A Single-arm Phase II Study of Chemoradiotherapy Plus Pembrolizumab as Adjuvant Therapy for Locally Advanced Esophageal Squamous Cell Carcinoma Patients at High Risk of Recurrence Following Preoperative Chemoradiotherapy Plus Surgery
Phase: PHASE2
Conditions: Esophageal Squamous Cell Carcinoma
Sponsor: National Taiwan University Hospital

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TITLE: A single-arm phase II study of chemoradiotherapy plus 
pembrolizumab as adjuvant therapy for locally advanced esophageal 
squamous cell carcinoma patients at high risk of recurrence following 
preoperative chemoradiotherapy plus surgery  
 
 
 
Principal Investigator: 
 
Chih-Hung Hsu  
M.D., Ph.D. 
Department of Oncology, National Taiwan University Hospital  
7 Chung-Shan South Road, Taipei, TAIWAN, 100 
Tel: 02-23123456 ext.  67680 
Fax: 02-23711174 
E-mail: chihhunghsu@ntu.edu.tw 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co-Investigators: 
 

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Division of Medical Oncology:  
 
 
Chia-Chi Lin 
M.D., Ph.D. 
 
             
Ta-Chen Huang             
M.D.          
 
 
Jhe-Cyuan Guo         
M.D.          
 
                     Hung-Yang Kuo                       M.D.                  
 
Tsung-Hao Liu 
M.D. 
 
 
 
Division of Radiation Oncology: 
 
Jason, Chia-Hsien, Cheng 
M.D., Ph.D. 
 
             
Feng-Ming Hsu             
M.D., Ph.D.       
 
 
Division of Chest Surgery: 
 
Jang-Ming Lee 
M.D., Ph.D. 
 
 
Pei-Ming Huang 
M.D., Ph.D. 
 
 
 
Department of Pathology: 
 
Min-Shu Hsieh 
M.D. 
 
 
 
Department of Internal Medicine: 
 
Hsiu-Po Wang 
M.D. 
 
 
 
 
 

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1.0 TRIAL SUMMARY 
2.0 TRIAL DESIGN 
3.0 OBJECTIVES & HYPOTHESES 
4.0 BACKGROUND & RATIONALE 
5.0 METHODOLOGY 
6.0 TRIAL FLOW CHART 
7.0 TRIAL PROCEDURES 
8.0 STATISTICAL ANALYSIS PLAN 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
11.0 APPENDICES 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Adjuvant 
cisplatin-chemoradiotherapy 
(CRT) 
followed 
by 
pembrolizumab in esophageal squamous cell carcinoma (ESCC) after 
preoperative CRT and surgery 
Trial Phase 
II 
Clinical Indication 
Locally 
advanced 
ESCC 
patients 
receiving 
preoperative 
chemoradiotherapy at high risk of recurrence (closed or involved 
resection margin or extranodal invasion of involved lymph nodes or 
ypN2-3) 
Trial Type 
Interventional 
Type of control 
N/A 
Route of administration 
Intravenous (IV) 
Trial Blinding 
Unblind 
Treatment Groups  
Cisplatin-CRT followed by Pembrolizumab 
Number of trial subjects 
Approximately 26 subjects will be enrolled 
Estimated enrollment period 
24 months 
Estimated duration of trial 
The trial will require approximately 60 months from the time the first 
subject signs the informed consent until the last subject’s last study-
related phone call or visit. 
Duration of Participation 
• 
Subjects need to sign the informed consent form to be enrolled into 
this trial.  
• 
After a screening phase up to 28 days, each subject will receive 
adjuvant weekly cisplatin –CRT (cisplatin, 30mg/m2/week x 2; 
radiotherapy, 180-200 cGy/fraction x 10-13) followed by 
pembrolizumab (200mg/3 weeks x 18) (approx. a total of 56 
weeks).  
• 
Treatment will continue until the completion of the planned 
cisplatin-CRT plus 18 cycles of pembrolizumab, or until recurrent 
disease, unacceptable adverse events, intercurrent illness that 
prevents further administration of treatment, investigator’s 
decision to withdraw the subject, subject withdrawal of consent, 
pregnancy of the subject, noncompliance with trial treatment, or 
administrative reasons requiring cessation of treatment.  
• 
To detect the tumor recurrence, all patients will be evaluated by 
pertinent evaluation and imaging studies every 4 cycles of 
pembrolizumab during treatment phase, then every 3 months for 
post-treatment year-1 to year-2, and every 6 months for post-
treatment year-3 and year-4.  
• 
Subjects who discontinue for reasons other than recurrent disease 
will have post-treatment follow-up visits for monitoring disease 
status as if they were still on treatment until recurrent disease, 
initiating a non-study cancer treatment, withdrawing consent from 
study participation, or becoming lost to follow-up.  
• 
All subjects will be followed (e.g., by telephone or visit) for 
overall survival until death, withdrawal of consent from study 
participation, or the end of the study, whichever comes first. After 
the end of study treatment, each subject will be followed for 30 
days for adverse event monitoring. Serious adverse events will be 

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collected for 90 days after the end of treatment or for 30 days after 
the end of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. 
Estimated average length of 
treatment per patient 
56 weeks 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
It is a single-arm phase II trial. The target population is patients with histologically diagnosed 
locally advanced ESCC patients (clinically staged at least T3 and/or any N and M0 by 
endoscopic ultrasonography [EUS] and fludeoxyglucose-positron emission tomography 
[FDG-PET]) who have received preoperative cisplatin-based chemoradiotherapy (CRT) 
followed by surgery, and exhibit high risk of tumor recurrence. Eligible patients will receive 
adjuvant cisplatin-based CRT followed by pembrolizumab for 18 cycles. 
The study hypothesizes that adjuvant cisplatin-based CRT followed by pembrolizumab will 
improve the 1-year relapse-free survival rate for these high-risk ESCC patients from 32% to 
60%.  With the two-sided type 1 error probability of 0.05 and type 2 error probability of 0.2, 
the study needs to enroll a total of 26 patients, taking another 10% of dropout rate.  The 
duration of patient accrual is expected as 24 months.  To detect the mature overall survival 
data, additional follow-up period of 36 months is needed. 
 

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2.2 
Trial Diagram 
 

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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
In locally advanced ESCC patients who have high risk of recurrence following preoperative 
CRT and esophagectomy, the study will explore the efficacy of adjuvant pembrolizumab in 
improving their outcomes. 
(1) Objective:   
a. To improve the 1-year relapse-free survival (RFS) rate, compared with historical 
control. 
(2) Hypothesis:   
a. The addition of pembrolizumab to adjuvant cisplatin- CRT would reduce the 
recurrent rate of locally advanced ESCC patients who have high risk of recurrence 
following preoperative CRT and esophagectomy. 
 
3.2 
Secondary Objective(s) & Hypothesis(es) 
The study will also explore other efficacy endpoints and safety of adjuvant pembrolizumab in 
locally advanced ESCC patients who have high risk of recurrence following preoperative 
CRT and esophagectomy. 
(1) Objective:  
a. To improve the median RFS, compared with historical control. 
b. To improve the 3-year RFS rate, compared with historical control 
c. To improve the 3-year overall survival (OS) rate, compared with historical control.  
d. To improve the median OS, compared with historical control. 
e. To determine the toxicity and safety. 
 
(2) Hypothesis:   
a. In addition to improving the 1-year RFS rate, the addition of pembrolizumab to 
adjuvant cisplatin- CRT would improve median RFS in locally advanced ESCC 
patients who have high risk of recurrence following preoperative CRT and 
esophagectomy. 
b. In addition to improving the 1-year RFS rate and the median RFS, the addition of 
pembrolizumab to adjuvant cisplatin- CRT would also improve the 3-yar RFS rate 
in locally advanced ESCC patients who have high risk of recurrence following 
preoperative CRT and esophagectomy. 

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c. The addition of pembrolizumab to adjuvant cisplatin- CRT would improve the OS, 
through reducing the recurrence rates, of locally advanced ESCC patients who have 
high risk of recurrence following preoperative CRT and esophagectomy. 
d. In addition to improving 3-year OS rate, the addition of pembrolizumab to adjuvant 
cisplatin- CRT would also improve the median OS in locally advanced ESCC 
patients who have high risk of recurrence following preoperative CRT and 
esophagectomy. 
e. The addition of pembrolizumab to adjuvant cisplatin- CRT is safe and does not result 
in significant toxicities in locally advanced ESCC patients who have high risk of 
recurrence following preoperative CRT and esophagectomy. 
 
3.3 
Exploratory Objective 
The study will also explore potential biomarkers in predicting the outcomes of locally 
advanced ESCC patients who have high risk of recurrence following preoperative CRT and 
esophagectomy, and are treated with adjuvant cisplatin-CRT and pembrolizumab. 
(1) 
Objective:  
a. To explore the ESCC tissue-based biomarkers associated with tumor recurrence. 
b. To explore the blood-based biomarkers associated with tumor recurrence 
(2) 
Hypothesis: 
a. Certain immune biomarkers in tumor microenvironment of esophagectomy tissues 
following preoperative CRT would associate with the outcomes of locally advanced 
ESCC patients following preoperative CRT and esophagectomy at high risk of 
recurrence.  These tissue-based biomarkers can be explored as prognostic or 
predictive biomarkers for locally advanced ESCC patients in the future. 
• 
Immunohistochemistry (IHC) of PD-L1 expression in tumor cells and in 
tumor-infiltrating immune cells. IHC for different lineages of tumor-
infiltrating immune cells (phenotype), including activated CD8+ T cells, 
regulatory T cells, natural killer cells, suppressor CD4+ T cells, tumor-
associated macrophages and myeloid derived suppressor cells.   
• 
Immune related gene expression profile (GEP) by NanoString technology  
• 
Immune repertoire of tumor (deep sequencing for CDR3 region of T-cell 
receptor [TCR]). 
• 
Mutation analysis of tumor (targeted genes sequencing or whole exome 
sequencing [WES]) 
b. Certain biomarkers in peripheral blood wound associate with the outcomes of locally 
advanced ESCC patients following preoperative CRT and esophagectomy at high 
risk of recurrence. These blood-based biomarkers can be explored as prognostic or 
predictive biomarkers for locally advanced ESCC patients in the future.  

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• 
Critical cytokines (such as interleukin (IL)-2, IL-6, IL-8, IL-9, IL-10, IL-17, IL-
21, interferon-gamma, transforming growth factor-beta, etc).  
• 
PD-L1 (enzyme-linked immunoassay for PD-L1 in serum). 
• 
Immune repertoire of peripheral blood (deep sequencing for CDR3 region of 
TCR) for correlation with tumor part. 
• 
Circulating cell-free DNA (targeted sequencing of genomic alterations of interest) 
for correlation with the mutation analysis of tumor. 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 

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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 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Esophageal cancer is a significant malignant disease worldwide. In 2012, more than 450,000 
patients were diagnosed with esophageal cancer and more than 400,000 patients died of 
esophageal cancer worldwide [1]. Esophageal cancer is an even more significant cancer type 
in Asia than other parts of the world because more than 80% of esophageal cancer patients 
are diagnosed from Asian countries. Squamous cell carcinoma (SCC) is the predominant 
histology, and accounts for >90% of esophageal cancer diagnosed in Asian countries [1,2]. In 
Taiwan, there were 2,372 newly diagnosed esophageal cancer patients in 2012 and the 
number is increasing; among them, more than 90% were squamous cell carcinoma in 
histology [3].  
Multimodality therapy for locoregional esophageal cancer 
Locoregional esophageal cancer is a potentially curable disease. In the past, patients with 
locoregional esophageal cancer were typically treated with either surgery or definitive 
chemoradiotherapy (CRT); however, only 15% to 25% of them experience long-term, 
disease-free survival [4–6]. Since 1990s, multimodality therapy has been actively 
investigated in esophageal cancer. Among different strategies to combine various types of 

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treatment modality, preoperative CRT followed by surgery has been most investigated by 
multiple randomized control trials. A meta-analysis compiling 12 randomized trials, the 
majority of which used cisplatin/5-FU-based CRT, found that the survival effect of 
preoperative CRT for resectable esophageal cancer showed the pooled hazard ratio (HR) was 
0.78 (95% CI 0·70 –0·88) , corresponding to an absolute survival benefit at 2 years of 8.7% 
[7].  
The most convincing data favoring preoperative CRT for locoregional esophageal cancer 
thus far is disclosed in the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery 
Study (CROSS). The trial randomized 368 patients with resectable esophageal and esophago-
gastric junctional (EGJ) cancer for the treatment of preoperative paclitaxel and carboplatin-
CRT or surgery alone. The data demonstrated an unequivocal survival benefit of preoperative 
CRT in locoregional esophageal cancer and EGJ cancer: median survivals were 49.4 months 
in the preoperative CRT group and 24.0 months in the surgery alone (HR, 0.657; 95% CI, 
0.495 to 0.871; P = 0.003) [8]. The survival benefit of preoperative CRT holds true in both 
SCC and adenocarcinoma subtypes.  
Preoperative CRT followed by surgery has thus become one of the standard-of-cares for 
loco-regional esophageal cancer in many centers around the world including our center, the 
National Taiwan University Hospital, Taipei, Taiwan. Between 2000 and 2012, we 
conducted three prospective phase II clinical studies investigating paclitaxel and cisplatin-
based regimen as preoperative CRT in patients with locally advanced esophageal cancer at 
National Taiwan University Hospital, Taipei, Taiwan [9–11]. The pooled analysis of 140 
locally advanced ESCC patients enrolled in the 3 phase II trials showed that the median 
overall survival of them was 30.9 months (95% CI 21.4–40.4) and the 3-year-OS rate of them 
was 45.6% (95% CI 37.2–54.0) [12].  
Overall, after intensive multimodality therapy such as preoperative CRT plus surgery, 40 to 
50% of patients diagnosed with locally advanced esophageal cancer can enjoy long-term 
disease-free. On the other hand, the rest 50-60% of the locally advanced esophageal cancer 
patients would succumbed to recurrence and metastasis of esophageal cancer.  
Prognostic factors for locoregional ESCC patents treated with preoperative CRT 
Several poor prognostic factors have been identified for patients with esophageal cancer 
receiving definitive locoregional therapy. Closed or involved resection margin (R1 resection) 
has been recognized as a poor prognostic factor for patients with ESCC received preoperative 
CRT followed by surgery [13,14]. Most treatment guidelines, including the National 
Comprehensive Cancer Network guidelines, suggest adjuvant radiotherapy for esophageal 
cancer patients having R1 resection following esophagectomy [15]. 
Lymph node metastasis identified in post-CRT surgical specimens has also been identified as 
a poor prognostic factor for locoregional cancer patients receiving preoperative CRT [16–18]. 
Our own analysis based on 140 ESCC patients receiving preoperative CRT also found that 
lymph node metastasis, especially ypN2-3, in post-CRT pathological staging was associated 
with inferior progression-free survival (PFS) and OS [12]. Further, we identified that 
extranodal invasion (ENI) of involved lymph nodes is an independent prognostic factor 

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associating with inferior PFS [12], a finding corroborating other reports of esophageal cancer 
patients who receive surgery alone [19,20].  
Overall, these observations in ESCC are in line with those in head and neck squamous cell 
carcinoma (HNSCC), a disease which shares very similar risk factors with ESCC. The 
close/involved resection margin and ENI have been recognized as the most significant 
prognostic factors for HNSCC. Hence, HNSCC patients with these poor prognostic factors 
are now routinely treated with postoperative CRT [21,22].  
Based on the afore-mentioned data, the local guidelines at our center thus recommend 
adjuvant CRT for locoregional esophageal cancer patients who have either close/involved 
margin or ENI of involved lymph nodes following preoperative CRT plus surgery.  
Nevertheless, our recent analysis indicated that despite of adjuvant CRT, the prognosis of 
these patients with high risk of recurrence, i.e., involved margin, positive LN with ENI, and 
ypN2-3, remains very poor.  Their median recurrence-free survival (RFS) was 6.7 months 
and their 1-year RFS rate was 32.3% (subgroup analysis for [12]).  
Immune checkpoint blockade holds promise as a promising therapy for ESCC  
Recently, blockade of immune checkpoints, including cytotoxic T lymphocyte antigen 4 
(CTLA-4) and PD-1/PD-L1, has demonstrated promising clinical activities in multiple cancer 
types. The clinical activity against multiple cancer types have been generally moderate, with 
objective tumor response rates in the range of 15~ 30%. Mutational load and neoantigen have 
been identified as one of the potential biomarkers for immune checkpoints blockade [23,24]. 
With the advance of sequencing techniques, large-scale genomic sequencing in increasing 
number of patients has been conducted in multiple cancer types, including ESCC. The 
mutational load of ESCC is more than median in many cancer types [25–29]. 
The expression of PD-L1/PD-L2, another one potential biomarker for PD-1/PD-L1 blockade, 
was found in 42% and 48%, respectively of ESCC tumors [30]. Intratumoral abundance of 
CD4 and CD8 T cells has also been reported as a prognostic factor in ESCC patients [31]. 
The preliminary anti-tumor activity of PD-1/PD-L1 immune checkpoint blockers as a single 
agent in advanced esophageal cancer patients who have progressed on standard systemic 
chemotherapy has been recently reported. The objective tumor response of pembrolizumab in 
ESCC patients with positive PD-L1 expression was 29% [32]. Another study using another 
anti-PD-1 monoclonal antibody in a group of ESCC patients (N = 65) reported a response 
rate of 16% [33].  
Potential synergism in antitumor effect of immune checkpoint blockade and CRT  
Synergism between chemotherapeutic agents and PD-1/PD-L1 immune checkpoint blockers 
was reported in preclinical models of various cancers.  Recently, the “abscopal effect”, which 
refers to a rare phenomenon of tumor regression at a site distant from the primary site of 
radiotherapy, was reported in patients treated with radiotherapy and immune-checkpoint 
inhibitors [34–36]. 
Collectively, the combination of PD-1/PD-L1 immune checkpoint inhibitor with CRT, which 
is of strong rationales to be highly synergistic in antitumor effects, is a potential strategy to 

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improve the outcome of locally advanced ESCC patients following preoperative CRT plus 
surgery at high risk of recurrence. 
 
4.2.2 Rationale for Dose Selection/Regimen of adjuvant CRT 
The dose of adjuvant radiotherapy will be 18-26 Gy given in 10-13 fractions dependent on 
the dose of preoperative radiotherapy.  The study will enroll subjects who have been treated 
with preoperative CRT with radiation dose of 40-45 Gy given in 20-25 fractions per our 
institutional treatment standards.  As a result, this radiation dose has been selected to assure 
that cumulated radiation dose at the loco-regional area not exceeding 66Gy, a dose range 
which is generally accepted as a safe and definitive RT for locoregional esophageal cancer.   
The chemotherapy to be administered is weekly cisplatin (30 mg/m2) given concurrently with 
radiation.  The rationales of using weekly cisplatin include: (1) cisplatin-based CRT has been 
established as a standard postoperative adjuvant therapy for patients with high-risk head and 
neck squamous cell carcinoma (HNSCC) [37-39], a disease that shares very similar risk 
factors and genetic alterations with ESCC; (2) although high-dose (100 mg/m2), once-every-
3-weeks cisplatin-CRT is the standard approach, it results in severe acute toxicity in more 
than three quarters of HNSCC patients; (3) weekly cisplatin at the dose of 30 to 40 mg/m2 
has been widely accepted as general clinical practice due to multiple advantages including 
easy administration, lesser requirement of supportive care, and lower toxicity [40]; (4) ESCC 
patients who have been treated with preoperative CRT followed by radical surgery are 
generally fragile and not fit for intensive chemotherapy such as high-dose once-every-3-
weeks cisplatin. 
4.2.3 Rationale for Dose Selection/Regimen/Modification 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.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity.  Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and 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.   
 

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A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
 
4.2.4 Rationale for Endpoints 
4.2.4.1 Efficacy Endpoints 
1. The primary endpoint is the 1-year RFS rate. 
2. The secondary endpoints include median RFS, 3-year OS rate, median OS time, 3-year 
RFS rate, safety and toxicity. 

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4.2.4.2 Biomarker Research 
1. Tumor tissue part:  
a. Pre-treatment tumor tissue (i.e., esophagectomy tissue following preoperative 
cisplatin-based CRT) is mandatory for biomarker study accompanying with the 
clinical trial. The biomarker study will evaluate the following immune biomarkers 
in tumor microenvironment:  
• 
IHC of PD-L1 expression in tumor cells and in tumor-infiltrating immune 
cells. IHC for different lineages of tumor-infiltrating immune cells 
(phenotype), including activated CD8+ T cells, regulatory T cells, natural 
killer cells, suppressor CD4+ T cells, tumor-associated macrophages and 
myeloid derived suppressor cells.   
• 
Immune related GEP by NanoString technology  
• 
Immune repertoire of tumor (deep sequencing for CDR3 region of TCR) 
• 
Mutation analysis of tumor (targeted genes sequencing or WES) 
b. The potential biomarkers will be correlated with patients’ RFS and OS. 
c. If recurrent disease is noted, the recurrent tumor tissues will be procured for 
biomarker study in comparison with the corresponding pre-treatment tumor tissues 
(optional). 
2. Peripheral blood part:  
a. Blood sample collection is optional for biomarker study accompanying with the 
clinical trial. The biomarker study will evaluate the following immune biomarkers 
in peripheral blood: 
• 
Critical cytokines (such as IL-2, IL-6, IL-8, IL-9, IL-10, IL-17, IL-21, 
interferon-gamma, transforming growth factor-beta, et al).  
• 
PD-L1 (enzyme-linked immunoassay for PD-L1 in serum). 
• 
Immune repertoire of peripheral blood (deep sequencing for CDR3 region of 
TCR) for correlation with tumor part. 
• 
Circulating cell-free DNA (targeted sequencing of genomic alterations of 
interest) for correlation with the mutation analysis of tumor. 
b. The potential biomarkers in peripheral blood will be correlated with patients’ RFS 
and OS.  
 

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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
1. Histologically proven squamous cell carcinoma of esophagus. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  20 years of age on day of signing informed consent. 
3. Be a diagnosed by pathology or cytology with a locally advanced ESCC, which is 
clinically stage according to the TNM system of the American Joint Committee on 
Cancer (AJCC) Cancer Staging System (8th edition), fulfilling one of the following 
criteria as 
determined by endoscopic ultrasound, computed tomography, 
bronchoscopy and positron emission tomography: 
a. 
T3, N0, M0;  
b. T4a, N0, M0;  
c. 
T1–4a, N1-3, M0. 
4. Have been treated with preoperative cisplatin-based CRT followed by esophagectomy 
with lymph node dissection for the locally advanced ESCC (defined by above 
criteria). 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Exhibit at least one risk factor of tumor recurrence in the post-CRT surgical tissues:  
a. 
Close (≤1mm) or involved margin;  
b. Residual tumor cells in lymph nodes with ENI. 
c. 
ypN2-3 
7. Demonstrate adequate organ function as defined in  
8. Table 1, all screening labs should be performed within 10 days of treatment initiation.   
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 

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Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL without transfusion or EPO dependency (within 7 
days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN 
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. 
 
9. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy[ test will 
be required.   
10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for 
the course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
11. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is diagnosed with adenocarcinoma of esophagus or gastroesophageal junction. 
2. Has synchronously diagnosed with a squamous cell carcinoma of aero-digestive way, 
other than esophageal cancer. 

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3. Has prior malignancy, except for: (a) adequately treated basal cell or squamous cell 
skin cancer; (b) in-situ cervical cancer; (c) previously diagnosed malignancy which 
have been adequately treated and shown no evidence of recurrence for more than 5 
years. 
 
4. 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. 
5. 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. 
 
6. Has a known history of active TB (Bacillus Tuberculosis) 
 
7. Hypersensitivity to pembrolizumab or any of its excipients. 
 
8. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
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.  
10. Has known history of, or any evidence of active, non-infectious pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 

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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. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Hepatitis B virus positive subjects (defined as HBsAg positive and/or detectable 
HBV DNA). 
- 
Participants who are HBsAg positive are eligible if they have received HBV 
antiviral therapy for at least 4 weeks and have undetectable HBV viral load 
prior to enrollment. 
- 
Participants should remain on anti-viral therapy throughout study intervention 
and follow local guidelines for HBV anti-viral therapy post completion of 
study intervention. 
18. Hepatitis C virus positive subjects (defined as anti-HCV Ab positive and detectable 
HCV RNA).  
- 
Participants with history of HCV infection are eligible if HCV viral load is 
undetectable at screening. 
- 
Participants must have completed curative anti-viral therapy at least 4 weeks 
prior to randomization.  
19. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV 
DNA) and active Hepatitis C virus (defined as anti-HCV Ab positive and detectable 
HCV RNA) infection.  
20. 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. 
21. Has received organ transplantation. 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2.  

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Table 2  Trial Treatment 
Drug or 
radiotherapy 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Cisplatin 
30 mg/m2 
QW 
IV infusion 
Day 1 of each week 
for 2 weeks, starting 
within 8 weeks after 
esophagectomy. 
Adjuvant CRT 
Radiotherapy 
180-200 cGy 
QD 
(Monday 
to Friday) 
 
Total 10-13 fractions 
Adjuvant CRT 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle for 18 
cycles, starting 
within 4 weeks after 
completing adjuvant 
cisplatin-CRT 
Experimental 
 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification (Escalation/Titration/Other) 
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 3 below. See Section 5.6 for 
supportive care guidelines, including use of corticosteroids. 
Table 3.1 Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/ 
Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 

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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
AST, ALT, or 
Increased 
Bilirubin 
2 
(AST/ALT
: 3-5 x 
upper limit 
of normal 
[ULN]; 
bilirubin: 
1.5-3 x 
ULN) 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Type 1 
diabetes 
mellitus (if 
new onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus or 
Grade 3-4 hyperglycemia 
associated with evidence of beta 
cell failure 
Resume pembrolizumab when patients are 
clinically and metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
Hyper-
thyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypo-
thyroidism 
 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
Therapy with pembrolizumab can be continued 
while thyroid replacement therapy is instituted 
Infusion 
Reaction 
2a 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops 
despite adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 or 
recurrent 
grade 2 
Permanently discontinue 
Permanently discontinue 
Renal Failure 
or Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Myocarditis 
3-4 
Permanently discontinue 
Permanently discontinue 
Skin or 
suspicious 
Steven-
Johnson 
syndrome 
(SJS) or toxic 
epidermal 
necrolysis 
(TEN) 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 

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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Skin 
4 
Permanently discontinue 
Permanently discontinue 
Confirmed 
SJS 
3-4 
Permanently discontinue 
Permanently discontinue 
Confirmed 
TEN 
4 
Permanently discontinue 
Permanently discontinue 
All Other 
Drug-Related 
Toxicityb 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
Persistent 2 or 3 except endocrine dysfunction 
under endocrine supplement with good control; 
toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day 
within 12 weeks 
Permanently discontinue 
Recurrent 
3 
Permanently discontinue 
Permanently discontinue 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a 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; 
Refer to Table 4– Infusion Treatment Guidelines for further management details. 
b Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of 
the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
Table 3.2 Dose Modification Guidelines for Cisplatin-CRT-Related Adverse Events 
Toxicities experienced  
at the day of starting a new cycle 
Recommended Cisplatin-CRT Protocol Treatment 
xRT 
Cisplatin(30 mg/m2/wk) 
When   
 
ANC <2,000 – 1,500//μl, or 
 
Platelet <100K – 75K//μl 
Continue 
30 mg/m2/wk 
When   
 
ANC <1,500 – 1,000//μl, or 
 
Platelet <75K – 50K//μl 
Continue 
25 mg/m2/wk 

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When   
 
ANC <1,000 – 500//μl, or 
 
Platelet <50K – 25K//μl 
Continue 
Hold 
When   
ANC <500/μl, or 
Platelet <25K/μl, or 
febrile neutropenia, or 
active infection, or  
other life-threatening 
conditions 
Hold 
Hold 
Serum creatinine >2 x ULN 
Continue 
Hold 
Persistent ≥ Gr. 3 toxicities, such as 
nausea or vomiting, despite of 
adequate supportive care 
Continue 
Hold 
 
5.2.2 Timing of Dose Administration  
5.2.2.1 Cisplatin-CRT:  
a. Cisplatin-CRT is to be started within 8-12 weeks after esophagectomy, when the 
patient recovers well from the operation.  
b. Cisplatin 30 mg/m2, IV infusion for 60~ 120 min, weekly, for 2 weeks. 
i. 
Sufficient hydration will be given at the discretion of the investigator.  
ii. 
Anti-emetics such as 5-HT3 antagonists, aprepitant, steroid, and 
metoclopramide will be given at the discretion of the investigator.  
c. Radiotherapy: (intensity modulated radiotherapy) 180-200 cGy/fraction, once daily, 5 
days a week, for a total of 10-13 fractions. 
i. 
Radiotherapy will be administered by megavoltage linear accelerators (≥ 6 
MV photon) using multiple fields (≥ 2) technique.  
ii. 
Planning CT (CT simulation) must be done for isodose distribution and 
evaluation of dose-volume histogram.  
iii. 
The target volumes of radiation should encompass the tumor volume (both 
primary esophageal tumor and metastatic lymphadenopathy) with adequate 
margins covering subclinical disease (including submucosal, mediastinal, 
and/or supraclavicular or celiac lymphatics) and treatment variability 
(including setup errors, breathing, and organ motion).  Gross tumor volume 
(GTV) is defined as the volume of all visible esophageal tumor and involved 
lymphadenopathy using all available imaging studies including CT scan, EUS, 
and 18F-FDG-PET scan.  The clinical target volume (CTV) is defined as the 

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GTV plus areas considered at significant risk of microscopic disease including 
a 0.5-1.0cm circumferential margin and 3-4 cm longitudinal margin. 
iv. 
Radiation will be delivered with intensity modulated radiotherapy technique, 
with a daily fraction size of 180-200 cGy, 5 days a week.  
 
5.2.2.2 Pembrolizumab:  
a. Pembrolizumab is to be started within 4 weeks after completing last dose of CRT, 
when the patient recovers well from the CRT.  
b. Pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0).  Trial treatment may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons. 
c. Pembrolizumab will be administered on an outpatient basis. 
d. Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 
weeks.  Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible.  However, given the variability of infusion pumps from site to 
site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 
minutes: -5 min/+10 min). 
e. The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.  
 
5.2.2.3 Visits during adjuvant therapy (also listed in 7.1.5.2):  
a. During the period of adjuvant cisplatin-CRT:  
i. 
The patient will be seen on a weekly basis until 2 weeks after completing CRT.  
ii. 
The patient will be evaluated for clinical symptoms and signs, hemogram, and 
biochemistry panel including bilirubin, AST, ALT, BUN, creatinine, Na, K, 
Ca, Mg, and other abnormalities found at screening check.     
b. During the period of adjuvant pembrolizumab therapy:  
i. 
The patient will be seen on a 3-weekly basis for a total of 54 weeks.  
ii. 
The patient will be evaluated for clinical symptoms and signs, hemogram, and 
biochemistry panels including bilirubin, AST, ALT, ALP, gamma-GT, LDH, 
albumin, BUN, creatinine, Na, Cl, K, Ca, Mg, glucose, and endocrine function 
(every 2 cycles) including TSH, T3, fT4, ACTH and cortisol.  
iii. 
Pregnancy Test – Urine or Serum beta-HCG (for woman only), coagulation 

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test with PT/INR and aPTT, and urinalysis will be checked every 2 cycles. 
 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Randomization or Treatment Allocation 
This is a single-arm study. 
5.4 
Stratification 
No stratification will be done 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
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. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic biological therapy not specified in this protocol 
• Immunotherapy not specified in this protocol 

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• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy not specified in this protocol 
• 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 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, 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 does 
not need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• 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. 

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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, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, 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 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, 

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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 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
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. 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   

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Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 

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• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 

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5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease recurrence 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects 
who discontinue for reasons other than recurrent disease will have post-treatment follow-up 
for disease status until disease recurrence, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease recurrence 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.9 
Subject Replacement Strategy 
No subject replacement strategy will be arranged. 

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5.10 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 

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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Adjuvant Cisplatin-
CRT 
Pembrolizumab 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
 
 
To be repeated beyond 4 cycles 
Discon 
Safety 
Follow-up 
Year-1  
&  
Year-2 
 
Year-3  
& 
Year-4 
1 
2 
1 
2 
3 
4 
Scheduling Window (Days): 
 
-28 to -1 
± 3 
± 3 
 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 3 
months  
 
 
Every 6 
months 
Pre-screening Consent 
V 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
V 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
V 
V 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
V 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
V 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administrationa 
 
 
V 
V 
V 
V 
V 
V 
 
 
 
 
Survival Statusb 
 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Review Adverse Eventsc 
 
 
 
V 
V 
V 
V 
V 
V 
V 
 
 
Full Physical Examination 
 
V 
 
 
V 
 
 
 
V 
V 
V 
V 
Directed Physical Examination 
 
 
V 
V 
 
V 
V 
V 
 
 
 
 
Vital Signs and Weight 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
ECOG Performance Status 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Pregnancy Test – Urine or Serum -HCG 
 
V 
 
 
V 
 
V 
 
V 
 
 
 
PT/INR and aPTT 
 
V 
 
 
V 
 
V 
 
V 
V 
 
 
CBC with Differential 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Comprehensive Serum Chemistry Paneld 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Urinalysis 
 
V 
 
 
V 
 
V 
 
V 
V 
 
 

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Trial Period: 
Screening Phase 
Adjuvant Cisplatin-
CRT 
Pembrolizumab 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
 
 
To be repeated beyond 4 cycles 
Discon 
Safety 
Follow-up 
Year-1  
&  
Year-2 
 
Year-3  
& 
Year-4 
1 
2 
1 
2 
3 
4 
Scheduling Window (Days): 
 
-28 to -1 
± 3 
± 3 
 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 3 
months  
 
 
Every 6 
months 
T3, FT4 and TSH 
 
V 
 
 
V 
 
V 
 
V 
V 
V 
V 
ACTH, Cortisol 
 
V 
 
 
V 
 
V 
 
V 
V 
V 
V 
Tumor Imaginge 
 
V 
 
 
 
 
 
V 
 
 
V 
V 
Archival or Newly Obtained Tissue 
Collectionf 
 
V 
 
 
V (optional) 
Correlative Studies Blood Collection 
(optional)g 
 
V 
 
V 
V (every 4 cycles and recurrence) 
 
V (Year-1 and 2: every 3 months 
until recurrence) 
aTrial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
bOnce a subject experiences confirmed disease recurrence or starts a new anti-cancer therapy, the subject moves into the survival follow-up phase and should be 
contacted by telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
cSAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. 
dCheck bilirubin, AST, ALT, BUN, creatinine, Na, K, Ca, Mg, and other abnormalities found at screening check during adjuvant cisplatin-CRT phase; check bilirubin, 
AST, ALT, ALP, gamma-GT, LDH, albumin, BUN, creatinine, Na, Cl, K, Ca, Mg, P, glucose during pembrolizumab phase and post-treatment Year-1 to Year-4. 
eTumor imaging includes CT scan with/without contrast (if renal function is acceptable) for neck, chest, abdomen and symptomatic regions and esophagoscopy. 
fTissue proof for recurrent lesion if feasible. 
gBlood samples for biomarker study. The collection will be performed until disease recurrence (last blood sample collection). 
 
 

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

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

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7.1.1.6 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to treatment allocation. Each subject will be 
assigned only one screening number.  Screening numbers must not be re-used for different 
subjects. Any subject who is screened multiple times will retain the original screening 
number assigned at the initial screening visit. 
7.1.1.7 Assignment of Treatment Number 
All eligible subjects will receive a treatment number. The treatment number identifies the 
subject for all procedures occurring after treatment allocation/randomization.  Once a 
treatment number is assigned to a subject, it can never be re-assigned to another subject. A 
single subject cannot be assigned more than 1 treatment number. 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between 
doses for non–drug-related or administrative reasons require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management. The total volume of study treatment infused will be compared to the 
total volume prepared to determine compliance with each dose administered. The instructions 
for preparing and administering study treatment are provided in the Pharmacy Manual.  
Administration of trial treatment will be witnessed by the investigator and/or trial staff or 
qualified designee per institutional guidelines and procedures. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  

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7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
The schedules of tumor imaging and assessment of tumor status are detailed in 7.1.5.4. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Please see 4.2.3.2 biomarker research about the detail for tumor tissue collection and 
correlative studies blood sampling. The time points about samples collection are summarized 
in 6.0 Study Flowchart. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   
 
 
 
 
 

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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Uric Acid 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
Calcium 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
Blood for correlative studies 
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
 
Blood Urea Nitrogen 
 
  
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.3.1 Blood Collection 
(1) On every occasion of collecting blood for exploratory biomarker research, 10 ml of blood 
will be collected through sodium citrate-containing tubes. 
(2) The blood samples will be sent to Lab for further processing within 30 minutes. 
(3) 10 ml blood for collection of plasma (in aliquots) and peripheral blood mononuclear cells 
(PBMCs) through Ficoll-Hypaque centrifugation. The PBMCs will be separated into two 
equal pellets: one to be freshly frozen; the other kept in RNAZol.  
The time points for blood sampling (Correlative Studies Blood Collection) are described in 
Section 6.0 – Trial Flow Chart.  
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.   
 
7.1.4.2 Blinding/Unblinding 
Not applicable.  
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 

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7.1.5.1 Screening 
Approximately 28 days prior to treatment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1. Screening procedures may 
be repeated.   
a. The candidate patient will be screened according to the 5.1 Entry Criteria.  
b. Laboratory tests performed according to Table 5 and Flow Chart 6.1.  
c. Tumor imaging performed according to Flow Chart 6.1. 
  
7.1.5.2 Treatment Period (also detailed in 6.1 Study Flow Chart):   
a. During the period of adjuvant cisplatin-CRT:  
i. 
The patient will be seen on a weekly basis until 2 weeks after completing CRT.  
ii. 
The patient will be evaluated for clinical symptoms and signs, hemogram, and 
biochemistry panel including bilirubin, AST, ALT, BUN, creatinine, Na, K, 
Ca, Mg, and other abnormalities found at screening check.    
b. During the period of adjuvant pembrolizumab therapy:  
i. 
The patient will be seen on a 3-weekly basis for a total of 54 weeks.  
ii. 
The patient will be evaluated for clinical symptoms and signs, hemogram, 
biochemistry panels including bilirubin, AST, ALT, ALP, gamma-GT, LDH, 
albumin, BUN, creatinine, Na, Cl, K, Ca, Mg, P, and glucose, and endocrine 
function (every 2 cycles) including TSH, T3, fT4, ACTH and cortisol.  
iii. 
Pregnancy Test – Urine or Serum beta-HCG (for woman only), coagulation 
test with PT/INR and aPTT, and urinalysis will be checked every 2 cycles. 
iv. 
Tumor imaging includes CT scan (of neck, chest, and abdomen) and 
esophagoscopy every 4 cycles of pembrolizumab. 
 
7.1.5.3 Post-Treatment Visits   
a. Safety Follow-UP Visit   
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment (pembrolizumab) or before the initiation of a new anti-cancer 
treatment, whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution 
of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever 

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occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a 
new anti-cancer treatment should also be followed and recorded.  Subjects who are eligible 
for retreatment with pembrolizumab (as described in Section 7.1.5.5) may have up to two 
safety follow-up visits, one after the Treatment Period and one after the Second Course 
Phase. 
 
7.1.5.4 Assessment of Tumor Status (also detailed in 6.1 Study Flow Chart):  
a. During the post-treatment year-1, and post-treatment year-2:  
i. 
Clinical evaluation, including physical examination;  
ii. 
Hemogram, and biochemistry panels including bilirubin, AST, ALT, ALP, 
gamma-GT, LDH, albumin, BUN, creatinine, Na, Cl, K, Ca, Mg, P, glucose, 
TSH, T3, fT4, ACTH and cortisol. 
iii. 
CT scan (of neck, chest, and abdomen) and esophagoscopy; 
iv. 
Repeated every 3 months. 
b. During the 4th and 5th years after esophagectomy (i.e., the post-treatment year-3, and 
post-treatment year-4):  
i. 
Clinical evaluation, including physical examination;  
ii. 
Hemogram, and biochemistry panels including bilirubin, AST, ALT, ALP, 
gamma-GT, LDH, albumin, BUN, creatinine, Na, Cl, K, Ca, Mg, P, TSH, T3, 
fT4, TSH, ACTH and cortisol.  
iii. 
CT scan (of neck, chest, and abdomen) and esophagoscopy; 
iv. 
Repeated every 6 months. 
 
7.1.5.5 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase. Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, 
death, end of the study or if the subject begins retreatment with pembrolizumab as detailed in 
Section 7.1.5.5.  Information regarding post-study anti-neoplastic treatment will be collected 
if new treatment is initiated. 
 
7.1.5.5.1 Survival Follow-up 
Once a subject experiences confirmed disease recurrence or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 

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every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 

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tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working day hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 

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Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event.  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any subject must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety if it causes the subject to 
be excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause whether or not related to the 
Merck product, must be reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 

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in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  

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7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 

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listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 

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

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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
The target sample size of this prospective, single-arm, phase 2 study is 26 patients. The 
estimated time for patient accrual is 2 years. It takes a minimum of additional 3 years to 
complete the follow up of the last accrued patient.  The total study period is planned to be 5 
years.   
The primary objective of the study is to improve the 1-year RFS rate for locally advanced 
ESCC patients who have received preoperative cisplatin-based CRT followed by surgery, 
and exhibit high risk of tumor recurrence.  The secondary objectives of the study included the 
median recurrence-free survival, overall survival and overall survival rate, and safety and 
toxicity. According to the subgroup analysis of our previous study [12], the median RFS for 
locally advanced ESCC patients who have received preoperative cisplatin-based CRT 
followed by surgery, and exhibit high risk of tumor recurrence (defined as closed or involved 
margin [≤ 1mm] or ENI or ypN2-3) is 6.7 months, equivalent to a 1-year RFS rate of 32.3%. 
 
8.2 
Statistical Analysis Plan 
8.2.1 Sample Size Determination 
According to the subgroup analysis of our previous study [12], the median RFS for locally 
advanced ESCC patients who have received preoperative cisplatin-based CRT followed by 
surgery, and exhibit high risk of tumor recurrence (defined as closed or involved margin [≤ 
1mm] or ENI or ypN2-3) is 6.7 months, equivalent to a 1-year RFS rate of 32.3%. It would 
need a sample size of 24 patients to detect a difference of the 1-year RFS rate from 32% to 
60% by calculated using an exact binomial test with a power of 80% and a 5% significance 
level. Having taken an additional 10% of early drop-out rate into consideration, the total 
enrolled patient number will be 26 for this study.  We estimate an enrollment rate of 12 
patients per year at my center.  Therefore, total study period will be 5 years, including 2 years 
of patient enrollment and 3 years of patient follow-up. 
 

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8.2.2 Definition of Variables 
8.2.2.1 Recurrence-free survival is the time from enrollment to disease recurrence or the last 
follow-up (censored). Recurrence is defined by suspicious lesion noted by tumor imaging 
according to RECIST 1.1. Tissue proof for suspicious lesion is recommended if it is feasible. 
8.2.2.2 Overall survival is the time from enrollment to death of any cause or the last follow-
up (censored). 
8.2.2.3 Evaluation of Toxicity: The incidence and severity of toxicity will be summarized 
according to the NCI Common Toxicity Criteria Version 4.0.  
 
8.2.3 General Statistical Consideration 
8.2.3.1 All statistical analyses will be performed for intent-to-treatment population.  
 
8.2.3.2 The survival estimates will be derived from Kaplan and Meier curves.  
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 

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9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 
Confidentiality of data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. 
10.2 
Compliance with Financial Disclosure Requirements 
Following the regulations of NTUH 

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10.3 
Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for  Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
10.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
10.5 
Quality Management System 
Following the regulations of NTUH 
10.6 
Data Management 
All available data will be displayed. Listings of patients with premature termination will be 
provided with the dates and reasons for termination. Missing data will not be replaced by any 
estimated or imputed values. 

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11.0 APPENDICES 
11.1 
ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
11.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
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15.  https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/ph
ysician_gls/pdf/esophageal.pdf 
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