumab 
3. Resection 
4. Pembrolizumab every 6 weeks for 1 year following surgery (beginning at 3-14 
weeks following resection) 
 
Cohort 2 
1. 
Induction chemotherapy with taxol/ carboplatin (q 3 weeks), with 
Pembrolizumab administered the week after chemotherapy. (i.e. weeks 2 and 
5). 
2. Chemoradiation – taxol/carboplatin weekly, with Pembrolizumab 
3. Resection 
4. Pembrolizumab every 6 weeks for 1 year following surgery (beginning at 3-14 
weeks following resection) 
Key Eligibility 
Patients with T2-4 or 
N+ non-metastatic 
locally non-advanced 
esophageal 
adenocarcinoma 
Surgical candidate 
pembro 
pembro 
pembro 
chemo 
chemo 
chemo 
chemo 
chemo 
Follow-up 
S U R G E R Y 
R A N D O M I Z E 
Radiation to 4140 cGY 
chemo 
chemo 
Pembro x 1 year from surgery 
pembro 
chemo 
pembro 
chemo 

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TABLE OF CONTENTS 
1. STUDY OBJECTIVES ................................................................................................................ 11 
1.1. Primary Objectives ........................................................................................................... 11 
1.2. Secondary Objectives ....................................................................................................... 11 
1.3. Exploratory Objectives .................................................................................................... 11 
2. BACKGROUND ................................................................................................................... 11 
2.1. Disease ............................................................................................................................. 11 
2.2. Investigational Agent or Device ...................................................................................... 13 
2.3. Study Rationale ................................................................................................................ 15 
2.3.1. Rationale for Dose Selection of Pembrolizumab ................................................... 16 
2.3.2. Rationale for Randomization ................................................................................. 16 
2.4. Correlative Studies ............................................................................................................ 16 
2.5. Hypothesis ....................................................................................................................... 17 
2.5.1. Primary Hypothesis ................................................................................................ 17 
2.5.2. Secondary Hypothesis ............................................................................................ 17 
2.5.3. Exploratory Hypothesis ........................................................................................ 17 
3. SUBJECT SELECTION ...................................................................................................... 17 
3.1. Inclusion Criteria ............................................................................................................. 17 
3.2. Exclusion Criteria ............................................................................................................ 19 
4. REGISTRATION PROCEDURES ..................................................................................... 20 
4.1. Patient Registration – Part (WCMC Only) ...................................................................... 20 
4.2. Patient Registration – Part 2 (All Sites) ........................................................................... 21 
5. STUDY PROCEDURE ......................................................................................................... 21 
5.1. Schedule of Assessment: Cohort 1 .................................................................................. 22 
5.2. Schedule of Assessment: Cohort 2… .............................................................................. 23 
5.2.1. Overview ............................................................................................................... 25 
5.2.2. Informed Consent & Subject Screening ................................................................ 25 
5.2.3. Pre-Study (Baseline) Evaluation ............................................................................ 25 
5.2.4. Active Treatment Period ....................................................................................... 26 
5.2.5. Surgery Period ....................................................................................................... 29 
5.2.6. Post-Surgery Period .............................................................................................. 29 
5.2.7. End of Treatment ................................................................................................... 31 
5.2.8. Surveillance & Follow-up ..................................................................................... 31 
5.3. Randomization ................................................................................................................. 31 
5.4. Treatment Administration ................................................................................................. 31 
5.4.1. Induction Chemotherapy ........................................................................................ 32 
5.4.2. Chemoradiation ...................................................................................................... 33 
5.4.3. Chemotherapy & Pembrolizumab .......................................................................... 33 
5.5. Radiation ........................................................................................................................... 34 
5.5.1. Technical Factors .................................................................................................. 34 

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5.5.2. Required Benchmarks and Pre-approval of 3D Treatment Plans ......................... 34 
5.5.3. Protocol Treatment Volumes ................................................................................ 34 
5.5.4. Target Dose and Normal Tissue Dose Constraints ................................................ 35 
5.5.5. Normal Tissue Dose Constraints ........................................................................... 35 
5.5.6. Treatment Planning ............................................................................................... 36 
5.5.6.1. 
3D Conformal Beam Arrangements ............................................................... 36 
5.5.6.2. 
IMRT – Beam Arrangement ........................................................................... 37 
5.5.7. Verification Film Review ...................................................................................... 37 
5.5.8. Definitions of Deviations in Protocol Performance ............................................... 37 
5.6. General Concomitant Medication and Supportive Care Guidelines for Pembrolizumab.38 
5.6.1. Acceptable Concomitant Medication ...................................................................... 38 
5.6.2. Rescue Medications & Supportive Care ............................................................... 39 
5.7. Surgery .............................................................................................................................. 43 
5.8. Post operative Pembrolizumab ......................................................................................... 44 
5.9. Diet/ Activity/ Other Considerations ............................................................................... 45 
Diet ................................................................................................................................... 45 
Contraception .................................................................................................................... 45 
Use during Pregnancy ....................................................................................................... 45 
Use in Nursing Women .................................................................................................... 46 
5.10. Duration of Therapy and Criteria for Removal from Study ......................................... 46 
5.11. Duration of Follow up .................................................................................................. 46 
6. DOSING DELAYS/DOSE MODIFICATIONS ................................................................. 46 
6.1. Timing of Chemotherapy Administration ....................................................................... 46 
6.2. Chemotherapy Dose Level and Attenuation Guidelines .................................................. 47 
6.3. Chemotherapy Dose Modifications .................................................................................. 48 
6.4. Pembrolizumab Related Toxicity ..................................................................................... 50 
7. ADVERSE EVENT REPORTING REQUIREMENTS .................................................... 53 
7.1. Adverse Event Definition ................................................................................................ 53 
7.1.1. Investigational Agent Risks .................................................................................. 53 
7.1.2. Adverse Event Characteristics and Related Attributions ....................................... 53 
7.1.3. Recording of Adverse Events ................................................................................ 54 
7.1.4. Reporting of AE to WCMC IRB ........................................................................... 54 
7.2. Definition of SAE ............................................................................................................ 54 
7.3. Reporting of SAE to IRB .................................................................................................. 54 
7.4. Reporting of SAE to FDA (where WCMC is the Sponsor-Investigator) ........................ 54 
7.5. Reporting of SAE to Merck ............................................................................................. 55 
Events of Clinical Interest ................................................................................................ 55 
7.6. AE/SAE Follow up .......................................................................................................... 56 
8. PHARMACEUTICAL INFORMATION ............................................................................ 56 
8.1. Investigational Agent ........................................................................................................ 56 
8.2. Agent Accountability ........................................................................................................ 57 
9. CORRELATIVE /SPECIAL STUDIES ............................................................................. 57 
9.1. To examine whether anti PD1 therapy is associated with a transcriptomic signature of 

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intra-tumoral immune activation predictive of response and improved 1 year survival..58 
9.2. To examine whether chemotherapy is associated with induction of PD-L1 expression in 
tumors .............................................................................................................................. 59 
9.2.1 PD-L1 Immnohistochemistry ................................................................................... 59 
9.3. To examine whether anti PD1 therapy is associated with increased intra-tumoral immune 
cell infiltration .................................................................................................................. 59 
9 4. To explore baseline tumor tissue expression as a predictor of pembrolizumab therapy 60 
9.4.1. RNA Expression Analysis ..................................................................................... 60 
9.5. To examine immune cytokine expression ........................................................................ 61 
9.6. Collection of Specimen(s) ................................................................................................ 61 
9.7. Handling of Specimens(s) ................................................................................................ 61 
9.8. Mouth Biome ................................................................................................................... 61 
9.9. To collect blood as a biomarker for future study ............................................................. 61 
10. MEASUREMENT OF EFFECT.......................................................................................... 62 
10.1. 
Response Criteria ........................................................................................................ 62 
10.2. 
Evaluation of Target Lesions ...................................................................................... 63 
10.3. 
Evaluation of Non-Target Lesions .............................................................................. 64 
10.4. 
Guidelines for Evaluation of Measurable Disease ....................................................... 64 
10.5. 
Confirmatory Measurement/Duration of Response ..................................................... 65 
11. DATA REPORTING & REGULATORY CONSIDERATIONS .................................... 65 
11.1. 
Data Collection ............................................................................................................ 65 
11.1.1. REDCap ................................................................................................................ 65 
11.2. 
Regulatory Considerations .......................................................................................... 66 
12. STATISTICAL CONSIDERATIONS ................................................................................. 66 
12.1. 
Study Design & Endpoints .......................................................................................... 66 
12.2. 
Sample Size & Accrual Rate ........................................................................................ 67 
12.3. 
Stratification Factors ................................................................................................... 67 
12.4. 
Analysis of Secondary Endpoints ................................................................................ 67 
12.5. 
Reporting & Exclusions .............................................................................................. 67 
12.5.1. Evaluation of toxicity .............................................................................................67 
12.5.2. Evaluation of response .......................................................................................... 67 
13. DATA & SAFETY MONITORING PLAN (DSMP) ..........................................................68 
13.1. 
DSMB Reporting ......................................................................................................... 69 
14. References ............................................................................................................................... 70 

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1 STUDY OBJECTIVES 
 
1.1 Primary Objectives 
To examine the safety and efficacy of the combination of Pembrolizumab with 
chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma as 
assessed by the major pathologic response rate (defined as complete response or near 
complete response). 
 
1.2 Secondary Objectives 
To examine other measures of efficacy of pre-operative therapy in combination with 
pembrolizumab, including the pathologic complete (or near complete) response rate, 
R0 resection rate, and median and 1-year disease free and overall survival rates. 
 
To explore the effect of the combination of pembrolizumab with chemotherapy as 
assessed by the local immune infiltration and clinical response in each treatment group. 
 
1.3 Exploratory Objectives 
To examine whether anti PD1 therapy is associated with a transcriptomic signature of 
intra-tumoral immune activation predictive of response and improved 1 year survival. 
 
To examine whether chemotherapy is associated with induction of PD-L1 expression 
or induction of an inflammatory signature in tumors. 
 
To examine whether anti PD1 therapy is associated with increased intra-tumoral 
immune cell infiltration. 
 
 
2 BACKGROUND 
 
2.1 Disease 
 
Esophageal cancer is the 8th most common cancer worldwide, and the 5th most common 
gastrointestinal malignancy in the U.S., with an estimated 18,170 new cases and 15,450 deaths 
in 20131,2. Esophageal cancer histology varies by location, with squamous cell carcinoma 
(SCC) more prevalent in the upper and middle thirds of the esophagus and more prevalent 
worldwide, and adenocarcinoma (ADC) more prevalent in the lower third of the esophagus 
and at the gastroesophageal junction (GEJ) and more prevalent in the West. There are two 
accepted treatment paradigms for the adjuvant therapy of esophageal/ GEJ carcinoma: (1) peri- 
operative chemotherapy for esophageal/GEJ ADC, and (2) pre-operative chemoradiation for 
both SCC and ADC. Our primary aim is to examine the safety and efficacy of pembrolizumab 
in both pre-operative treatment paradigms for esophageal/GEJ carcinoma. The specific 
rationale for our study design is rooted in three unanswered questions: (1) does the addition of 

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an immune check-point inhibitor (pembrolizumab) enhance the efficacy of cytotoxic therapy 
(chemotherapy with chemoradiation) as determined by response rates, nodal own-staging and 1 
year disease free survival in comparison to historical controls, (2) what are the pathological 
effects of combining pembrolizumab with chemotherapy alone, and (3) what are the molecular 
(PD-L1 expression), immunological (TILs extent) and gene- expression signatures associated 
with the efficacy of pembrolizumab in the neoadjuvant setting. 
 
Preoperative Chemoradiation for Esophageal Carcinoma: 
Based on the Dutch CROSS trial, tri-modality therapy is also a standard option for the 
management of potentially resectable esophageal carcinoma, particularly SCC3. This study 
enrolled 366 patients, randomized to preoperative chemoradiation with paclitaxel and 
carboplatin versus surgery alone. Preoperative chemoradiotherapy improved OS (median OS 
49.4 vs. 24.0 months, 3-year OS 58% vs. 44%, p=0.003). Patients with SCC of the esophagus 
derived the most benefit with trimodality therapy, with HR 0.42 (95% CI 0.226-0.788), 
whereas patients with esophageal ADC had HR 0.74 (95% CI 0.536-1.024)3. 
Induction Chemotherapy and the Effects on Tumor Infiltrating Lymphocytes 
Induction chemotherapy (eg. chemotherapy given prior to the initiation of chemoradiation) is 
commonly employed to initiate therapy while the treatment planning for radiation is 
underway. It is associated with dysphagia relief, and is a standard practice, accepted by the 
US Intergroup (eg. induction carboplatin/taxol is one of the arms of the intergroup study 
CALGB 80101). In our own experience, when given without radiation, carboplatin and 
paclitaxel was associated with high response rates, including a 11% pathology complete 
response rate seen in esophageal adenocarcinoma.4 Chemotherapy is known to affect the 
infiltrating tumor lymphocytes. In a study evaluating T cell subpopulations in peripheral 
circulation of patients with ovarian carcinoma receiving taxol/carboplatin, it was noted that 
there was a profound increase in the cytotoxic T cell response beginning about 12-14 days 
following chemotherapy in these patients5. Specifically, the proportions of Th1, Tc1, 
CD45RO memory T, NKT cells and the ratio of Tc1 to Tc2 cells increased significantly 12- 
14 days following chemotherapy, associated with a decrease in regulatory T cells5. Given the 
significant potential of carboplatin/ paclitaxel to increase the antigenic load (based on the 
induction of apoptosis), and the known effects of augmenting a CD8 infiltrate, there is 
significant potential for pembrolizumab to have an added effect when given following 
chemotherapy. This justifies the randomization during induction therapy. 
Pathologic Node+ Esophageal Cancer Patients Have a High Risk of Relapse: 
Unfortunately, despite pre-operative therapy, the majority of patients with esophageal 
adenocarcinoma eventually will recur and die of their disease. Pathologically involved lymph 
nodes have a particularly poor prognosis. Patients with persistent node-positive disease at 
surgery (ypN+) have significantly worse disease-free survival compared to ypN0 patients 
(10–11 months vs. 30-32 months)6. 
This provides the rationale to continue with post- 
operative pembrolizumab following resection. 
 
PD-1 and Pembrolizumab: 
Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for 
its role in the maintenance of self-tolerance and prevention of autoimmunity7. Engagement of 
PD-L1 on dendritic cells with the programmed death 1 (PD-1) receptor on T cells delivers an 
inhibitory signal that promotes T cell anergy or apoptosis8,9. Tumor cells often over-express 

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PD-L1 (or PD-L2), resulting in T-cell anergy and escape from immunosurveillance in the 
tumor microenvironment. Blockade of the interaction between PD-L1 or PD-L2 on tumor 
cells and PD-1 on T cells reverses T cell suppression within tumors, thereby promoting 
effective anti-tumor immune responses. Pembrolizumab is a highly selective, humanized 
monoclonal IgG4-kappa isotype antibody against PD-1 that successfully blocks the negative 
regulatory signaling of the PD-1 receptor expressed on T cells10, and has received FDA 
approval in September 2014 for its activity in melanoma11. 
 
Immunosurveillance in Esophageal/GEJ carcinoma: 
Several investigators have demonstrated the significance of immunosurveillance in 
esophageal cancer12-14. Specifically, tumor infiltrating lymphocytes (TILs) correlated with 
improved survival13,14, and expression of PD-L1 and PD-L2 was associated with poor survival 
in esophageal carcinoma12,13. Notably, 43% of esophageal SCC and 70% of esophageal 
adenocarcinoma express PD-L113, and its expression is independently associated with worse 
survival 12. 
PD-1/PD-LI Inhibitors in Gastroesophageal Cancer: 
There has been early demonstration of activity of PD-1/ anti-PD-L1 antibody immune 
checkpoint inhibitors in upper GI malignancies. Activity has been demonstrated with the PD- 
L1 antibody MEDI14736 in advanced gastric cancer. Segal et al evaluated MEDI4736 in 16 
patients with gastroesophageal adenocarcinoma15. Four patients had a partial response. 
Several responses were also seen in pancreatic cancer – another disease type not typically 
associated with activity from immune therapy. Pembrolizumab also appears to have 
substantial activity in patients with advanced gastric cancer expressing PD-L1 as reported at 
ESMO 2014. Of the 39 patients enrolled, 19 were from Asia-Pacific and 20 were from other 
areas of the world. At a median follow-up of approximately 6 months, the ORR was 31% 
(31.6% in Asians and 30% in non-Asians). There were no complete responses and six partial 
responses each in Asians and non-Asians. In Asian patients, the median time to response was 
8 weeks (range, 7-8 weeks) and six of the six responses are ongoing. The response duration 
ranged from 8+ to 16+ weeks and the median duration of response has not been reached. In 
the non-Asian group, the median time to response was 12 weeks (range, 7-17 weeks) and five 
of the six responses are ongoing. The response duration ranged from 9+ to 20+ weeks, and 
the median duration of response has also not been reached. There are planned studies of the 
addition of immune checkpoint inhibitors with chemotherapy. However, there is very little 
data any sequence dependency of combined therapy. One study in non-small-cell lung cancer 
suggests that chemotherapy prior to immune checkpoint inhibition (in this case, anti-CTLA- 
4 therapy with ipilimumab) was superior (as assessed by PFS) to a strategy of immediately 
administering chemotherapy/ipilimumab simultaneously16. Conversely, activating the anergic 
T cells prior to cytotoxic therapy also appears to be a rational approach, as it allows for T cell 
activation prior to the potentially negative impact of steroids and cytotoxic therapy on these 
cells17. Biomarkers predictive of immune checkpoint inhibition efficacy are also being 
investigated. 
Pathologic Response and Pre-operative Chemoradiotherapy in Esophageal Cancer: 
Histopathologic response has been established as a predictor of patient outcome following 
preoperative chemoradiotherapy. 
An assessment of vital residual tumor cells can be 
performed to determine the degree of pathologic response23. Across over 250 patients, the 
major pathologic response rate, defined as complete response or near complete response, i.e. 
< 10% residual tumor cells), for esophageal adenocarcinoma is approximately 30%24,25. 
Prognostically, this group of patients with a major histologic response have a much better 

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survival than non-responders26, where the pooled hazard ratio was 0.46 (95% CI 0.32-0.66). 
 
2.2 Investigational Agent or Device 
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 IgVariable-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 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 

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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. 

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2.3 Study Rationale 
Esophageal cancer is a prevalent and deadly malignancy. Because of early symptoms of 
dysphagia and weight loss, patients commonly present prior to the development of 
metastases, 
and 
thus, 
our 
opportunity 
to 
improve 
survival 
with 
improved 
immunosurveillance in the adjuvant and neo-adjuvant setting is substantial. PD-L1 and PD- 
L2 is overexpressed in upper gastrointestinal cancers, and there is preclinical and preliminary 
clinical evidence of a synergistic or additive effect of immune checkpoint inhibitors when 
combined with cytotoxic therapy in the advanced disease setting. Our considered 
neoadjuvant approach will address important questions of the sequence dependence of 
pembrolizumab when combined with chemotherapy, and will provide important safety and 
efficacy data of the combination of chemoradiation and pembrolizumab. Additionally, the 
neoadjuvant approach where tumor tissue and blood samples can be obtained prior to and 
after therapy, affords a unique opportunity for the evaluation of biomarkers predictive of 
response and resistance to pembrolizumab. 
 
2.3.1 Rationale for Dose Selection of Pembrolizumab 
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. Recent data from other 
clinical studies within the MK-3475 program has shown that a lower dose of MK-3475 and a 
less frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and 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 

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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 reducewastage. 
2.3.2 Rationale for Randomization 
The primary endpoint of the study is to evaluate the addition of pembrolizumab to 
chemoradiation in patients with locally advanced esophageal cancer compared with 
historical control. The rationale for randomizing patients to chemotherapy + pembrolizumab 
versus chemotherapy alone during induction therapy is to examine the impact of 
pembrolizumab in augmenting tumor lymphocyte infiltration following chemotherapy. 
During the induction chemotherapy phase, patients will be randomly assigned to 
chemotherapy alone or chemotherapy followed 1 week later by pembrolizumab. The 
rationale is to examine the hypothesis that cytotoxic chemotherapy, by virtue of cell killing, 
will increase the breadth and density of neoantigens present for immune system recognition. 
Patients who receive pembrolizumab following chemotherapy may therefore have a more 
robust immune response, as assessed by the lymphocytic infiltrate in the tumor and possibly 
by a greater response to treatment as assessed radiographically. This is an exploratory 
hypothesis. 
2.4 Correlative Studies 
 
(1) We will determine the frequency and character of immune cell infiltration before and 
after therapy with pembrolizumab by flow cytometry. 
(2) We will perform whole tumor RNASeq and deconvolution to determine the frequency 
and activation state of tumor infiltration of stromal and immune cells. 

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2.5 Hypotheses 
 
2.5.1 Primary Hypothesis 
The addition of pembrolizumab to chemotherapy and chemoradiation will be associated 
with improved anti-tumor efficacy resulting in improved patient survival in patients with 
esophagus/GEJ carcinoma treated with a curative paradigm. 
 
2.5.2 Secondary Hypotheses 
Cytotoxic therapy can augment the activation of the immune system by pembrolizumab 
when these two treatment strategies are combined. We believe that we will be able to 
generate preliminary evidence of this relationship by assessing the character and extent of 
immune infiltration following combined therapy as well as assessing the clinical response 
to the tumor. 
 
Pembrolizumab can be given safely with chemoradiation in the preoperative setting for 
localized esophageal squamous cell carcinoma. 
 
2.5.3 Exploratory Hypothesis 
Treatment with pembrolizumab is associated with a specific immune related gene- 
expression signature predictive of pembrolizumab efficacy as assessed by improved 
clinical outcome. 
 
Chemotherapy and/or radiotherapy can induce PD-L1 expression and thus potentially 
enhance efficacy of pembrolizumab. 
 
Clinical efficacy of pembrolizumab is associated with increased tumor infiltration by 
CD8+ lymphocytes. 
 
3 SUBJECT SELECTION 
 
3.1 Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 
3.1.1 
Patients must have histologically or cytologically confirmed esophageal or GEJ 
adenocarcinoma 
 
3.1.2 
Clinical tumor stage should be T2 Npositive M0 or T3-T4 Nany M0 
 
3.1.3 
Be willing and able to provide written informed consent/assent for thetrial 
 
3.1.4 
Be ζ 18 years of age on day of signing informed consent. 
3.1.5 
Be a candidate for surgical resection. 

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3.1.6 
Be willing to provide tissue during endoscopic assessment of theirtumor. 
 
3.1.7 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
3.1.8 
Demonstrate adequate organ function asdefined in 
Table 1, all 
screening labs should be performed within 14 days of treatmentinitiation. 
 
 
Table 1 Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion within 7 
days of assessment 
Renal 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT) 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
3.1.9 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 7 days prior to receiving the first dose of studymedication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 

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3.1.10 Female subjects 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 5.7.2). Subjects of childbearing potential are those who have 
not been surgically sterilized or have not been free from menses for > 1 year. 
3.1.11 Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy. 
 
3.2 Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
3.2.1. Is currently participating and receiving study therapy or has participated in a study 
of an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment. 
3.2.2. Evidence of metastatic disease. 
3.2.3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose 
of trial treatment. 
3.2.4. Has active TB or a history of active TB within 10 years of registration (Bacillus 
Tuberculosis) 
3.2.5. Hypersensitivity to pembrolizumab or any of its excipients. 
3.2.6. Has had a prior anti-cancer treatment, including chemotherapy, radiation, or 
monoclonal antibody (mAb) for their current diagnosis of esophageal 
adenocarcinoma. 
3.2.7. Has a known additional malignancy that is active. 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. 
3.2.8. Has a previous invasive malignancy treated with curative intent less than 3 years 
from time of registration. Exceptions include prostate cancer, basal cell squamous 
skin cancer, and cervical cancer. 
3.2.9. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
3.2.10. Has known history of, or any evidence of active, non-infectiouspneumonitis. 

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3.2.11. Has an active infection requiring systemic therapy. 
3.2.12. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
3.2.13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
3.2.14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
3.2.15. Has received prior therapywith an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
3.2.16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
3.2.17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
3.2.18. Has received a 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. 
 
 
 
4 REGISTRATION PROCEDURES 
4.1 Patient Registration – Part 1 (WCMC Only) 
Patients will be centrally registered with the Office of Billing Compliance. To register 
a patient, submit the following documents via the JIRA Registration Process: 
• Legible copy of the HRBAF 
• First and last page of signed informed consent form 
Registration must be completed within 24 hours of the signing of informed consent. 

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4.2 Patient Registration – Part 2 (All Sites) 
Study participants will be centrally registered with the Weill Cornell Medicine Joint 
Clinical Trials Office (JCTO). To register a new study subject, email the following 
documents to JCTOIIT@med.cornell.edu : 
 
o Completed WCM subject registration form 
o First and last page of the fully executed informed consent form, plus additional 
pages if checkboxes for correlative studies are required. 
o Fully executed HIPAA research authorization form (if separate from the consent 
document) 
o Eligibility checklist signed and dated byinvestigator and research nurse 
o Source documents verifying eligibility including 
■ 
Pathology report confirming diagnosis 
■ 
Radiology reports (CT or MRI scan) 
■ 
Endocopy report (EGD or EUS) to confirm disease location 
■ 
Laboratory reports confirming all required eligibility criteria have been met 
■ 
On-study visit note documenting PS and consenting process 
o Documentation of any eligibility waivers granted 
Note that attachments larger than 4.5 MB are not accepted, so larger attachments should 
be split into more than one email. 
Central registration information is reviewed and entered into the centralized research 
database. Documentation of subject registration will be faxed to the Investigational 
Pharmacy to allow for release of study agent. 
 
5 Study Procedures 
The Schedule of Evaluations - Section 5.1 summarizes the trial procedures to be performed 
at each visit. Individual trial procedures are described in detail below 

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5.1 
Schedule of Assessment: Cohort 1 
Screening Phase 
Treatment Phase 
Surgery 
Post-Surgery 
End of 
Treatment 
Post- 
Treatment 
Treatment Title 
Part 1 
(-28 to -1) 
Part 2 
(-14 to -1) 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
5 
Wk 
6-7 
Wk 
86 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
14 
Wk 
15-19 
Every 6 
weeks x 
12 mo 
3 mo 
6 mo 
9 mo 12 mo 
At time of 
discon 
Every 6 
months post 
discon 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical History 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
Randomization 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test – Urine or Serum 
β-HCG 
X7 
X 
Mouth Wash 
X 
PT/INR and aPTT 
X 
X 
X 
CBC with Differential, 
Comprehensive Serum Chemistry 
Panel, Liver Function Tests+ T bili 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CEA & CA19-9 
X 
Collect as clinically indicated 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
X 
Tumor Imaging1, 2, 3, 4 
X1 
X2 
X3 
Every 6 months and as 
clinically indicated4 
X 
RECIST 1.1 Assessment8 
X 
X 
X 
X 
Tissue Biopsy5 
X 
X 
X 
Correlative Blood Collection 
X 
X 
X 
X 
X 
X 
X 
Chemotherapy Administration10 
X 
X 
X 
X 
X 
X 
X 
Radiation Administration 
X 
X 
X 
X 
X 
Pembrolizumab Administration9,10 
X 
X 
X 
X 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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5.2 Schedule of Assessments: Cohort 2 
 
Screening Phase 
Treatment Phase 
Surgery 
Post-Surgery 
End of 
Treatment 
Post-Treatment 
Treatment Title 
Part 1 
(-28 to -1) 
Part 2 
(-14 to -1) 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
5 
Wk 
6-7 
Wk 
86 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
14 
Wk 
15-19 
Every 6 
weeks x 
12 mo 
3 mo 
6 mo 
9 mo 
12 mo 
At time of 
discon 
Every 6 months 
post discon 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical 
History 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
Randomization 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test – Urine or Serum 
β-HCG 
X7 
X 
Mouth Wash 
X 
PT/INR and Aptt 
X 
X 
X 
CBC with Differential, 
Comprehensive Serum Chemistry 
Panel, Liver Function Tests+ T bili 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CEA & CA19-9 
X 
Collect as clinically indicated 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
X 
Tumor Imaging1, 2, 3, 4 
X1 
X2 
X3 
Every 6 months and as 
clinically indicated4 
X 
RECIST 1.1 Assessment8 
X 
X 
X 
X 
Tissue Biopsy5 
X 
X 
X 
Correlative Blood Collection 
X 
X 
X 
X 
X 
X 
X 
Chemotherapy Administration10 
X 
X 
X 
X 
X 
X 
X 
Radiation Administration 
X 
X 
X 
X 
X 
Pembrolizumab Administration9, 10 
X 
X 
X 
X 
X 
X 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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1. 
Tumor imaging during screening can be performed as one procedure, PET/CT with diagnostic quality, or can be performed as 2 individual procedures. 
2. 
Tumor Imaging performed during week 6-7 should be PET-CT without diagnostic quality CT. If PET-CT not feasible, CT CA is acceptable. 
3. 
Tumor Imaging pre-surgery should be performed either as PET/CT without diagnostic CT or CT-CA, and as clinically necessary. 
4. 
Tumor Imaging performed after surgery should be contrast-enhanced CT chest and abdomen, only. 
5. 
Tissue sample collection should be performed at screening, week 6/ 7 (if medically feasible), and during surgery. 
6. 
Chemoradiation should start on week 8 +/- 1 week (eg. Treatment can start from week 7-9). 
7. 
Pregnancy test should be performed for women of childbearing potential within 7 days. 
8. 
RECIST 1.1 Assessment is not required postsurgery 
9. 
Pembrolizumab dose is 200 mg flat dose every 3 weeks prior to surgery, and 400 mg flat dose every 6 weeks post surgery. Patient can be switched to low dose pembrolizumab in 
the adjuvant setting if high dose is not tolerated well. 
10. Chemotherapy and pembrolizumab may be administered +/- 3 days to accommodate scheduling (i.e. holidays, travel, etc.) 

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5.2.1. Overview 
This study consist of the screening and enrollment phase, active protocol treatment phase, and then the 
follow-up phase. Patient’s baseline is established during the screening and enrollment. The component of 
the patient’s baseline include the baseline objective (radiologic) disease assessment, tissue samples and the 
pre-study evaluation, consisting of medical history, physical examination, laboratory assessments, and a 
review of active symptoms and current medications. 
The active protocol treatment phase begins on week 1 and regular evaluations per the schedule of 
assessment. Continued monitoring occurs with regular evaluations. Tumor assessments are obtained at 
scheduled times until radiologic disease progression or recurrence is documented. 
 
The active treatment phase closes with an End of Active Treatment visit, to be scheduled at the time of 
treatment discontinuation at 12 months from resection. The follow –up phase begins after the End of Active 
Treatment visit. 
 
In general, unless otherwise noted, each study visit should be scheduled on the same day of the weekly 
treatments with a +/- 3 days window for administrative purposes. 
5.2.2. Informed Consent & subject screening 
Patients who agree to participate will sign the approved informed and will be provided a copy of the 
signed document. 
 
Informed consent should be obtained within approximately one month (28 days) prior to week 1 treatment. 
An appropriate informed consent must be completed prior to undergoing any laboratory or radiologic 
evaluations that are specifically being performed for the purpose of screening for this study. Assessments 
or laboratory evaluations performed as part of standard of care (and not specifically for the study) may be 
used to qualify the patient for enrollment, provided the test result is within the time-frames specified for 
eligibility. All screening procedures should be performed within the time-frames indicated in the schedule 
of assessment calendar. 
 
The treating investigator must verify that the patient meets all inclusion/exclusion criteria. The patient is 
considered enrolled into the study when he or she has been successfully randomized and begins week 1 
treatment, though a log will be kept of all patients who sign informed consent. If the patient did not enroll, 
then the reason the patient did not enroll must be documented. 
 
5.2.3. Pre-Study (Baseline) Evaluation 
The following procedures must be completed no more than 28 days from enrollment. 
• 
Informed Consent 
• 
Inclusion/Exclusion Criteria 
• 
Demographics and Medical History 
• 
Prior and Concomitant Medication Review 

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• 
Tumor Imaging – PET-CT (with diagnostic quality CT). It can be performed as one 
procedure (PET/CT with diagnostic CT), or as 2 individual procedures. Diagnostic CT 
would include CT Chest and Abdomen. 
 
The following tests need to be performed with results within eligibility criteria range within 14 days of 
Day 1, unless otherwise indicated: 
• 
Physical Exam 
• 
Vitals Signs and Weight 
• 
ECOG Performance Status 
• 
CBC with Differential, Comprehensive Serum Chemistry Panel, Liver Function Tests+ 
T bili , Comprehensive Serum Chemistry Panel 
• 
Liver Function Tests, including total bilirubin 
• 
Thyroid function panel 
• 
Pregnancy Test (Urine or Serum β-HCG) (done within 7 days of Day 1) 
• 
CEA & CA19-9 
• 
Mouth Wash 
• 
Tissue Biopsy 
• 
Correlative Studies Blood Collection 
• 
Urinalysis 
• 
Coagulation Tests (PT/PTT) 
 
Randomization (section 5.3) – within 72 hours prior to treatment initiation 
 
5.2.4. Active Treatment Period 
Week 1 
■ 
Prior and Concomitant Medication Review 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
ECOG performance status 
■ 
Review Adverse Events 
■ 
Chemotherapy Administration (see Section 5.2) 
Week 2 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs+ T bili 
■ 
Review Adverse Events 
■ 
Pembrolizumab Administration Cohort 2 only (see Section 5.2) 

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Week 4 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
ECOG performance status 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 
■ 
Coagulation tests (PT/PTT) 
■ 
Review Adverse Events 
■ 
Chemotherapy Administration (see Section 5.2) 
Week 5 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, Liver Function Tests+ T 
bili 
■ 
Review Adverse Events 
■ 
Pembrolizumab Administration Cohort 2 only (see Section 5.2) 
Weeks 6-7 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs+ T bili 
■ 
Thyroid function panel 
■ 
Review Adverse Events 
■ 
Tumor Imaging – PET-CT (CT portion does not have to be of diagnosticquality) 
■ 
Correlative Studies Blood Collection 
■ 
Urinalysis 
■ 
Tissue Biopsy (if medically feasible) 
 
Week 8 (Can occur +/- 7 days) 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
ECOG performance status 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 

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■ 
Review Adverse events 
■ 
Chemotherapy administration (see Section 5.2) 
■ 
Pembrolizumab administration (see Section 5.2) 
■ 
Radiation administration (see Section 5.2) 
■ 
Concomitant Medication Review 
Weeks 9-10 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 
■ 
Review Adverse Events 
■ 
Chemotherapy Administration (see Section 5.2) 
■ 
Radiation Administration (see Section5.2) 
Week 11 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
ECOG performance status 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 
■ 
Review Adverse Events 
■ 
Chemotherapy Administration (see Section 5.2) 
■ 
Pembrolizumab Administration (see Section 5.2) 
■ 
Radiation Administration (see Section5.2) 
Week 12 
■ 
Physical Exam 
■ 
Vital Signs and Weight 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 
■ 
Review Adverse Events 
■ 
Chemotherapy Administration (see Section 5.2) 
■ 
Radiation Administration (see Section5.2) 
Week 14 
■ 
Physical Exam 
■ 
Vital Signs and Weight 

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■ 
ECOG performance status 
■ 
CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 
■ 
Thyroid panel 
■ 
Pregnancy Test 
■ 
Urinalysis 
■ 
Review Adverse Events 
■ 
Pembrolizumab Administration (week 14) (see Section 5.4) 
 
5.2.5. Surgery Period 
 
Week 15-19 
■ 
Review Adverse Events 
■ 
Tumor Imaging – PET-CT (without diagnostic quality CT chest, abdomen and pelvis) or 
CT-CA – must occur after last pembrolizumab dose and before surgical resection. 
Additional imaging as clinically necessary. 
■ 
Correlative Studies Blood Collection 
■ 
Tissue Biopsy (tissue to be collected during surgicalresection) 
 
5.2.6. Post-Surgery Period 
Pembrolizumab Treatment 
Pembrolizumab treatment can start three to fourteen weeks after surgery as standard of care and will be 
given every 6 weeks (Pembrolizumab 400 mg flat dose) thereafter for 1 year (completion is 1 year from 
surgery +/- 7 weeks). 
 
Tumor Imaging – computed tomography (CT) of the chest, abdomen and pelvis is performed every 6 
months and as clinical indicated. 
 
• Physical Exam 
• Vital Signs and Weight 
• CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 
• Pembrolizumab Administration (see Section 5.4) 
• Review Adverse Events 

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At 3 months post surgery 
• Physical Exam 
• Vital Signs and Weight 
• ECOG Performance status 
• Correlative blood studies 
• Urinalysis 
• Thyroid panel 
 
At 6 months post surgery 
• Tumor Imaging – computed tomography (CT) of the chest and abdomen only 
• Physical Exam 
• Vital Signs and Weight 
• ECOG Performance status 
• Correlative blood studies 
• Urinalysis 
• Thyroid panel 
• Concomitant Medication Review 
 
At 9 months post surgery 
• Physical Exam 
• Vital Signs and Weight 
• ECOG Performance status 
• Correlative blood studies 
• Urinalysis 
• Thyroid panel 
 
At 12 months post surgery 
• Tumor Imaging – computed tomography (CT) of chest and abdomen 
• Physical Exam 
• Vital Signs and Weight 
• ECOG Performance status 
• Correlative blood studies 
• Urinalysis 
• Thyroid panel 
• Concomitant Medication Review 

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• An upper Endoscopy is recommended 
 
5.2.7. End of Treatment 
(At the time of treatment discontinuation at 12 months from resection) 
• Physical Exam 
• Vital Signs and Weight 
• CBC with Differential, Comprehensive Serum Chemistry Panel, LFTs + T bili 
• Review Adverse Events 
5.2.8. Surveillance and Follow up 
• Patients should be followed for recurrence as per standard practice for 5 years (from surgery) 
• Guideline Recommendations include physician evaluation and blood work at 18, 24, 30, 36, 42, 
48, 54 and 60 months 
o Physical exam 
o Vital Signs and Weight 
o CBC (absolute neutrophil count, hemoglobin, platelet count) 
o Comprehensive Serum Chemistry Panel 
o Liver Function Tests, including total bilirubin 
o CT (or similar) imaging at 18, 24, 30, 36 months 
o EGD as per symptoms 
• 
After recurrence or the development of metastases, patients will be followed for survival. A phone 
call every 3 months will be sufficient for this. 
5.3 Randomization (within 72 hours prior to treatment initiation) 
Stratified and blocked randomization will be performed at all participating sites. Randomization 
will be stratified by location of cancer (i.e., gastro-esophageal junction vs. esophagus) and 
participating site. A series of randomized blocks of 2 will be generated for each cancer location 
stratum within each participating site with a 1:1 allocation ratio. This will provide assurance that 
after four patients are enrolled in any given cancer location stratum at a participating site, there 
will be two patients assigned to receive pembrolizumab prior to chemotherapy and two patients 
assigned to receive pembrolizumab following chemotherapy. This procedure will allow for each 
cancer location stratum within a participating site to contribute similar numbers of pre- 
chemotherapy pembrolizumab patients and post-chemotherapy pembrolizumab patients. 
 
5.4 Treatment Administration 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are 
described in Section 7. Appropriate dose modifications for Investigational Agent are described in 
Section 6. 
Cohort 1 
 
5. 
Induction chemotherapy with taxol/carboplatin (q 3 week) 

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6. 
Chemoradiation – taxol/carboplatin weekly, with Pembrolizumab 
7. 
Resection 
8. 
Pembrolizumab every 6 weeks for 1 year following surgery (beginning at 3-14 weeks 
following resection) 
 
Cohort 2 
1. Induction chemotherapy with taxol/ carboplatin (q 3 weeks), with Pembrolizumab administered 
the week after chemotherapy. (i.e. weeks 2 and 5). 
2. Chemoradiation – taxol/carboplatin weekly, with Pembrolizumab 
3. Resection 
4. Pembrolizumab every 6 weeks for 1 year following surgery (beginning at 3-14 weeks 
following resection) 
 
5.4.1 Induction Chemotherapy 
 
Patients assigned to both Cohort 1 and Cohort 2 will receive the same induction 
chemotherapy regimen of every 3 weekly dosing of paclitaxel and carboplatin. 
Paclitaxel is to be given first, over 3 hours, followed by carboplatin over 1 hour. The 
suggested premedication regimen is as follows: 
 
Dexamethasone 10 mg PO/IV 
Pepcid 20 mg PO/IV (or equivalent) 
Aloxi 0.25 mg IV (can be substituted for HT3 inhibitors) 
Benadryl (diphenhydramine) 25mg IV/po 
 
For patients below the age of 70, the every 3 weekly dosing of paclitaxel and carboplatin, as per 
the table below: 
 
Agent 
Dose 
Route 
IV Duration 
Days 
Treatment Frequency 
Paclitaxel 
175 mg/m2 
IV 
3 hours 
W1 and W4 
every 3 weeks 
Carboplatin 
AUC 5* 
IV 
1 hour 
W1 and W4 
every 3 weeks 
For patients 70 years and older, the paclitaxel and carboplatin dosing is as follows: 
 
Agent 
Dose 
Route 
IV Duration 
Days 
Treatment Frequency 
Paclitaxel 
150 mg/m2 
IV 
3 hours 
W1 and W4 
every 3 weeks 
Carboplatin 
AUC 4* 
IV 
1 hour 
W1 and W4 
every 3 weeks 
*Creatinine clearance (CrCl) will be calculated using the Cockroft-Gault equation as follows: 
CrCl (ml/min) = (140-age) x actual wt (in kg) 
72 x serum creatinine (mg/dl) 
FOR FEMALES, USE 85% OF CALCULATED CrCl VALUE 

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Dose of carboplatin (mg) = 5 x [CrCl (ml/min) + 25] 
Use the serum Cr value reported by the laboratory; do not apply any correction factors to 
the reported value. 
The maximum CrCl that can be used in this calculation, for both women and men, is 125 
ml/min. Thus the maximum carboplatin dose is 625mg for patients below the age of 70 and 
600 mg for patients 70 years and older. In the case of low creatinine values resulting in high 
CrCl values that seem to overestimate renal function, a 24-hour urine collection for 
determination of CrCl is recommended. 
 
Patients Assigned to Cohort 2 will receive additional Pembrolizumab during induction 
chemotherapy 
Pembrolizumab 200 mg IV will be given on W2 and W5 over 30 minutes (-5 or +10min) 
 
5.4.2 Chemoradiation 
 
Chemoradiation will start on week 8 of the protocol, starting on a Monday. If necessary for 
administrative issues, radiation can start on Tuesday or Wednesday during week 8. A +/- 1week 
window is permitted to start radiation. If radiation is to start on week 7 or week 9, all of the study 
procedures will be shifted by 1 week accordingly. 
 
5.4.3 Chemotherapy and Pembrolizumab 
 
Patients assigned to both Cohort 1 and Cohort 2 will receive the same chemotherapy 
regimen during radiation consisting of weekly paclitaxel and carboplatin. Paclitaxel is 
to be given first, over 1 hour, followed by carboplatin over 30 minutes. The suggested 
premedication regimen is as follows: 
Dexamethasone 10 mg PO/IV 
Pepcid 20 mg PO/IV (or equivalent) 
Metacloperamide 10 mg IV/PO at physician discretion 
Benadryl (diphenhydramine) 25mg IV/po 
 
Treatment 
Paclitaxel 50 mg/m2 IV over 1 hour, + carboplatin AUC 2 IV over 30 minutes, weekly x 5 weeks 
Pembrolizumab 200 mg IV is given during weeks 8 and 11 (administered prior to chemotherapy), 
and 14 (as monotherapy) of the protocol (eg. twice during chemo/RT and once prior to surgery) 
 
Note, if the patient required a dose reduction during the induction chemotherapy treatment, then a dose 
reduction in weekly taxol/carboplatin is recommended as per the Dose Attenuation Guidelines (section 6). 

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5.5 Radiation 
 
Radiation therapy will begin on week 8 (+/- 1 week) per the assessment table, combined chemoradiation 
should start within the first 3 days of radiation therapy preferably on Monday Total dose of RT will be 
4140cGy in 180cGy fractions. Subjects will receive radiation dose of 180cGy for 23 days (23 fractions) 
during week 8 to week 12 as per standard of care. Patients can undergo simulation for radiotherapy 
planning prior to the second PET scan since the treatment volumes are based on pre-chemotherapy 
tumor involvement. The simulation should be performed at least 2 weeks prior to the start date for 
radiotherapy so that submission of dose-volume-histograms can be done and approved centrally without 
delaying the start date of the radiotherapy. 
 
5.5.1 Technical Factors 
Linear accelerators with a minimum energy of 6 MV will be used. A multiple field 3-D conformal 
technique or IMRT will be used. All fields will be treated each day. The patient will be treated in 
the supine position. Radiation will be delivered 5 days/week, once per day. 4D planning may be 
used (described below, Section 5.5.3) 
5.5.2 Required Benchmarks and Pre-approval of 3D Treatment Plans 
CT-based conformal planning is required on this study. As noted above, 3-D conformal or IMRT 
techinique will be allowed. Digital submission of treatment plans is required for this portion of 
study, specifically one axial, cornonal, and sagittal dosimetry plan and the dose volume histogram. 
Treatment plans must be reviewed and approved by the radiation therapy monitor (Nicholas 
Sanfilippo, MD) during the initial week of treatment. Records should be submitted to Weill Cornell 
Medicine, Joint Clinical Trials Office, Investigator-Initiated Trials and Multicenter Protocol 
Operations Team: jctoiit@med.cornell.edu. 
5.5.3 Protocol Treatment Volumes 
 
A volumetric treatment planning CT study will be required for this study. Each patient will be 
positioned in an individualized immobilization device in the treatment position on a flat table. 
Contiguous CT slices, 3-5 mm thickness of the regions harboring gross tumor and grossly enlarged 
nodes and 8-10 mm thickness of the remaining regions, are to be obtained starting from the level of 
the cricoid cartilage and extending inferiorly through the liver. 
 
4-D CT planning is permitted: 4-D CT may be employed through the respiratory cycle for the 
purpose of forming an internal target volume (ITV). The ITV is the union of the gross tumor 
volumes (GTV) of primary tumor and pathlogic nodes contoured on the maximum intensity 
projection image (MIP) to form the envelope that encompasses the motion of the GTV for a 
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Gross Tumor Volume (GTV): The GTV is based on the pre-chemotherapy extent of disease using 
the initial PET/CT scan, endoscopy report, and CT scan. The entire esophageal wall, including any 
disease that has extended through the wall should be contoured as the GTV as well as any PET/CT- 
avid or enlarged lymph nodes. 
Clinical Target Volume (CTV): The intent of pre-operative treatment is to include the tumor bed 
plus the nodal groups at risk (whether clinically positive or negative). The clinical target volume 
(CTV) should encompass the peri-esophageal lymph nodes, mediastinal lymph nodes for mid- and 
upper- thoracic esophageal tumors, and the submucosal spread longitudinally along theesophagus. 
This is generally a 3.5-4 cm expansion on the GTV (or ITV when 4D planning is employed) 
superiorly and inferiorly and 1.0 cm expansion radially. For distal esophageal tumors and GE 
junction tumors, the CTV should include the celiac lymph nodes. For tumors above the carina, the 
supraclavicular lymph nodes should be included in the CTV. 
Planning Target Volume: The PTV is established by expanding the CTV by 0.5 cm in all 
directions. This will result in a margin of up to 5 cm superior and inferior and approximately 1.0-2 
cm radially to the extent of tumor (GTV or ITV). For distal esophageal and GE junction tumors 
where 4D planning is not being used, the superior-inferior expansion can be 0.7-1.0 cm to account 
for the respiratory motion at the discretion of the attending physician while radial expansions remain 
at 0.5 cm. 
. 
5.5.4 Target Dose and Normal Tissue Dose Constraints 
Dose Prescription 
The prescribed dose to the PTV is 4140 cGy delivered in 180 cGy/day over 23 fractions (for 23 
days). 
Dose Uniformity 
The dose to 99% of the PTV must be at least 93% of the prescribed dose, and a contiguous volume 
of no more than 2cc inside the PTV may exceed 20% of the prescribed dose. 
Tissue Heterogeneity 
Calculation shall take into account the effects of tissue heterogeneities. Planning must be performed 
using an approved dose calculation algorithm. Approved algorithms include: convolution 
superposition, collapsed cone convolution, and Monte Carlo. 
5.5.5 Normal tissue Dose Constraints 
The normal structures to be contoured will depend on the level of the esophagus involved, but can 
include left and right lungs, heart, esophagus, brachial plexus, left and right kidneys, liver, stomach, 
small intestine, and spinal canal. The dose to normal tissues should be kept within the parameters 
described below. 
Normal Tissue Constraints: 
1. Lungs 
a. V20Gy ≤ 20% 
b. and V30Gy ≤ 15% 

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c. and V40Gy ≤ 10% 
d. V10Gy ≤ 40% 
2. Cord 
a. Max ≤ 4500 cGy 
3. Bowel 
a. 
Max bowel dose < Max PTV dose 
b. 
and D05 ≤ 4500 cGy 
4. Heart 
a. V30Gy ≤ 30% (closer to 20% preferred) 
b. 
Mean < 3000 cGy 
5. Lt_Kidney, Rt_Kidney (evaluate each one separately): 
a. 
No more than 33% of the volume can receive 1800 cGy 
6. Liver 
a. 
V20Gy ≤ 30 % 
b. V30Gy ≤ 20 
c. mean < 2500 cGy 
7. Stomach 
a. 
Mean < 3000 cGy (if not within PTV) 
b. 
Max dose < 54Gy 
5.5.6 Treatment Planning 
Simulation: Patients will be positioned supine with arms above the head, immobilized in an 
aquaplast mold. A CT simulation should be performed using oral contrast, when possible, using 3- 
5 mm slice thickness. Intravenous contrast is permitted but not required. 
Motion Management: As noted above, 4D planning is permitted, but not required. This is especially 
useful for distal esophageal and G-E junction tumors. This scan will be performed throughout the 
breathing cycle so that a MIP scan can be used for formation of and ITV, as described above.. 
Treatment delivery can be done using the motion management technique available at the institution 
and can include treatment during free-breathing as long as an internal target volume (ITV) has been 
designed based on the motion of the tumor on the 4DCT. 
Beam Arrangements: 
5.5.6.1 3D Conformal Beam Arrangements 
Beam arrangement selection for 3D conformal treatment will vary based on the shape, size, and 
location of the CTV and the resulting PTV in relation to normal organs. The most common 
arrangement is an AP/PA with Right and Left Lateral beams. 

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5.5.6.2 
IMRT - Beam Arrangement 
A five-field beam arrangement is preferred to minimize the low dose distributed to the lungs. 
Suggested beam arrangements are: 
a. 
For distal esophagus the following beam arrangement is useful for minimizing dose to 
the heart and lungs: 
LPO (155), LAO(70-80), AP(0), RAO(280-290), RPO(205) 
Note that the range of gantry angles for the LAO and RAO fields is due to the fact that one needs 
to find the best compromise between the amount of heart and lung in the field. 
b. 
For GE-junction esophagus, the following beam arrangement may be substituted if it is 
better for minimizing dose to the kidney. All beams are 15 MVx: 
PA (180º), close to LL (90º+/-10º), LAO (30-35º), RAO (325-330º), close to RL 
(270º+/-10º) 
These recommended beam arrangements may be changed to one more fitting for the patient’s 
particular anatomy. Volumetric modulated arc therapy (VMAT) is also permitted. The treating 
physician may select whichever technique results in the optimal dose distribution 
 
Field verification: As a minimum requirement, institutions are required to obtain verification images 
at the start of treatment and each week thereafter. Prior to the first treatment images that verify the 
position of the isocenter placement must be obtained. For 3D-CRT this imaging can include 
individual portal views. Weekly imaging can consist of portal views for 3D-CRT. For IMRT 
orthogonal images (KV or MV) verifying isocenter position are perferred. More frequent (daily) 
imaging is allowed, but not required. Cone-beam verification is allowed. 
5.5.7 
Verification Film Review 
All verification images should be reviewed promptly, as is customary. First day images should be 
reviewed prior to the first fraction and subsequent images should be reviewed before the next 
treatment. 
5.5.8 Definitions of Deviations in Protocol Performance 
Prescription Dose 
• 
No Deviation: ≥ 99% of the PTV receives ≥ 93% of the prescribed dose, and a contiguous 
volume of no more than 2cc inside PTV exceeds 20% of the prescribed dose. 
• 
Minor Deviation: Deviations of this magnitude are not desirable, but are acceptable. Coverage 
that is equal to 93% of the prescribed dose and falls between 99% and 95% of the PTV, or a 
contiguous volume of no more than 2cc inside the PTV exceeds 20-25% of the prescribed dose. 
• 
Major Deviation: Doses in this region are not acceptable. More than 1 cm3 of tissue outside the 
PTV receives ≥ 120% of the prescribed dose, or 93% of the prescribed dose falls below 95% of 
the PTV, or a contiguous volume of no more than 2cc inside the PTV exceeds 25% of the 
prescribed dose. 
Volume 

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• 
Minor Deviation: Margins less than specified, or field(s) 1-3 cm greater than specified. 
• 
Major Deviation: Fields transect tumor or specified target volume(s), or fields are more than 
3 cm greater than specified. 
Critical Organ 
• 
Major Deviation: The maximum dose to the spinal cord exceeds 4500cGy; the heart mean dose 
exceeds 3000cGy; the lung V20 exceeds 30% or the V10 exceeds 50% (see dose limits in section 
8.3.5). 
• Minor Deviation: The lung V20 exceeds 20% or the V10 exceeds 40% (see dose limits in 
section 8.3.5). 
• These deviation will be assessed with the initial submission of dosimetry information as noted 
in section 5.5.2. 
 
 
Treatment Interruption 
• Minor Deviation: Treatment interruptions between five and nine normally scheduled treatment 
days with documentation of the reason for interruption.. 
• Major Deviations: Treatment interruptions totalling more than nine normal scheduled 
treatment days with documentation of the reason for interruption. 
At the conclusion of treatment, the treating physician must send information of any treatment 
interruption to Nicholas Sanfilippo, MD. 
 
5.6 General Concomitant Medication and Supportive Care Guidelines for Pembrolizumab 
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 berequired. 
The investigator should discuss any questions regarding this with the Principal Investigator. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician. 
 
5.6.1 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 7.2. 

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Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase 
(including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology. 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. 
5.6.2 Rescue Medications & Supportive Care 
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. 

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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. 
 
• Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
• Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus). 
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
o For 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. 
• 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 

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and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
■ 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
■ 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism 
■ 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
■ 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o When symptoms improve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
• 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 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Table 4 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Increase monitoring of vital signs as 
None 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 
50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the 
subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab (MK-3475) 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
during the period of drug administration. 
 
5.7 Surgery 
 
All patients will proceed to surgical resection regardless of local tumor response. Treatment 
will be interrupted and surgical resection performed if at any time the patient develops 1) 
unacceptable adverse events, 2) intercurrent illness precluding further treatment or 3) 
withdraws consent from the study. Surgical resection will be performed 3-7 weeks after the 
last dose of chemotherapy. Surgical resection will be performed using standard surgical 
practices. All post-operative adverse events will be recorded using NCI common toxicity 
criteria version 4. 
Any of the following surgical approaches are deemed acceptable, as long the approach 
includes the surgical removal of any lymph nodes felt to be suspicious: 
• Ivor Lewis esophagogastrectomy 
• Thoracoabdominal esophagectomy 
• 3-hole esophagectomy (Mckeown procedure) 
• Transhiatal esophagectomy 
• Minimally invasive esophagectomy 
A gross surgical margin of at least 5 cm both proximally and distallyare recommended. A 
frozen section of both the proximal and distal surgical margin should be obtained to 
confirm a negative microscopic surgical margin. 
Pathologic specimens will undergo the standard histopathologic and immunohistochemical 
evaluation for esophageal cancer. The pathologic response will be assessed based on the 
estimated percentage of vital residual tumor cells (VRTCs) (Schneider, Ann Surg 2005). 
The degree of histomorphologic regression will be classified into the following categories: 
No response: > 50% residual tumor cells (or < 50% treatment effect) 
Partial response; 10-50% VRTCs (or > 50% treatment effect, but < 90%) 
Near complete response: < 10% VRTCs (or > 90% treatment effect) 
Complete response: 0% VRTCs (or 100% treatment effect), ypCR, ypT0 
 
Fresh frozen samples of tumor and non-tumor adjacent esophagus will be harvested from 
waste material immediately after resection. Tissue specimens will be stored at -80˚ C for 
correlative studies. Similarly paraffin embedded tissue will be obtained from resected 
tumor andnon-tumor adjacent tissue for correlative studies. 

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5.8 Post-operative Pembrolizumab 
Post-operative pembrolizumab will start around week 6 following resection (and may begin anywhere 
from 3-14 weeks following surgery). To initiate therapy, patients must be in stable clinical condition, 
without having an active infection, the need of intravenous antibiotics, or the need of total parenteral 
nutrition. 
 
In both cohorts, Pembrolizumab 400 mg IV will be administered every 6 weeks for up to 1 year (end date 
will be up to 1 year from the time of resection). If Pembrolizumab 400 mg dose is not well tolerated, 
patient may be switched to 200 mg dose at the discretion of the principle investigator. 

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5.9 Diet/ Activity/ Other Considerations 
 
Diet  
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
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 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 
7.2.2-Reporting of Pregnancy and Lactation to the Sponsor and 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. 
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). 

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The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn to the 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 7.2.2. 
 
 
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. 
5.10 Duration of Therapy and Criteria for Removal From Study 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one 
of the following criteria applies: 
o Disease progression, 
o Intercurrent illness that prevents further administration of treatment, 
o Unacceptable adverse event(s), 
o Patient decides to withdraw from the study, or 
o General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.11 Duration of Follow up 
All patients will be followed for up to 5 years following resection or disease recurrence, 
whichever occurs first. Subjects with recurrence or progression prior to surgery will receive a 
follow up phone call every 3 months for survival. Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. 
 
 
6.1 DOSING DELAYS/ DOSE MODIFICATIONS 
6.2 Timing of Chemotherapy Administration 
Trial treatment should be administered on Day 1 of each treatment week after all 
procedures/assessments have been completed as detailed on the study assessment chart (Section 
5.2). Trial treatment may be administered up to 3 days before or after the scheduled treatmentday 
due to administrative reasons. 

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All trial treatments will be administered on an outpatient basis. 
 
Prior to resection, pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 
3 weeks. Following resection, pembrolizumab 400 mg IV infusion over 30 minutes will be 
administered every 6 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: 25min or up 
to 40min). If the subject is not tolerating the 400 mg flat dose following resection, the subject can 
continue to receive 200 mg flat dose of pembrolizumab every three weeks at the discretion of the 
principle investigator. 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
6.3 Chemotherapy Dose Levels and Attenuation Guidelines 
 
General guidelines and Chemotherapy Dose Levels 
• If multiple adverse events are seen, administer dose based on greatest reduction required for 
any single adverse event observed. Reductions apply to treatment given in the preceding 
week and are based on adverse events observed since the prior dose. 
• 
Neither paclitaxel nor carboplatin will be re-escalated once reduced. 
• 
If both paclitaxel and carboplatin are held for one week during induction chemotherapy, it 
is not to be made up. Proceed with chemoradiation as scheduled. 
• Depending on the specific toxicity, a single chemotherapy drug (i.e. either carboplatin or 
paclitaxel) may be modified without alteration of the other drug. 
Dose levels of chemotherapy during Induction Therapy 
Induction period for Age < 70 
 
Dose 
Level 
Drug Name 
Dose (mg/m2) 
0* 
Paclitaxel 
175 
-1 
Paclitaxel 
140 
* Dose level 0 refers to the starting dose. 
Induction period for age > 70 
Dose 
Level 
Drug Name 
Dose (mg/m2) 
0* 
Paclitaxel 
150 
-1 
Paclitaxel 
110 
* Dose level 0 refers to the starting dose. 
Induction period for Age < 70 

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* Dose level 0 refers to the starting dose. 
Induction period for age > 70 
 
Dose 
Level 
Drug Name 
AUC 
0* 
Carboplatin 
4 
-1 
Carboplatin 
2.5 
* Dose level 0 refers to the starting dose. 
 
Dose levels of chemotherapy during Chemoradiation 
* If a dose reduction was recommended during induction therapy, the patient should initiate the 
corresponding chemotherapy at dose level -1 during chemoradiation. 
 
 
Dose 
Level 
Drug Name 
Dose (mg/m2) 
0* 
Paclitaxel 
50 
-1 
Paclitaxel 
40 
-2 
Paclitaxel 
30 
* Dose level 0 refers to the starting dose of no dose reduction was required during induction therapy. 
 
Dose 
Level 
Drug Name 
AUC 
0* 
Carboplatin 
2 
-1 
Carboplatin 
1.5 
-2 
Carboplatin 
1.2 
* Dose level 0 refers to the starting dose if no dose reduction was required during induction therapy. 
 
6.4 Chemotherapy Dose Modifications 
Hematologic Toxicities 
For grade 3 neutrophil count decreased on day 1, delay paclitaxel and carboplatin until grade ≤ 
2, then resume paclitaxel at 1 dose level decreased, and carboplatin at same dose 
For grade 4 neutrophil count decreased or grade 3 or 4 febrile neutropenia, delay paclitaxel 
and carboplatin until grade ≤ 2, then resume paclitaxel and carboplatin with one dose level 
decreased 
Dose 
Level 
Drug Name 
AUC 
0* 
Carboplatin 
5 
-1 
Carboplatin 
3.5 

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For grade 2 platelet count decreased, delay paclitaxel and carboplatin until grade ≤ 1, then 
resume paclitaxel at one dose level decreased, and carboplatin at same dose 
For grade 3 or 4 platelet count decreased, delay paclitaxel and carboplatin until grade ≤ 1, then 
resume paclitaxel and carboplatin with one dose level decreased 
Neurotoxicity 
For grade 2 neuropathy, continue paclitaxel at one dose level decreased, and carboplatin at the 
same dose 
For grade 3 or 4 neuropathy, discontinue paclitaxel 
Gastrointestinal Toxicity 
For grade 3 nausea or vomiting, delay paclitaxel and carboplatin until grade ≤ 2, then restart 
carboplatin at 1 dose level decreased, and paclitaxel at the same dose 
For grade 4 vomiting, delay paclitaxel and carboplatin until grade ≤ 2, then restart paclitaxel and 
carboplatin with one dose decreased 
For grade 2 diarrhea, delay paclitaxel and carboplatin until grade ≤ 1, then restart paclitaxel and 
carboplatin at same dose 
For grade 3 or 4 diarrhea, delay paclitaxel and carboplatin until grade ≤ 1, then restart paclitaxel 
and carboplatin at one dose decreased 
For grade 3 or 4 anorexia, delay paclitaxel and carboplatin until grade ≤ 2, then restart paclitaxel 
and carboplatin at 1 dose level reduced 
For grade 2 stomatitis, treat with paclitaxel at 1 dose level reduced and carboplatin at same dose 
level 
For grade 3 or 4 stomatitis, delay paclitaxel and carboplatin until grade ≤ 1, then restart 
carboplatin and paclitaxel at 1 dose level reduced 
Hepatobiliary Toxicity 
For grade 2 or 3 AST or ALT elevation, delay paclitaxel and carboplatin until grade ≤ 1, then 
restart paclitaxel and carboplatin at one dose level decreased 
For grade 4 AST or ALT elevation, discontinue paclitaxel and carboplatin 
For grade 2 total bilirubin elevation, delay paclitaxel and carboplatin until grade ≤ 1, then restart 
paclitaxel and carboplatin at 1 dose level decreased 
For grade 3 or 4 total bilirubin elevation, discontinue paclitaxel and carboplatin 
Renal Insufficiency: 
For grade 3 or 4 creatinine increased and NOT attributed to study treatment, delay paclitaxel and 
carboplatin until grade ≤ 1 then restart paclitaxel and carboplatin at same dose 
Opthalmalogic Toxicities: 
For grade 3 watering eyes, delay paclitaxel until grade ≤ 1, then restart paclitaxel at 1 dose level 
decreased 

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For any grade cystoid macular edema, discontinue paclitaxel 
General disorders 
For grade 3 or 4 edema, omit paclitaxel until grade < 2, then resume paclitaxel at one dose level 
decreased 
For grade 3 or 4 fatigue, delay paclitaxel and carboplatin until grade ≤ 2, then resume paclitaxel 
and carboplatin at 1 dose level decreased 
For grade 4 hypersensitivity reaction, discontinue offending study agent. 
Non-hematologic Toxicities 
For all other grade 3 or 4 non-hematologic toxicities likely related to paclitaxel and/or 
carboplatin, omit paclitaxel and/or carboplatin until resolved to < grade 1, then resume paclitaxel 
and/or carboplatin at one dose decreased 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely by 
actual weight without any modification unless explicitly described in the protocol. This will 
eliminate the risk of calculation error and the possible introduction of variability in dose 
administration. Failure to use actual body weight in the calculation of drug dosages will be 
considered a major protocol deviation. 
 
 
6.5 Pembrolizumab Related Toxicity 
Pembrolizumab dose is 200 mg flat dose every 3 weeks prior to surgery, and 400 mg flat dose 
every 6 weeks post surgery. There are no dose modifications to this treatment. 
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 3 below. See Section 5.5 and Events of 
Clinical Interest Guidance Document for supportive care guidelines, including use of 
corticosteroids. 
Table 3 
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 

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Pembrolizumab 
 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 
or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune- 
related AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4.0) 
Action taken 
to 
pembrolizuma 
b 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor 
participants 
for 
signs 
and 
symptoms of pneumonitis 
• 
Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
• 
Add 
prophylactic 
antibiotics 
for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis 
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor 
participants 
for 
signs 
and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signsand ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4 
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 

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Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycem 
ia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of φ3-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM 
• Administer 
anti- 
hyperglycemic 
 
in 
participants 
with 
hyperglycemia 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• 
Administer corticosteroids 
and 
initiate 
hormonal 
replacements as clinically 
indicated. 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidi 
sm 
Grade 2 
Continue 
• Treat 
with 
non-selective 
beta-blockers 
(eg, 
propranolol) or thionamides 
as appropriate 
• 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hypothyroidi 
sm 
Grade 2-4 
Continue 
• Initiate thyroid replacement 
hormones 
(eg, 
levothyroxine 
or 
liothyroinine) per standard 
of care 
• 
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold 
• 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) 
followed 
by 
taper. 
• 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune- 
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type and severity 
of 
AE 
administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 

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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, 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. 
 
9.0 ADVERSE EVENT REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The investigator 
will be required to provide appropriate information concerning any findings that suggest significant 
hazards, contraindications, side effects, or precautions pertinent to the safe use of the drug or device 
under investigation. Safety will be monitored by evaluation of adverse events reported by patients or 
observed by investigators or research staff, as well as by other investigations such as clinical laboratory 
tests, x-rays, electrocardiographs, etc. 
 
7.1 Adverse Event Definition 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality. An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose. 
 
7.1.1 Investigational Agent Risks 
 
Please refer to the Investigational Brochure for Risks. 
 
7.1.2 Adverse Event Characteristics and Related Attributions 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 will be utilized for AE reporting. A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab 
may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic 
control (in case of T1DM). 

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- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – the AE is clearly not to the study treatment. 
 
7.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE log will be 
maintained by the research staff and kept in the patient’s research chart. 
 
 
7.1.4 Reporting of AE to WCMC IRB 
 
All AEs occurring on this study will be reported to the IRB according to the WCMC IRB policy, 
which can be accessed via the following link: 
 
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli 
cy.pdf. 
 
 
7.2 Definition of SAE 
SAE’s include death, life threatening adverse experiences, hospitalization or prolongation 
of hospitalization, disability or incapacitation, overdose, congenital anomalies and any 
other serious events that may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
7.3 Reporting of SAE to IRB 
All SAEs occurring on this study will be reported to the IRB according to the WCMC IRB policy 
 
 
 
7.4 Reporting of SAE to FDA (where WCMC is the Sponsor-Investigator) 
 
If an SAE occurs on this study and meets the FDA reporting criteria, 
the event will be filed on a MedWatch form with the FDA. The 
investigator must notify the FDA of any SAE’s as soon as possible 
but no later than 7 calendar days after the initial receipt of the 
information.Food and Drug Administration 
Center for Drug Evaluation and Research 
Therapeutic Biologic Products Document Room 

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5901-B Ammendale Road 
Beltsville, MD 20705-1266 
 
7.5 Reporting of SAE to MERCK 
Institution will send Merck copies of any and all serious adverse event reports filed with the 
FDA or other applicable regulatory authorities, as well as copies of any correspondence with 
the FDA or other applicable regulatory authorities, regarding any and all serious adverse 
events, irrespective of association with the Study Drug(s) in the course of the Clinical Trial, 
within two (2) working days of such report or correspondence being sent to the FDA or other 
applicable regulatory authorities. Copies should be faxed directly to Merck Global Safety 
Department at 1-215-993-1220. 
 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)Events of 
clinical interest for this trial include: 
 
1. an overdose of Merck product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 
2X the upper limit of normal and, at the same time, an alkaline phosphatase lab 
value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
 
1. Additional adverse events: 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune- 
Related Adverse Event Guidance Document”). This document can be found in 
Appendix 4 and provides guidance regarding identification, evaluation and 
management of ECIs and irAEs. 

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ECIs (both non-serious and serious adverse events) identified in this guidance 
document from the date of first dose through 90 days following cessation of treatment, 
or 30 days after the initiation of a new anticancer therapy, whichever is earlier, need to 
be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220), regardless of attribution 
to study treatment, consistent with standard SAE reporting guidelines. 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event. Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes. If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes. If no other cause is found, then it is 
assumed to be immune-related. 
 
7.6 AE/ SAE Follow up 
All SAEs and AEs reported during treatment on this study will be followed until resolution or until 
the investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the patient discontinues 
participation from the study. 
 
 
 
 
 
 
8. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with Investigational Agent (Pembrolizumab) 
can be found in the Investigator’s Brochure. Paclitaxel and Carboplatin are commercially available 
 
8.1 Investigational Agent 
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 

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Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
8.2 Agent Accountability 
Pembrolizumab Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all agents received 
from Sponsor on a Drug Accountability Record Form (DARF). 
 
9. CORRELATIVE/ SPECIAL STUDIES 
This study will provide a unique opportunity to evaluate the impact of pembrolizumab on the quality 
and character of the immune infiltrate in patient tumor samples. The primary aims of the correlative 
studies is to use IHC to determine PD-L1 expression in tumors before and after treatment, utilize flow 
cytometry to characterize immune infiltrate profiles before and after therapy with pembrolizumab, and, 
perform RNA Sequencing to determine any correlation between transciptomic signatures of intra- 
tumoral immune activation and response/survival. We will plan to collect tumor and non-tumor 
adjacent and tissue (4-6 tissue biopsies for each per time point), blood for plasma biomarkers 
throughout the study, and mouth wash at screening. The protocol schema is provided below that 
highlights blood and tissue ascertainment as it relates to this study. 

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9.1 To examine whether anti PD1 therapy is associated with a transcriptomic signature of 
intra-tumoral immune activation predictive of response and improved 1 year survival. 
From fresh biopsy samples, we will perform RNA Sequence analysis of tumors at baseline and 
following induction chemotherapy or induction chemotherapy with pembrolizumab to examine the 
T cell signature of the immune infiltrate from these tissue biopsysamples. 
 
We have previously performed an analysis on the TCGA involving the T cell gene signature in gastric 
cancer. The large sets of genomic data collected by the TCGA project provide an opportunity to examine 
the tumor-immune interactions. One such approach is to examine the expression levels of immune-specific 
genes to quantify the levels of tumor-infiltrating T cells in samples21,22. The method is based simply on 
selecting a small list of T cell specific genes and generating a “meta gene” expression signature by 
eigenvalue decomposition of the expression matrix. We applied this algorithm on the stomach TCGA 
RNA-sequence data to generate a measure of T cell infiltration in the TCGA samples (Figure 8). We found 
that the majority of the chromosomal instability (CIN) subtype samples (as defined by the TCGA study) 
have a distinct T cell signature (p ≤ 1e-6, Fisher exact test). As expected, EBV samples have elevated 
levels of T cell infiltration (Figure 8) which is also consistent with previous studies demonstrating 
increased levels of cytolytic markers in gastric EBV subtypes21. 

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Figure 8. T cell signature of TCGA gastric samples. Hierarchical clustering of the samples by 15 genes characteristic 
of T cell signature identified two predominant clusters one of which is enriched with CIN tumor subtype. 
 
9.2 To examine whether chemotherapy is associated with induction of PD-L1 expression in 
tumors. 
9.2.1 
PD-L1 Immunohistochemistry 
 
The PD-1/PD-L1 pathway is thought to be involved in tumor immune evasion and is a prospective 
therapeutic target. Pembrolizumab directly blocks the interaction between PD-1 and PD-L1 (as 
well as PD-L2) and current clinical data indicates a potential additive effect of immune checkpoint 
inhibitors when combined with cytotoxic therapy. Chemotherapy as well as radiotherapy is known 
to stimulate PD-L1 expression and we hypothesis this will enhance the efficacy of pembrolizumab. 
We will assess changes in PD-L1 expression in patients by performing IHC staining in tumor tissue 
taken prior to and after treatment with pembrolizumab. 
 
9.3 To examine whether anti PD1 therapy is associated with increased intra-tumoral immune 
cell infiltration. 
 
We will examine the intra-tumoral response to chemotherapy and anti-PD1 therapy in by 
both flow cytometery and immunohistochemistry. Tissue will be obtained at baseline, 
following induction chemotherapy, and at the time of surgical resection. 
Phenotypic and functional characterization of T cells isolated from human endoscopic biopsies. 
We have optimized a 16-color flow cytometry panel with the following antibodies of interest: 
CD3+ (Total T cells), CD8+ (Cytotoxic T cells), CD4+ (T helper cells), CD45+ (total 
hematopoietic cells), FOXP3+ (Treg cells), CD33+ (myeloid precursor cells), CD20+ (B cells), 

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CD16+ (neutrophils), CD62L (isotype control), and viability dye. Flow cytometric analysis will 
be performed in collaboration with Dr. 
Gregory Sonnenberg at Weill Cornell 
Medical  College. 
We 
will 
comprehensively 
interrogate 
the 
immunologic parameters of the innate 
and adaptive immune system including 
analyses of CD4+ T cell subsets and 
their associated cytokines including 
Th1 cells (IL-12, TNFα and IFN7), Th2 
cells (IL-4, IL-5 and IL-13), regulatory 
T cells (IL-10) and Th17 cells (IL-17A, 
IL-17F, IL-21, IL-22). 
Further we can profile ILCs and 
examine 
for 
expression 
of 
the 
associated cytokines IL-4, IL-5, IL-13, 
Figure 2. Phenotypic and functional characterization of T cells 
isolated from endoscopic biopsies. Immune cells were isolated 
from enzymatically digested tissue, and stained with mAbs for flow 
cytometry, Gated on live CD45+ cells. 
IL-17A,  IFNψ  and  IL-22.  We 
developed a new protocol to enable the 
isolation, processing and storage of 
live immune cells from tissue biopsies. 
Our preliminary analysis (performed on a gastric biopsy) identified an accumulation of CD4+ T 
cells in the tumor that were positive for intracellular IFNg, TNF and IL-17A (Figure 2). Employing 
this approach, we propose to examine the phenotype and functional potential of CD4+ and CD8+ 
T cells, as well as ILCs isolated from the tumor before and while on STAT3 inhibition therapy to 
assess whether there is an augmentation of the immune infiltrate and to evaluate the character of 
that infiltrate. 
 
 
IHC and Flow 
 
The immune cell subsets within the tumor tissue will also be evaluated by IHC using cell-specific 
surface markers. This will include CD45+ hematopoietic cells including T cells (CD3+), 
CD3+CD4+ T helper cells and CD3+CD8+ effector T cells, CD4+ CD25+ FoxP3+ T regs. IHC 
analysis will be done on formalin-fixed, OCT embedded tissue sections (5-10 μm thickness) that 
will be stained with the fluorescence-labeled antibodies described above. Fluorescent images will 
be obtained using an Axiovert 200M fluorescent microscope (Carl Zeiss Inc.). 
9.4 To explore baseline tumor tissue expression as a predictor of pembrolizumab therapy. 
9.4.1 RNA Expression Analysis 
Anti PD-1 therapy may be related to a transcriptomic signature of intra-tumoral immune 
activation and could be predictive of both response and survival. Through RNA Sequencing 
we will evaluate and monitor the expression levels of immune-specific genes over the various 
time points for each patient. RNA Sequencing will be performed on tissue biopsies acquired 

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at baseline (prior to treatment), on-treatment (within the first week of the 2nd treatment), and at 
time of surgical resection. We will also sequence germline DNA from the whole blood of each 
patient to ensure any gene alterations/mutations we find in the tumor tissue is somatic and not 
germline. 
 
9.6 
Collection of Specimen(s) 
Fresh tissue will be collected during study specified upper endoscopy performed to assess 
response. Biopsies will be collected prior to initiation of the study and again prior to radiation 
therapy (optional). A third collection of tissue specimens will be taken at the time of surgical 
resection. 
 
9.7 
Handling of Specimens(s) 
Biopsies will be collected in the endoscopic suite or surgical pathology, processed and shipped 
according to the study Lab Manual. 
 
9.8 
Mouth Biome 
Mouthwash samples will be collected for all subjects during screening to understand how 
alternation of regional mucosal microbiome alters the tumor microenvironment, thus creating 
conditions conducive to tumorigenesis. (All samples will be collected, processed, handled and 
shipped according to the study Lab Manual) 
 
 
9.9 To collect blood as a biomarker for future study (All samples will be processed, handled 
and shipped according to the study Lab Manual) 
 
Whole exome sequencing (WES) will be collected in the study for the purpose of a normal 
DNA comparison. Blood for WES will be collected at the same time points as tissue 
procurement (baseline, on-treatment and surgical resection). We will also consider further 
examining the whole blood to identify polymorphisms thought to be important in drug 
metabolism and correlate these findings with toxicity and efficacy (as an exploratory sub- 
aim of the correlative aim). 
 
RNAseq will be collected in the study for the purpose of a normal RNA comparison. Blood 
for RNAseq will be collected at the same time points as tissue procurement (baseline, on- 
treatment and surgical resection). 
 
Blood tubes at various time points in patients enrolled in this study for the purpose of 
banking plasma. Blood will be drawn at baseline, on-treatment following chemotherapy, 
prior to surgical resection and every 3 months post surgery for up to a year. Plasma will be 
stored at -80C, in the future, plasma samples will be used to explore biomarkers that may be 
predictive of response and resistance to pembrolizumab. Also, in the future, we will use 

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these plasma samples to assess circulating tumor DNA in the patients at the various time 
points. 
 
Blood tubes will also be collected at various time points in patients enrolled in this study for 
the purpose of banking serum. Blood will be drawn at baseline, on-treatment following 
chemotherapy, prior to surgical resection and every 3 months post surgery for up to a year. 
Serum will be stored at -80C, in the future, serum will be used to explore biomarkers that 
may be predictive of response and resistance to pembrolizumab. 
 
10 MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be evaluated for response every 6 weeks of 
chemotherapy. 
 
10.1 Response Criteria 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. We will be using RECIST v1.1 for this study [Eisenhauer EA et al. New 
response evaluation criteria in solid tumor:revised RECIST guideline (version1.1). Eur J Cancer 
2009;45:228-47). Selected sections of RECIST 1.1. are provided below. 
 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below. For the purposes of this study, stomach, GEJ, or esophageal wall thickening will 
be considered non-measurable. 
 
a. Measurable Tumor Lesions 
Tumor Lesions. Tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size as follows: 
• 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (CT/MRI 
scan slice thickness/interval no greater than 5 mm) 
• 10-mm caliper measurement by clinical examination (lesions that cannot be accurately measured 
with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and follow-up, only the short axis will be 
measured and followed. See also notes below on “Baseline Documentation of Target and Non- 
Target Lesions” for information on lymph node measurement. 
 
b. Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or pathological 

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lymph nodes with short axis ≥ 10 but < 15 mm) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, peritoneal 
spread, and abdominal mass/abdominal organomegaly identified by physical examination that is 
not measurable by reproducible imaging techniques. 
 
c. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
• Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions. However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic Lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
10.2 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Endoscopy must be without 
evidence of tumor with negative cytologic brushings and esophageal biopsies. The patient must be 
free of all symptoms of cancer. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions taking as reference the baseline sum LD. Positive washing, brushing or biopsy and/or 
residual tumor may still be evident on endoscopy and/or CT scan. No lesion may increase in size 
and no new lesion may appear. 
Progression (PD): At least a 20% increase in the sum of LD of target lesions taking as reference 
the smallest sum LD recorded since the treatment started or the appearance of one or more new 
lesions. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum LD. 

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10.3 Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. 
Non-Complete Response (non CR): Persistence of one or more non-target lesions or/ and 
maintenance of tumor marker level above the normal limits. All lymph nodes must be non- 
pathological in size (< 10 mm short axis). 
Progression (PD): Appearance of one or more new lesions. Unequivocal progression of existing 
non-target lesions. (Although a clear progression of "non-target" lesions only is exceptional, in 
such circumstances, the opinion of the treating physician should prevail, and the progression status 
should be confirmed at a later time by the reference radiologist (or studychair). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as "symptomatic 
deterioration". Every effort should be made to document the objective progression even after 
discontinuation of treatment. All subjects with progression should be followed and assessed every 
3 months for survival. 
2. In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. 
10.4 Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. 
Note: Tumor lesions in a previously irradiated area are not optimally considered measurable 
disease. 

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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin nodules, 
palpable lymph nodes). In the case of skin lesions, documentation by color photography including 
a ruler to estimate the size of the lesion is recommended. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable. 
• 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. 
This applies to the chest, abdomen, and pelvis. Head & neck and extremities usually require 
specific protocols. 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should 
not be used to measure tumor lesions that are clinically not easily accessible. It is a possible 
alternative to clinical measurements of superficial palpable nodes, subcutaneous lesions, and 
thyroid nodules. US might also be useful to confirm the complete disappearance of superficial 
lesions usually assessed by clinical examination. 
10.5 Confirmatory Measurement/Duration of Response 
Confirmation: The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such studies that the responses are not confirmed. To be 
assigned a status of PR or CR changes in tumor measurements must be confirmed by repeat studies 
that should be performed 4 weeks after the criteria for response are first met. In the case of SD, 
follow-up measurements must have met the SD criteria at least once after study entry at a minimum 
interval of 8 weeks. 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented, taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectivelydocumented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
11 DATA REPORTING / REGULATORY CONSIDERATIONS 
 
11.1 Data Collection 

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The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, 
efficacy, and adverse event data for all enrolled patients. 
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system that 
is fully supported by the Weill-Cornell Medical Center CTSC. It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, 
reporting tools, and a full array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data manipulation and 
export procedures. REDCap is maintained on CTSC-owned servers that are backed up nightly 
and support encrypted (SSL-based) connections. Nationally, the software is developed, 
enhanced and supported through a multi-institutional consortium led by the Vanderbilt 
University CTSA. 
 
 
 
 
 
11.2 Regulatory Considerations 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator. Merck & Co., Inc. will have the opportunity to review and approve the changes 
prior to submission of these changes to the local IRB and distribution to participating sites. 
 
12 STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
The primary aim of this study is to demonstrate that the use of the experimental therapy (pembrolizumab + 
standard pre-operative chemotherapy and chemoradiation) is associated with an improvement in the major 
pathological response proportion from 30% (historical control) to approximately 47% with the use of the new 
regimen. With a sample size of 36 patients receiving the experimental therapy, a one-sided chi-square test will 
have 80% power to detect the difference between a major pathological response proportion of 30% (i.e., 
historical control) and an alternative hypothesis major pathological response proportion of 47% (new regimen), 
with a 0.10 one-sided significance level. As well, a sample size of 36 patients will allow a two-sided 95% 
confidence interval for the expected major pathological response proportion (47%) to be constructed to be 
within ± 16.3% of the observed major pathological response proportion. We anticipate that up to 15% of 
patients may not proceed to surgery, and will therefore enroll up to a total of 42. 
 
Primary Endpoint: The primary endpoint of the major pathological response proportion will be calculated, and 
a 95% confidence interval will be estimated via binomial proportions. The primary endpoint of major 
pathological response proportion will be compared to the historical major pathological response proportion by 
an exact one-sample chi-square test. Patients will be considered evaluable for the primary endpoint if they 
undergo resection of their primary tumor, or if they are found to have disease progression prior to resection. 

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12.2 
Sample Size/Accrual 
The sample size is 42 patients. 
 
12.3 
Stratification Factors 
There are no stratification factors for the primary endpoint. The randomization is performed primarily for 
the correlative studies to evaluate the impact of pembrolizumab on the immune infiltration following 
chemotherapy. Stratified and blocked randomization will be performed at all participating sites. 
Randomization will be stratified by location of cancer (i.e., gastro-esophageal junction vs. esophagus) and 
participating site. A series of randomized blocks of 2 will be generated for each cancer location stratum 
within each participating site with a 1:1 allocation ratio. This will provide assurance that after four patients 
are enrolled in any given cancer location stratum at a participating site, there will be two patients assigned 
to receive pembrolizumab prior to chemotherapy and two patients assigned to receive pembrolizumab 
following chemotherapy. This procedure will allow for each cancer location stratum within a participating 
site to contribute similar numbers of pre-chemotherapy pembrolizumab patients and post-chemotherapy 
pembrolizumab patients. 
 
12.4 
Analysis of Secondary Endpoints 
Secondary Clinical Endpoints: Disease-free and overall survival (DFS) will also be estimated using the 
Kaplan-Meier method, and 95% confidence intervals for DFS estimates will be calculated using 
Greenwood’s formula. Median DFS will also be estimated along with a 95% confidence interval. 
 
23 patients will be randomly assigned to receive pembrolizumab prior to or following chemotherapy in 
the induction period. Only a descriptive (non-inferential) comparison will be made between the twoarms 
in this cohort (i.e. pembrolizumab prior to chemotherapy vs. following chemotherapy). Endpoints to be 
descriptively compared include pathologic complete response rate and the character and extent of immune 
infiltration in the biopsy specimen following induction chemotherapy, and the resection specimen 
following chemoradiation. Ninety-five percent confidence intervals for differences in outcome 
proportions between the two sub-arms will be calculated to assess the precision of the obtained estimates. 
 
Correlative endpoints: Descriptive statistics (including mean, standard deviation, median, range, 
frequency, and percent) will be calculated to 1) evaluate the prevalence of specific immune related gene- 
expression signatures among pembrolizumab-treated patients with improved clinical outcomes, 2) 
evaluate the prevalence of PD-L1 expression in chemotherapy and/or radiation-treated patients, and 3) 
evaluate the prevalence of tumor infiltration by CD8+ lymphocytes in pembrolizumab-treated patients. 
All correlative endpoints will include an associated 95% confidence interval to assess the precision of the 
obtained estimates. 
 
All analyses will be performed in SAS Version 9.4 (SAS Institute, Inc., Cary, North Carolina) and STATA 
Version 14.0 (StataCorp, College Station, Texas). 
. 
12.5 Reporting and Exclusions 

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12.5.1 Evaluation of toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with Investigational Agent. 
 
12.5.2 Evaluation of response. All patients included in the study will be assessed for response 
to treatment if they have completed chemoradiation therapy. A separate analysis will 
be performed for patients who are able to complete chemoradiation therapy and 
undergo resection. 
 
Approximately 5-10% of patients are unable to proceed with surgery due to known toxicity of 
chemoradiation. If greater than 25% of the first 20 enrolled patients in the study are unable to proceed to 
resection (i.e., > 5 patients out of the first 20 enrolled patients, regardless of study arm), the study will be 
stopped due to excessive toxicity. This rule does not require that 20 patients be enrolled before we assess 
the toxicity proportion. If at any point up to the enrollment of the 20th patient, 6 patients have been 
determined not to be able to proceed to resection, the study will be stopped due to excessive toxicity. 
 
 
13 Data and Safety Monitoring Plan (DSMP) 
This study will utilize the Weill Cornell Medical College (WCMC) Institutional Data Safety 
Monitoring Board (DSMB) and follow its policies and procedures for monitoring this study for 
safety concerns, with ongoing updates from the Study Chair on an ongoing basis. The interim 
analysis will be performed by the DSMB and the decision to proceed or stop the trial will be 
provided to the Study Chair. 
 
The Weill Cornell DSMB is comprised of medical specialists and advisors on human rights 
issues in human subjects research. The DSMB currently has 9 members, meets at quarterly 
intervals during the year, and carries out ongoing review of protocols submitted throughout the 
year. Once a protocol has been submitted and approved by the Institutional Review Board 
(IRB) and is recommended for oversight by the DSMB, the Board determines if the protocol 
will be reviewed quarterly, semi-annually, or annually. 
The DSMB evaluates the accumulated data from the study in order to monitor the safety of 
subjects throughout the trial and reviews the risks and benefits, as well as the efficacy, of the 
study. The DSMB will also evaluate the overall trial conduct and progress. Ultimately, the 
DSMB validates the continuation of the trial or determines if a study needs modification or 
termination. 
Reports to the DSMB will include the following items for review: 
1. Completed DSMB Periodic Review Form. 
2. Synopsis of the study to date. 
3. IRB approved consent form. 
4. IRB current protocol. 
5. Summary table of study results. 
6. Adverse event table. 

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7. Data safety monitoring plan. 
Safety monitoring is carried out to ensure and maintain the scientific integrity of human subject 
research projects and to protect the safety of human subjects. Safety monitoring can be viewed 
as any process during a clinical trial that involves the review of accumulated outcome data for 
groups of patient-subjects to determine if any of the treatment procedures practiced should be 
altered or stopped. NIH Guidelines (1998, 2000) specify that all clinical trials should have a 
system in place for appropriate oversight and monitoring to ensure the safety of participants 
and the validity of the data. 
 
Monitoring activities will be commensurate with the nature, size, and complexity of the trial 
in accordance with institutional policies and will be determined after IRB and DSMB review 
of the protocol immediately prior to study activation. For a small, single-center study, the 
monitoring is usually performed by a statistician in conjunction with a Safety Officer. For those 
single-site, high risk trials, a DSMB may be appropriate. For larger, single or multi-site studies, 
the monitoring is usually performed by a committee, often called a Data Safety Monitoring 
Board (DSMB). Ongoing review of the data by an independent individual or committee assures 
the investigators, the IRB, the study’s sponsor, and the funding agency that the trial can 
continue without jeopardizing subjects’ safety. 
Weill Cornell Medical College requires that all research approved by the WCMC IRB include 
an appropriate plan for the monitoring of data to ensure the safety of human subjects. Research 
supported by Federal agencies will be monitored according to all regulations and guidelines of 
the relevant Federal agency. 
 
13.1 DSMB Reporting 
Reports will be made to the DSMB at the following timepoints: 
• After the first 5 patients are treated 
• After the first 23 patients are treated 
• Semi-annual basis from then on 

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Wu X, Feng QM, Wang Y, Shi J, Ge HL, Di W. The immunologi aspets in advanced ovarian 
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