Clinical trial NCT02844075
Conditions: Esophageal Squamous Cell Carcinoma
Keywords: Esophageal Squamous Cell Carcinoma pembrolizumab PD-1 neoadjuvant chemoradiation
Sponsor: Yonsei University
Start date: 2017-01-01; Completion date: 2021-04-26
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this study, participants with esophageal squamous cell carcinoma will receive preoperative chemoradiotherapy with paclitaxel,carboplatin and pembrolizumab then undergo surgery. The primary study hypothesis is that adding pembrolizumab will increase complete pathologic response rate at surgery.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: MK-3475(pembrolizumab)
Intervention descriptions: intervention 1: Neo-adjuvant chemoradiation period:The treatment consisted of taxol, carboplatin, pembrolizumab and radiation. The radiation treatment comprises 44.1Gy (2.1Gy/Fr, total 21Fr) and that will be about 5 weeks. Intensity modulated RT (IMRT) or 3D CRT (three-dimensional conformal radiotherapy) will be allowed.

Surgery:Before surgery, abdomen/chest CT scan, endoscopic ultrasound (EUS), and gastroscopy with biopsy will be done. Surgery should be done within 12 weeks after last neo-adjuvant treatment.

Adjuvant period:Adjuvant treatment with pembrolizumab 200mg every 2week (maximum 2 years) should be performed within 8 weeks after surgery (recommended period : 3-6 weeks after surgery). Gastroscopy and abdomen/chest CT scan will be performed at 6 month after surgery.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
TITLE: A Phase II trial of Preoperative chemoradiotherapy and MK-3475 for 
Esophageal Squamous Cell Carcinoma 
 
 
Protocol version number: 1.06 
Protocol version date: 27Mar2018 
 
 
NCT number: 02844075 


 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
A Phase II trial of Preoperative chemoradiotherapy and MK-
3475 for Esophageal Squamous Cell Carcinoma 
Trial Phase 
Single arm phase II trial 
Clinical Indication 
Stage Ib-III esophageal squamous cell carcinoma 
Trial Type 
Interventional 
Type of control 
Single arm 
Route of administration 
IV 
Treatment Groups  
 
Number of trial subjects 
28 
Estimated enrollment period 
May 2016 –May 2018 
Estimated duration of trial 
May  2016 – May 2022 
Duration of Participation 
May 2016 – May 2022 
Estimated average length of 
treatment per patient 
1 year 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
Single arm phase II  
2.2 
Trial Diagram 
 
 


 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To evaluate antitumor efficacy of pembrolizumab in combination with 
chemoradiotherapy : pathologic complete response (pCR) rate 
Hypothesis: Pembrolizumab in combination with chemoradiotherapy is tolerable and 
synergistic for esophageal squamous cell carcinoma 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  
1) To evaluate antitumor efficacy  
• Disease free survival, overall survival, pathologic response rate, and clinical response 
2) Safety  
Hypothesis: Pembrolizumab in combination with chemoradiotherapy is tolerable and 
synergistic for esophageal squamous cell carcinoma 
3.3 
Exploratory Objective 
Objective:  
 
• 
To identify the potential immune dynamics after pembrolizumab using serial biopsied 
fresh tumor.  
•  To explore the predictive biomarkers of pembrolizumab using exome sequencing and 
RNA sequencing 
 
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 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  metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as 
determined by an FDA-approved test with disease progression on or after platinum-
containing chemotherapy and, if EGFR or ALK genomic tumor aberrations positive, 
should have disease progression on FDA-approved therapy for these aberrations prior to 
receiving KEYTRUDA. 


 
 
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 (EC) is the eighth most common cancer worldwide. It is a 
highly lethal disease, causing more than 400,000 deaths per year. Despite adequate 
preoperative staging, 25% of patients treated with primary surgery have microscopically 
positive resection margins (R1), and the 5-year survival rate rarely exceeds 40%. 
Therefore, neoadjuvant chemoradiotherapy has been studied for better oncologic outcome. 
The role of neoadjuvant chemoradiotherapy has been debated for several decades. 
Recent randomized, controlled, phase 3 study compared neoadjuvant chemoradiotherapy 
followed by surgery with surgery alone in patients with potentially curable esophageal or 
esophagogastricjunction carcinoma(1). Overall survival was significantly better in the 
chemoradiotherapy–surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 
0.871; P = 0.003). Median overall survival was 49.4 months in the chemoradiotherapy–
surgery group versus 24.0 months in the surgery group and adverse-event was acceptable. 
Especially, in the subgroup analysis, squamous cell histology demonstrated better trend 
with 
preoperative 
chemoradiotherapy 
(figure 
1). 
Therefore, 
preoperative 
chemoradiotherapy is safe and leads to a significant increase in overall survival for ESCC. 
 
Figure 1. Survival According to Treatment Group (ACC: adenocarcinoma SCC: 
squamous cell carcinoma) 
EC consists of two major histologic subtypes; esophageal squamous cell 
carcinoma (ESCC) and adenocarcinoma (EAC). Both histologic subtypes have different 
risk factors and epidemiology. ESCC continues to be the major subtype of EC in Asia, 
and the main risk factors include smoking and alcohol abuse. Given widely different 
epidemiological and clinical features, EAC and ESCC may represent distinct disease 
entities which may benefit from different therapeutic approaches. Therefore, further 
neoadjuvant clinical trial with homogenous ESCC cohort is strongly warranted. 


 
 
4.2.2 Rationale for the Chemoradiotherapy in Combination with Pembrolizumab 
Pembrolizumab (MK3475) is a humanized IgG4 monoclonal antibody to human 
programmed cell death-1 (PD-1). PD-1 is a receptor of the CD28 family, which is 
expressed on activated lymphocytes (T cells, B cells and NKT cells) and myeloid cells. 
PD-1 binds to PD-1 ligands (PD-L1 and PD-L2), which are expressed on antigen-
presenting cells, and transmits regulatory stimuli to lymphocytes to down-modulate the 
activation of lymphocytes. PD-1 ligand is also expressed in various human cancer tissues 
other than antigen presentation cells. Regarding the radiotherapy, irradiated tumor cells 
are known to release antigens that help immune system against tumor. Treatment with 
anti-PD-L1 antibodies also synergizes with radiation, and appears to exert benefit through 
reduction in the accumulation in irradiated tumor.(2, 3) In mice, inhibiting PD-L1 
restored both T cell function and tumor response to radiation therapy and anti-CTLA4, 
increase overall survival. PD-L1 on tumor cells is known as dominant resistance 
mechanism to radiation therapy. Therefore, combination treatment of pembrolizumab 
with chemoradiotherapy is ongoing for head/neck cancer, renal cell carcinoma, melanoma, 
and non-small cell lung cancer (NCT02318771) and pancreatic cancer (NCT02305186). 
Combining pembrolizumab with neoadjuvant chemoradiotherapy is a promising strategy 
to improve clinical outcome in ESCC. Using serial biopsied fresh tissue and the 
novel/high-throughput RNA sequencing technologies, we suggest a study to identify 
predictive biomarkers of pembrolizumab in ESCC patients with neoadjuvant 
chemoradiotherapy. 
4.2.3 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the 
safety and clinical activity of single agent MK-3475.  The dose escalation portion of this 
trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of MK-
3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been 
identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose 
and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial tumor 
activity.  Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days).  This early PK and pharmacodynamic data provides scientific 
rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 


 
 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between 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 
The primary endpoint of phase II study is to assess complete pathologic response rate. 
Definition of complete pathologic response is “no cancer cell, including lymph nodes” 
which corresponds with tumor regression score 0. Definition of pathologic response  is as 
follows. Tumor regression score Grade 0 and 1 will be defined as “responder” and 2 and 
3 will be considered as “non-responders” 
Tumor regression score * 
Ryan et al. description  
0 (Complete response) 
No cancer cell, including lymph nodes  


 
 
1 (Moderate response) 
Single cells or small groups of cancer cells  
2 (Minimal response)  
Residual cancer cells outgrown by fibrosis  
3 (Poor response)  
Minimum or no treatment effect: extensive residual cancer  
*NCCN 2015 
4.2.4.2 Biomarker Research 
1) Exome sequencing (tumor/normal pairs) of fresh-frozen tumor tissues at pre-treatment 
and at recurrence to identify potential immune epitope and mechanisms of acquired 
resistance. 
2) RNA sequencing or nanostring nCounter of fresh-frozen tumor tissues at pre-treatment, 
on-treatment and to identify potential immune-related gene signatures 
3) T cell function and phenotype analysis in tumor microenvironment [CD4/CD8+ T cell, 
FoxP3+ Treg cell, immune checkpoint expression (PD1,PDL1, LAG3, TIM3, CTLA4)]  
4) Analysis of immune marker using FACS  
-Examine the phenotypic characteristics of CD4 and CD8 T cells in terms of  various 
immune check points (PD-1, CTLA4, TIM3, LAG3) and memory markers in fresh tissue 
and PBMC by FACS on pre-treatment, after 3 weeks and post- treatment.  
-Examine the tumor infiltrating immune cells including Treg cells and MDSCs on pre-
treatment, after 3 weeks and post- treatment.  
-Blood cytokine analysis will be performed at the time points with multi cytokine bead 
analysis on pre-treatment, after 3 weeks and post- treatment.  
5) Analysis of T cell function using ex vivo stimulation  
-Stimulate T cell with Dynabeads Human T-activator CD3/CD28 in ex vivo and measure 
the IFN-r by ELISA. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Histologically confirmed stage T1N1-2 or T2-4aN0-2 (AJCC 7 TNM 
classification) esophageal squamous cell carcinoma (ESCC) 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Histologically confirmed ESCC 


 
 
2. Clinical stage T1N1-2 or T2-4aN0-2 (AJCC 7 TNM classification) 
3. No evidence of metastasis  
4. Be willing and able to provide written informed consent/assent for the trial. 
5. Be  20 years of age on day of signing informed consent. 
6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a 
tumor lesion through repeated biopsies.  Newly-obtained is defined as a specimen 
obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1.  
Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible 
or subject safety concern) may submit an archived specimen only upon agreement 
from the Sponsor. 
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in 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 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN 
 
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 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. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose 
of trial treatment. 
 
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion 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.   
7. Has another malignancy within the last 5 years. Exceptions include basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin that has undergone 
potentially curative surgery, or in situ cervical cancer. 


 
 
8. 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.  
9. Has known history of, or any evidence of active, non-infectious pneumonitis. 
10. Has an active infection requiring systemic therapy. 
11. 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.   
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
13. 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. 
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
17. 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. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. The treatment consisted 
of 3 phases – neo-adjuvant chemoradiotherapy, surgery, and post-operative adjuvant 
treatment. 
Table 2  Trial Treatment 
 
Neo-adjuvant chemoradiation 
(about 5 weeks) 
Post op maintain treatment 
(within 8 weeks after surgery) 
 
 
Drug 
Dose/Potency 
Dose Frequency 
Dose/Pote
ncy 
Dose Frequency 
Regimen/ 
Treatment Period 
Use 
Pembrolizum
ab 
200 mg  
Day 1 and 22  
200 mg 
Every 3 weeks 
until recurrence 
During 2yrs 
5 weeks 
+ 
Experimental 


 
 
 
Neo-adjuvant chemoradiation 
(about 5 weeks) 
Post op maintain treatment 
(within 8 weeks after surgery) 
 
 
Drug 
Dose/Potency 
Dose Frequency 
Dose/Pote
ncy 
Dose Frequency 
Regimen/ 
Treatment Period 
Use 
Taxol 
50 mg/m2 
Day 
1,8,15,22,29 
 
 
2 years  
Standard  
Carboplatin  
AUC 
2mg/ml*min  
Day 
1,8,15,22,29 
 
 
Standard 
 
5.2.1 Treatment procedure 
5.2.1.1 Neo-adjuvant chemoradiation period 
The treatment consisted of taxol, carboplatin, pembrolizumab, and radiation. The 
radiation treatment comprises 44.1Gy (2.1Gy/Fr, total 21Fr) and that will be about 5 
weeks period. The investigator should make an effort to delivery enough amount of 
radiation to the patients.Intensity modulated RT (IMRT) or 3D CRT (three-dimensional 
conformal radiotherapy) will be allowed. The maximum chemotherapy dosing will be 5. 
5.2.1.2 Surgery 
Before surgery, abdomen/chest CT scan and gastroscopy with biopsy will be done with 
other laboratory tests. Surgery should be done within 12 weeks after last neo-adjuvant 
treatment (recommend within 4-8 weeks after last treatment). The operational method 
will depend on the best clinical judgement of investigators or responsible surgeon.  
5.2.1.3 Adjuvant period 
Adjuvant treatment should be performed within 8 weeks after surgery (recommended 
period : 3-6 weeks after surgery). Pembrolizumab 200mg will be administered every 3 
week until 2 years, disease recurrence, death, unacceptable toxicity or consent withdrawal 
which comes first. A Abdomen/chest CT scan will be performed every 12 weeks (3 
months) after surgery, and an optional gastroscopy may be performed every 24 weeks (6 
months).  
5.2.2 Dose Selection/Modification 
5.2.2.1 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 Medication package insert.   
5.2.2.2 Dose Modification (Escalation/Titration/Other) 
Reduction or holding of one agent and not the other agents is appropriate if, in the 
opinion of the Investigator, the toxicity is clearly related to one of the study drugs. If, in 


 
 
the opinion of the Investigator, the toxicity is related to the combination of two agents, 
both drugs should be reduced or held according to recommended dose modifications. If 
the toxicity is related to the combination of three agents, all three agents should be 
reduced or held according to the recommended dose modifications. If one or more study 
agent(s) are held for toxicity, the schedule for restarting the agent(s) should correspond 
with the next treatment cycle once the toxicity has resolved according to the 
recommended guidelines. 
 If any of the individual study drugs must be delayed for a day or more, all agents 
should be delayed for the same timeframe. If a patient requires a dose delay of 
taxol/carboplatin components of study treatment for > 2 weeks due to toxicity, the 
treatment regimen will be permanently discontinued for unacceptable toxicity.  
 
5.2.2.2.1 Dose Modification of pembrolizumab  
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
AEs as per Table 3 below. See Section 5.6 for supportive care guidelines, including use of 
corticosteroids. 
Table 3 
Dose Modification Guidelines for Drug-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 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below) a 
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. 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
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 
2b 
Toxicity resolves to Grade 0-1  
 


 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Myocarditis 
1-2 
Toxicity resolves to Grade 0 
 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Stevens-Johnson 
Syndrome (SJS) 
and Toxic 
Epidermal 
Necrolysis (TEN) 
 
 
In case of signs or symptoms of SJS or TEN, withhold 
administration and refer the patient to specialized care for 
evaluation and treatment. 
Permanently discontinue if SJS or TEN is confirmed. 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b 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  – Infusion Treatment Guidelines for further management details. 
c 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. 
 
5.2.2.2.2 Dose Modification of taxol/carboplatin 
Table 4. Dose modification s for hematologic toxicity  
Event 
Action 
Grade 1-3 
1st occurrence 
Hold until recovery to ≤ grade 1 or baseline. 
Resume without reduction 
Consider G-CSF support  
2nd occurrence 
Reduce by 1 dose level (DL). 
Consider G-CSF support 


 
 
3rd occurrence 
Reduce by 2DL 
Consider G-CSF support 
Grade 3 
Febrile 
neutropenia 
1st occurrence 
Hold until recovery to ≤ grade 1 or baseline. 
Reduce by 1DL 
Consider G-CSF support 
2nd occurrence 
Reduce by 2DL 
Consider G-CSF support 
3rd occurrence 
Discontinue 
Grade 
4 
Febrile 
neutropenia 
1st occurrence 
Reduce by 2DL 
Consider G-CSF support 
2nd occurrence 
Discontinue 
If AE is considered independently related to a specific drug, reduction or holding one 
agent and not the other agents is permitted based on the investigator’s opinion. The first 
dose reduction is a 25% reduction in both drugs, and the second dose reduction is a 50% 
reduction. 
 
Table 5.  Dose modification s for non-hematologic toxicity  
Event 
Action 
Grade 
3-4 
non-
hematologic 
toxicities 
1st occurrence 
Hold until recovery to ≤ grade 1 or baseline. 
Reduce by 1 DL 
2nd occurrence 
Reduce by 2 DL. 
3rd occurrence 
Discontinue 


 
 
Grade 
4 
Laboratory 
Adverse 
Events 
1st occurrence 
Hold until recovery to ≤ grade 1 or baseline. 
Reduce by 1DL 
2nd occurrence 
Reduce by 2DL 
 If AE is considered independently related to a specific drug, reduction or holding one 
agent and not the other agents is permitted based on the investigator’s opinion.  
 
5.2.2.2.3 Dose Modification of radiation 
Regarding toxicity associated with radiation, every adverse events should be recorded 
according to NCI CTCAE version 4.0. Radiation treatment will be omitted or delayed 
based on the physician’s judgement.   
5.2.3 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the 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. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks 
during neo-adjuvant and adjuvant period.  Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.Paclitaxel 50mg/m2 
via intravenous infusion over 1 hour, followed by carboplatin dose targeted to achieve an 
AUC 2 mg/mL*min over 30 minutes on day 1,8,15,22, and 29 in neo-adjuvant period. 
 
5.2.4 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or other 


 
 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required.  The investigator should discuss any 
questions regarding this with the Merck Clinical team.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial treatment 
should be recorded for SAEs and ECIs as defined in Section 7.2. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase  of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Radiation therapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
o  
 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. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines for Pembrolizumab 
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. 
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, 
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.  
 
 Myocarditis 
o For Grade 1-4 events, administer corticosteroids based on the severity of 
the events.  
o Perform appropriate evaluation to confirm the cause and/or exclude other 
causes. 
 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 2 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 2 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 


 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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. 
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. 
 
 
5.4.2 Supportive Care Guidelines for Paclitaxel (lung cancer protocol) 
Paclitaxel: Paclitaxel 50 mg/m2 will be administered as an IV infusion on day 1, 8, 15, 22, 
29 every cycle and should precede infusion with carboplatin. 
All subjects receiving the above chemotherapy should be pre-medicated with oral or 
injectable steroids according to the approved product label and/or standard practice. 
Additional pre-medications should be administered as per standard practice. 
For additional details, refer to approved product labels for details regarding dose 
calculation, 
reconstitution, preparation of the infusion fluid, and administration for each of the 
standard 
of care chemotherapies. 
 
5.4.3 Supportive Care Guidelines for Carboplatin 
Carboplatin: Carboplatin AUC 2 will be administered as an IV infusion over 30 
minutes day 1, 8, 15, 22, 29 of every week cycle following paclitaxel infusions. 
 
 


 
 
5.4.4 Supportive Care Guidelines for Radiotherapy 
Treatment interruptions should be avoided as much as possible. However, if esophagitis 
of CTCAE Grade 4 has occurred, interruption of radiation therapy up to Grade 2 is 
permitted.  Treatment should resume as soon as esophagitis has reduced to grade 3 or less. 
Patients whose radiotherapy interruption exceeds 4 weeks will not be given further doses 
of the study drug.  
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea or vomiting. 
5.5.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 120 
days after the last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
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) 
• 
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. 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed 
or terminated.  The outcome of the pregnancy will be reported to the Sponsor and to 
Merck without delay and within 24 hours to the Sponsor and within 2 working days to 
Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a 
male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and to Merck and 
followed as described above and in Section 7.2.2. 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.4 – 
Other Procedures. 
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 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 
 Completed 2 years of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication post-operation, whichever is later. 
Note: 2 years of study medication is calculated from the date of first dose after 
surgery. Subjects (This criterion is studied, permanently discontinued, but does 
not qualify as a dropout) 
 For the patient who progresses during neoadjuvant period or is not candidate for 
the surgery or does not achieve R0 resection, study medication will be stopped 
and the patient will be managed by investigator's judgement. 
 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 recurrence will have post-treatment 
follow-up for disease status until recurrence, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented 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. 
5.6.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed CR that have been treated for at least 24 weeks with pembrolizumab and had at 
least two treatments with pembrolizumab beyond the date when the initial CR was 
declared.   
5.7 
Subject Replacement Strategy 
5.8 
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. 
 


Product:  Pembrolizumab 
26 
Protocol/Amendment No.:   
 
 
 
 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Neo-adjuvant Treatment Cycles and 
Radiotherapy 
Operation 
Post op maintain -
Treatment 
Completion of 
Maintain 
treatment or 
Discontinuation 
of Treatment 
1st Follow Up 
Visit After 
Completion of 
Maintain 
treatment or 
Discontinuation 
of Treatment  
Follow Up Visits 
after 1st Follow 
Up Visit  
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 2) 
1 
D1 
2  
D8 
3 
D15 
4 
D22 
5 
D29 
Esophagect
omy  
Maintain treatment  
Every 3 week 
until recurrence 
During 2yrs 
Completion of 
Maintain treatment 
During 2yrs or 
Discontinuation of 
Treatment   
30 days After last 
administration 
Every 4m for 1yr  
Every 6m for 3yr  
Then annually 
Follow-Up 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
  
± 3 
±7 
± 7 
± 14 
 
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
x 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration 
 Weekly taxol (50 mg/m2)/carbo (AUC2) 
   
x 
x 
x 
x 
x 
 
 
 
 
 
Trial Treatment Administration 
 Pembrolizumab 200mg IV 
 
x 
 
 
x 
 
 
x 
 
 
 
Radiation Therapy1 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Survival Status 
  
 
 
 
 
 
 
 
 
 
x2 
 
Clinical Procedures/Assessments 
Review Adverse Events 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
Full Physical Examination 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
Vital Signs and Weight 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 


Product:  Pembrolizumab 
27 
Protocol/Amendment No.:   
 
 
 
 
 
 
 
 
 
1. Radiation therapy consists of 21 treatments during 5 weeks.  
Pregnancy Test – Urine or Serum -HCG 
x 
 
 
 
 
 
 
 
x 
x 
 
PT/INR and aPTT 
x 
 
 
 
 
 
 
 
x 
x 
 
CBC with Differential 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
Comprehensive Serum Chemistry Panel 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
Urinalysis 
x 
 
 
 
 
x 
 
x 
x 
x 
 
T3, FT4 and TSH 
x 
 
 
 
 
x 
 
  
x 
x 
 
ECG 
x 
x 
 
 
x 
 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging  
  (Abdominal CT, chest CT)  
x 
 
 
 
 
x9 
x9 
X 3 
x4 
 
x5 
Upper GI endoscopy 
x 
 
 
x 
(opti
onal) 
 
X 
(opti
onal) 
 
X6  
x7 
 
x8 
EUS (endoscopic ultrasound) 
x 
 
 
x 
(optio
nal) 
 
x 
(opti
onal) 
 
 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Fresh Tissue 
Collection 
x 
 
 
x 
(optio
nal) 
 
x 
(opti
onal) 
x 
 
x  
(optional) 
 
 
Correlative Studies Blood Collection 
x 
 
 
x 
(opti
onal) 
 
x 
(opti
onal) 
x 
 
x 
 
x 
(optional) 
 
 


Product:  Pembrolizumab 
28 
Protocol/Amendment No.:   
 
 
 
 
 
 
2. All subjects who complete trial treatments and those who discontinue for any reason will be checked for survival on a schedule.3. Imaging is performed every 12 weeks (3 
months) during maintain treatment.  
4. If maintain treatment is completed, imaging will be performed according to the originally planned schedule; if discontinued due to AE, imaging will be required if no imaging 
has been performed within 4 months.  
5. Imaging (optional: gastrointestinal endoscopy) will be performed every 4 months for subjects who have completed trial treatments. 
6. During maintain treatment, an optional gastroscopy will be performed every 24 weeks (6 months) to check for recurrence. 
7. If maintain treatment is completed, it will proceed according to the originally planned schedule, and in case of discontinuation due to AE, imaging will be required if no 
examination has been performed within 4 months. 
8. Imaging (optional: gastrointestinal endoscopy) will be performed every 4 months for subjects who have completed trial treatments. 
9 Tumor imaging (chest CT, abdominal CT) should be performed at any time between D29 and preoperative (within 12 weeks of last treatment, preferably within 4-8 weeks). 
 


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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 day 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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Protocol/Amendment No.:   
 
 
 
 
 
 
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,  
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 
Lesion assessment method and timing, evaluation of disease, determining DFS will be 
conducted according to RECIST version 1.1. Disease assessment modalities include imaging 
(e.g., CT, MRI, bone scan, plain radiography), physical examination (as indicated for 
palpable/superficial lesions) and upper gastrointestinal endoscopy. Assessments must be 
performed on a calendar schedule and should not be affected by dose interruptions/delays.  


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Protocol/Amendment No.:   
 
 
 
 
 
 
To meet screening criteria, baseline tumor imaging must be performed within 28 days prior 
to the first dose of pembrolizumab. Repeat radiographic assessment will be performed on 
Day 29 of concurrent chemoradiotherapy. To ensure comparability between the baseline and 
subsequent assessments, the same method of assessment and the same technique should be 
used when assessing response. 
 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Every effort should be made to collect tumor specimens if they are accessible and can be 
easily sampled. These biopsies and blood samples will be taken in subjects who have signed 
the corresponding section of the ICF.  
For tissues, tumor and normal tissues will be paired, and the time points will be baseline, Day 
15 and Day 29 (post-dose), surgery, and disease progression. At baseline and at surgery, this 
will be mandatory; otherwise, it will be optional. Blood will be collected at baseline, surgery, 
completion of maintain treatment, or discontinuation of treatment, and will be optional at 
other times.   
Sample volumes will be as follows. 
Tissue 
Time points 
Volume 
Baseline (mandatory) 
10 slides or 1 core each of tumor/normal tissue (approximately ~3 
mm3) 
Day 15 (post-dose) (optional) 
10 slides or 1 core each of tumor/normal tissue (approximately ~3 
mm3) 
Day 29 (post-dose) (optional) 
10 slides or 1 core each of tumor/normal tissue (approximately ~3 
mm3) 
Surgery (mandatory) 
10 slides or 1 core each of tumor/normal tissue (approximately ~3 
mm3) 
Disease progression (optional) 
10 slides or 1 core each of tumor/normal tissue (approximately ~3 
mm3) 
 
Blood sample 
Time points 
Volume 
Baseline (mandatory) 
19ml (mandatory) 
Day 15 (post-dose) (optional) 
19ml (optional) 


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Protocol/Amendment No.:   
 
 
 
 
 
 
Day 29 (post-dose) (optional) 
19ml (optional) 
Surgery (mandatory) 
19ml (mandatory) 
Completion of Maintain treatment or Discontinuation of 
Treatment (mandatory) 
19ml (mandatory) 
Follow Up visit or Discontinuation of Treatment (optional) 
19ml (optional) 
 
 
Collateral research aims include the followings:  
1. Exome sequencing (tumor/normal pairs) of fresh-frozen tumor tissues at pretreatment and 
at recurrence to identify potential immune epitope and mechanisms of acquired resistance. 
2. RNA sequencing or nanostring nCounter of fresh-frozen tumor tissues at pre-treatment, 
on-treatment and to identify potential immune-related gene signature 
3. T cell function and phenotype analysis in tumor microenvironment [CD4/CD8+ T cell, 
FoxP3+ Treg cell, immune checkpoint expression (PD1,PDL1, LAG3, TIM3, CTLA4)]  
4. Analysis of immune marker using FACS  
- 
Examine the phenotypic characteristics of CD4 and CD8 T cells in terms of  various 
immune check points (PD-1, CTLA4, TIM3, LAG3) and memory markers in fresh tissue 
and PBMC by FACS on pre-treatment, after 3 weeks and post- treatment.  
- 
Examine the tumor infiltrating immune cells including Treg cells and MDSCs on pre-
treatment, after 3 weeks and post- treatment.  
- 
Blood cytokine analysis will be performed at the time points with multi cytokine bead 
analysis on pre-treatment, after 3 weeks and post- treatment.  
 
5. Analysis of T cell function using ex vivo stimulation  
- 
Stimulate T cell with Dynabeads Human T-activator CD3/CD28 in ex vivo and measure 
the IFN-r by ELISA.  
 
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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Protocol/Amendment No.:   
 
 
 
 
 
 
Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


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Protocol/Amendment No.:   
 
 
 
 
 
 
 
 
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.   
 
7.1.5 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. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
A signed, written ICF must be obtained from the subject prior to any study-specific 
procedures or assessments. Screening assessments and procedures will be performed as 
indicated in the 6.1. Study Flow Chart 6.1. 
7.1.5.2 Treatment Period 
Treatment will begin after screening procedure is performed, and visit requirements are 
outlined in Section 6.0 – Trial Flow Chart.  
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.   
 


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Protocol/Amendment No.:   
 
 
 
 
 
 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than recurrence will move into the 
Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic imaging 
to monitor disease status.  After 1 year, the imaging time point will occur every 9 weeks (± 7 
days). Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, recurrence, death, end of the study.  Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed 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.  
 
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. 
Recurrence of the cancer under study is not considered an adverse event.  


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Protocol/Amendment No.:   
 
 
 
 
 
 
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 
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 days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 


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Protocol/Amendment No.:   
 
 
 
 
 
 
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. 
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 an other 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. 


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Protocol/Amendment No.:   
 
 
 
 
 
 
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 other than recurrence of the cancer under study (reference 
Section 7.2.3.3 for additional details) 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 other than recurrence of the 
cancer under study (reference Section 7.2.3.3 for additional details). 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 
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. 


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Protocol/Amendment No.:   
 
 
 
 
 
 
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. Site instructions for assessment and follow-
up of these criteria are included in the Investigator Trial File Binder (or equivalent document). 
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
recurrence of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not recurrence of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not recurrence of the cancer under 
study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 
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 


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Protocol/Amendment No.:   
 
 
 
 
 
 
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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Protocol/Amendment No.:   
 
 
 
 
 
 
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 preexisting 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 
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 


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Protocol/Amendment No.:   
 
 
 
 
 
 
factors 
 
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was 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 
For sample size calculation, the current trial originally used a two-stage, Minimax 
design to evaluate the null hypothesis that the true pathologic complete response (pCR) rate 
will be 10% and the alternative hypothesis that the pCR rate≥ 30%, with type I error (α) 
level of 10% and type II error (β) of 0.10. If 1 or more successes are observed in the first 16 
patients, accrual for that stratum will be continued until a total of 25 patients. If, of these 25 
patients, 5 or more pathologic complete responses, additional investigation is warranted. 
Allowing for a follow-up loss rate of 10 %, the total sample size is expected as 28 patients. 
8.2 
Statistical Analysis Plan 
Analyses of pRR and DFS will be performed on the ITT population. The Kaplan-Meier 
approach will be used to estimate median OS with 95% CI. The efficacy variables in this 
study are DFS and OS.  
Disease-free survival is defined as the time between the day of first cycle and the date of 
first documentation of recurrence or date of death, whichever occurs first. Documentation of 
recurrence will be defined as per RECIST v1.1 criteria based on investigator assessment. 
Patients without documented recurrence or death will be censored at the date of last tumor 
assessment (or, if no tumor assessments are performed after the baseline visit).  
 
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. 


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Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
 
 
Regarding, taxol and carboplatin, where permitted by regulations, sites will obtain and 
use commercially available drugs. For further details, see the local prescribing information 
for each agent. 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the 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. 


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10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Only the subject number and subject initials will be recorded in the case report form.  
Study findings stored on a computer will be stored in accordance with local data protection 
laws.  The subjects will be informed that representatives of the institutional review board 
(IRB), or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with the Korean Medical Service Act. The investigator 
will maintain a personal subject identification list (subject numbers with the corresponding 
subject names) to enable records to be identified In this multicenter trial, in order to facilitate 
contact between investigators, the PI may share an investigator’s name and contact 
information with other participating investigators upon request. 
 
10.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug 
Administration Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). 
It is the PI's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
 
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. 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and 
regulatory authority inspection of trial-related documents and procedures and provide for 
direct access to all trial-related source data and documents. 
The investigator shall prepare and maintain complete and accurate trial 
documentation in compliance with Good Clinical Practice standards and applicable federal, 


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state and local laws, rules and regulations; and, for each subject participating in the trial, 
provide all data, and, upon completion or termination of the clinical trial, submit any other 
reports to the PI as required by this protocol. Trial documentation will be promptly and fully 
disclosed to the PI by the investigator upon request and also shall be made available at the 
trial site upon request for inspection, copying, review and audit at reasonable times by 
representatives of the regulatory authorities. The investigator agrees to promptly take any 
reasonable steps that are requested by regulatory authorities as a result of an audit to cure 
deficiencies in the trial documentation and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae. It is anticipated that the 
retention period can be up to 15 years after protocol database lock. 
 
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 
The investigators agrees to be responsible for implementing and maintaining a quality 
management system with written development procedures and functional area standard 
operating procedures (SOPs) to ensure that trials are conducted and data are generated, 
documented, and reported in compliance with the protocol, 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.  
 
10.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the 
accuracy of subject data. 


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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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11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
11.4 References 
1. 
Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant 
chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an 
updated meta-analysis. Lancet Oncol 2011;12: 681–92. 
2.        van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen 
MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or 
junctional cancer. N Engl J Med 2012;366:2074-84. 
3. 
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. 
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in 
mice. J Clin Invest 2014;124:687-95. 
4. 
Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD-1 
blockade and stereotactic radiation produce long-term survival in mice with 
intracranial gliomas. Int J Radiat Oncol Biol Phys 2013;86:343-9.