Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-gastric Diseases (PROCEED)
Phase: PHASE2
Conditions: Locally Advanced Esophageal and Gastric Cancers (EGC)
Sponsor: Duke University

 
PROCEED v_05.05.2021                                                                                                                     pg. 1 
 
 
 
SPONSOR: Department of Radiation Oncology, Duke University 
FUNDING: MERCK 
 
TITLE: Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of 
Malignant Esophago-gastric Diseases. (PROCEED) 
 
NCT NUMBER: 03064490 
 
 
IND NUMBER:  134839 (IND Exemption granted 4.10.2017) 
 
Pro00081010 
Original Version April 12th 2017

 
PROCEED v_05.05.2021                                                                                                                     pg. 2 
 
 
Principal Investigator:  
Manisha Palta, MD 
Assistant Professor 
Department of Radiation Oncology 
Duke University Box 3085 
Durham, NC 27710 
 
 
 
 

 
PROCEED v_05.05.2021                                                                                                                     pg. 3 
 
 
TABLE OF CONTENTS 
TITLE PAGE................................................................. …….……………………………..1 
GLOSSARY OF ABBREVIATIONS...................................................................................5 
1.0 TRIAL SUMMARY…....................................................... ………………………….....6 
 
2.0 TRIAL DESIGN..……………………………………………………………………....6 
2.1 Trial Design...............................................................................................................6 
2.2 Trial Diagram............................................................................................................8 
3.0 OBJECTIVES AND HYPOTHESIS..…………………………………………………8 
3.1 Primary Objective and Hypothesis............................................................................8 
3.2 Exploratory Objectives..............................................................................................9 
4.0 BACKGROUND AND RATIONALE.……………………..………………………….9 
4.1 Background................................................................................................................9 
4.2 Rationale ..................................................................................................................10 
5.0 METHODOLOGY.........................................................................................................13 
5.1 Entry Criteria................................................................ …………………………...13 
5.2 Trial Treatment: Pembroluzimab............................................................................. 16 
5.3 Trial Treatment: Radiation Therapy.........................................................................20 
5.4 Treatment Arm……………………………………………………………………..23 
5.5 Concomitant Medications/Vaccinations...…………………………………………24 
5.6 Rescue Medications & Supportive Care...…………………………………………25 
5.7 Diet/Activity/Other Considerations……..………………………………………....28 
5.8 Subject Withdrawal/Discontinuation Criteria..……………………………………28 
5.9 Subject Replacement Strategy.…..………………………………………………...30 
5.10 Clinical Criteria for Early Trial Termination..…………………………………...30 
6.0 TRIAL FLOW CHART..………………………………………………………………31 
6.1 Study Flow Chart..………………………………………………………………...31 
7.0 TRIAL PROCEDURES.................................................................................................34 

 
PROCEED v_05.05.2021                                                                                                                     pg. 4 
 
7.1 Trial Procedures……………………………………………………………………34 
7.2 Assessing and Recording Adverse Events…………………………......…….…….41 
8.0 CORRELATIVE/SPECIAL STUDIES………………………………………………..51 
8.1 Collection, Handling, and Shipping Specimens…………………………………...51 
8.2 Correlative Studies………………………................................................................52 
9.0 STUDY EVALUATIONS AND STUDY CALENDAR...............................................54 
9.1 Screening Studies..…………….............................................................................. 54 
9.2 On Study Evaluation..…….....................................................................................55 
9.3 Off Study Evaluation..……………........................................................................ 56 
10.0 STATISTICAL ANALYSIS PLAN...........................................................................56 
10.1 Statistical Analysis Plan.…………....................................................................... 56 
11.0 LABELING,PACKAGING,STORAGE & RETURN OF CLINICAL SUPPLIES.. 57 
11.1 Investigational Product……………………......................................................... 57 
11.2 Packaging and Labeling Information.……………............................................... 57 
11.3 Clinical Supplies Disclosure................................................................................. 58 
11.4 Storage and Handling Requirements..................................................................... 58 
11.5 Returns and Reconciliation..…………….............................................................. 58 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS..….....................................58 
12.1 Confidentiality..……………………………………............................................. 58 
12.2 Compliance with Financial Disclosure Requirements.……………………….…..58 
12.3 Compliance with Law, Audit and Debarment…..………………………….…….59 
12.4 Compliance with Trial Registration and Results Posting Requirements..…….….60 
12.5 Quality Management System..…………………………………………………....60 
12.6 Data Management..…………………………………………………………….…60 
13.0 APPENDICES..…………………………..………………………………………….63 
13.1 ECOG Performance Status..……………………………………………………...63 
13.2 Common Terminology Criteria for Adverse Events..……………………………63 
14.0 REFERENCES..…..…………………………………………………………………65

 
PROCEED v_05.05.2021                                                                                                                     pg. 5 
 
 
GLOSSARY OF ABBREVIATIONS 
 
EGC  
esophago-gastric cancers 
pCR 
 
pathologic complete response 
3D 
 
3-dimensional 
IMRT  
intensity modulated radiotherapy 
PET 
 
positron emission tomography 
CT 
 
computed tomography 
CTCAE  
common terminology criteria for adverse events 
AUC  
area under curve 
CRT   
chemoradiotherapy 
TTLR   
time to local recurrence 
TTDR   
time to distant recurrence 
PFS  
 
progression free survival 
OS  
 
overall survival 
T regs  
regulatory T-cells 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
PD-1  
programmed death 1 
CD 28  
cluster of differentiation 28 
Ig 
 
immunoglobulin 
IgV-type  
Ig Variable–type 
CS 
 
Correlative science 
TE 
 
Tumor microenvironment 
PMBCs 
Peripheral blood mononuclear cells 
DIPC   
Duke Immune Profiling Core 
Treg 
 
T cell 
m-MDSC  
monocytic myeloid-derived suppressor cells 

 
PROCEED v_05.05.2021                                                                                                                     pg. 6 
 
1.0 TRIAL SUMMARY 
 
Abbreviated Title 
Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant 
Treatment of Malignant Esophago-gastric Diseases. (PROCEED) 
Trial Phase 
Phase II trial 
Clinical Indication 
Resectable, 
non-metastatic 
locally 
advanced 
esophagus, 
gastroesophageal junction and gastric cancers 
Trial Type 
Single arm with initial safety-run-in 
Type of control 
n/a 
Route of administration 
Intravenous 
Trial Blinding 
n/a 
Treatment Group 
1) Neoadjuvant pembrolizumab (3 cycles) with concurrent 
chemoradiotherapy with carboplatin/paclitaxel, followed by 
surgical resection and 3 cycles of adjuvant pembrolizumab 
Primary Objective 
1) To 
investigate 
whether 
neoadjuvant 
chemoradiotherapy 
combined with pembrolizumab improves pathologic complete 
response 
compared 
to 
historical 
control 
with 
chemoradiotherapy. 
Number of trial subjects 
30-38 
Estimated enrollment period 
May 1, 2017 – May 31, 2019 
Estimated duration of trial 
3 years (2.5 years for enrollment + 6 months follow-up) 
All patients will be followed from enrollment until the study end date, 
which will occur when the last patient has been followed for 6 months, 
based on an estimated 2.5 year recruitment period. 
Duration of Participation 
1 year 
Estimated average length of 
treatment per patient 
5 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single-institution, prospective phase II trial with an initial safety run-in to evaluate 
the efficacy and safety of neoadjuvant pembrolizumab combined with chemoradiotherapy 
and adjuvant pembrolizumab in patients with locally advanced esophageal and gastric 
cancers (EGC). Chemoradiation therapy (45Gy in 25 fractions with concurrent, weekly 
carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of 
pembrolizumab will be administered as neoadjuvant therapy. These patients will also 
receive three cycles of adjuvant pembrolizumab after surgical resection (1). 
An initial safety run-in of 5 patients will be performed to evaluate safety of concurrent 
pembrolizumab and chemoradiotherapy for EGC. If no more than 1 grade 3+ toxicity is 
definitely related to concurrent pembrolizumab and observed within 30 days of the last 
dose of neoadjuvant pembrolizumab (i.e. cycle 3) for the fifth patient, then the study will 

 
PROCEED v_05.05.2021                                                                                                                     pg. 7 
 
continue to accrue.  In the event that more than 1 of the first 5 patients has a grade 3+ 
toxicity definitely related to concurrent pembrolizumab, then an additional five patients 
(total 10 patients) will be enrolled with close toxicity assessment. 
Enrolled patients will receive three doses of neoadjuvant pembrolizumab (200 mg 
administered as an intravenous infusion over 30 minutes every 3 weeks). The first dose of 
pembrolizumab will be administered approximately 14 days prior to initiating radiotherapy. 
The second dose will be administered three weeks later (week 1 +/- 1 week of 
chemoradiation). The third dose will be administered 3 weeks later (week 4 +/- 1 week of 
chemoradiotherapy). Pembrolizumab will be given every 3 weeks and may be given at the 
same time as systemic therapy. All patients will receive radiation treatment (45Gy in 25 
fractions at 1.8 Gy/fraction) using image-guided radiation therapy with concurrent, weekly 
carboplatin (AUC 2) and paclitaxel (50mg/m2 of BSA). Restaging will be performed per 
standard of care approximately 4-8 weeks after completing chemoradiotherapy. Resection 
will be performed approximately 6-16 weeks after completing chemoradiotherapy per 
standard of care. Postoperatively, three additional cycles of pembrolizumab (200 mg every 
3 weeks) will be administered as adjuvant therapy.  Timing will be at the discretion of the 
treating physician based on patient healing and recovery from any postoperative 
complications. 
Patients will be evaluated at least weekly during radiation treatment, every 3-6 months for 
the first 2 years after treatment, and every 6-12 months in years 3 to 5. PET/CT or CT 
chest/abdomen/pelvis (C/A/P) will be performed at the time of these scheduled follow up 
visits to evaluate for local or distant tumor recurrence. Additional imaging will be 
performed if clinically indicated. Adverse events will be recorded and graded according to 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (2). 
 
 
 
 
 
 
 
 
 
 

 
PROCEED v_05.05.2021                                                                                                                     pg. 8 
 
2.2 
Trial Diagram 
 
 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives & Hypotheses 
(1) Objective: To investigate whether neoadjuvant chemoradiotherapy combined with 
pembrolizumab followed by resection improves pathologic complete response (pCR) 
compared to historical control with standard of care neoadjuvant chemoradiotherapy 
followed by resection (23%).(3) 
Hypothesis: Neoadjuvant chemoradiotherapy combined with pembrolizumab followed by 
resection will improve pCR compared to standard of care neoadjuvant radiotherapy 
followed by resection. 
3.1.1 Secondary Objectives & Hypotheses 
(1) Objective: To assess the safety of neoadjuvant pembrolizumab administered with 
conventionally fractionated chemoradiotherapy in EGC. 

 
PROCEED v_05.05.2021                                                                                                                     pg. 9 
 
Hypothesis: Neoadjuvant chemoradiotherapy combined with pembrolizumab will be 
associated with an acceptable toxicity profile. 
3.2 
Exploratory Objectives 
(1) 
Objective: To identify immune related biomarkers as predictors of clinical response 
to pembrolizumab and chemoradiotherapy 
(2) 
Objective: To estimate the distribution of time to local recurrence (TTLR), time to 
distant recurrence (TTDR), progression free survival (PFS), and overall survival (OS) 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact functions of 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 

 
PROCEED v_05.05.2021                                                                                                                     pg. 10 
 
no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilumumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. It is also approved in the treatment of metastatic non-small cell lung 
cancer and recurrent or metastatic head and neck cancers. 
 
4.1.2 Preclinical and Clinical Trial Data 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
EGC is the fourth most common cancer with incidence of 1 million people 
worldwide.(4) In the United States nearly 42,000 patients are diagnosed with esophageal or 
gastric malignancies.(5) For the individuals who present with locally advanced, resectable, 
non-metastatic disease the mainstay of treatment involves a combination of neoadjuvant 
chemoradiation followed by surgery. With neoadjuvant treatment the current pCR is 
approximately 30%. Long term survival in patients receiving neoadjuvant chemoradiation 
with carboplatin/paclitaxel and surgery is median 49.4 months and corresponding 5 year 
survival of 47% (1) Data suggests that long term outcomes in patients who achieve a pCR 
is significantly higher than non-responders. (6) We hypothesize that concurrent 
administration of pembrolizumab with chemoradiation for locally advanced EGC will 
enhance local tumor response and activate the immune system to eliminate occult 
micrometastatic disease. 
Antibodies 
targeting 
immune 
checkpoints, 
including 
the 
anti-PD-1 
antibody 
pembrolizumab, have induced durable responses in patients with metastatic cancers of 
many types (7-19).  Furthermore, anti-PD-1 antibodies are generally well tolerated, with 
therapies targeting the PD-1 pathway associated with less toxicity than anti-CTLA-4 
antibodies. Experience with immune checkpoint blockade in EGC is limited. At the 2014 
European Society of Medical Oncology meeting recent data from Japan evaluated patients 
with recurrent or metastatic esophago-gastric adenocarcinomas for PD-1 expression, and if 
positive, enrollment on a Phase 1b study with pembrolizumab. Statistically significant 

 
PROCEED v_05.05.2021                                                                                                                     pg. 11 
 
associations between PD-1 expression and progression free survival (PFS, p=0.032) and 
objective response rate (ORR, P=0.071) were seen. These results were achieved with most 
common adverse events being fatigue and hypothyroidism.(20) In light of these data, Phase 
II and III studies for advanced gastric cancer are ongoing. 
To date, no clinical trials have examined combined anti-PD-1 therapy and chemoradiation 
treatment for EGC.  Data from a phase I clinical trial in metastatic melanoma and several 
preclinical studies in various tumor models indicate that radiotherapy enhances the 
therapeutic effect of immune checkpoint inhibitors (21-25).  Radiation therapy may 
augment the anti-tumor immune response by inducing exposure of new tumor antigens 
through cross presentation, upregulating MHC-I expression, stimulating chemokines that 
recruit cytotoxic T-cells, and upregulating death receptors which promote cytotoxic T-cell 
activity (26).  Furthermore, isolated case reports of the abscopal effect, in which localized 
radiation treatment triggers distant tumor regression through a systemic immune-mediated 
response, suggest a synergistic interplay between radiotherapy and the immune system (27, 
28). 
When immune checkpoint inhibitors are administered in the absence of radiation therapy, 
tumor mutational load correlates with the efficacy of immunotherapy (15, 29, 30). We 
hypothesize that immune stimulation by radiotherapy will trigger a response to immune 
checkpoint blockade that will enhance local tumor response and eradicate micro-
metastases. 
4.2.2 Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) NCT01295827 is being conducted to evaluate 
the safety and clinical activity of single agent MK-3475 ( Pembrolizumab).  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 ( Pembrolizumab) 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 ( Pembrolizumab) and a less 
frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475( Pembrolizumab) 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 ( Pembrolizumab)  were found to be dependent on body weight. 

 
PROCEED v_05.05.2021                                                                                                                     pg. 12 
 
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 ( Pembrolizumab)  
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 ( Pembrolizumab) 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. 
4.2.2.1 Efficacy Endpoints 
pCR will be the primary study endpoint and safety will be the secondary endpoint.  The 
rationale is that combined pembrolizumab and chemoradiotherapy will stimulate an anti-
tumor immune response, leading to enhanced local tumor effect and be well tolerated. With 
neoadjuvant treatment the pCR is approximately 23% in patients with adenocarcinoma 
histology. (1) Data suggests that long term outcomes in patients who achieve a pCR is 
significantly better than non-responders. (6) 
4.2.2.2 Biomarker Research 
See section 8.0. 

 
PROCEED v_05.05.2021                                                                                                                     pg. 13 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Patients with potentially resectable, locally advanced esophagus or gastric adenocarcinoma 
are eligible for entry into the trial. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Has a pathologic diagnosis of invasive esophageal, gastroesophageal or gastric 
adenocarcinoma. 
4. Staging CT CAP or PET/CT shows no evidence of metastatic disease. 
5. Have a performance status of 0-2 on the ECOG Performance Scale. 
6. Plan for neoadjuvant chemoradiation. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 14 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) 
 
≤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 

 
PROCEED v_05.05.2021                                                                                                                     pg. 14 
 
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 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Female subject of childbearing potential should have a negative serum pregnancy 
within 48 hours prior to receiving the first dose of study medication. 
9. Female and male subjects of childbearing potential must be willing to use an adequate 
method of contraception as outlined in the Duke Contraception Policy. 
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 
for the current diagnosis of EGC. 
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
(all patients with prior radiotherapy must be reviewed by the PI to determine if 
patient is eligible). 
8. Has known metastatic disease.  Staging CT C/A/P or PET/CT will be mandatory no 
more than 45 days prior to enrollment to evaluate for the presence of metastatic 
disease. 
9. Has unresectable disease or is medically inoperable. 
10. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with chronic use of disease modifying agents, corticosteroids or 

 
PROCEED v_05.05.2021                                                                                                                     pg. 15 
 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic 
corticosteroid 
replacement 
therapy 
for 
adrenal 
or 
pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
11. Has known history of, or any evidence of active, non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. Has a history or current evidence of physical or physiological contraindication to 
participation in this study, at the discretion of the treating investigator. 
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. Is pregnant or breastfeeding, or expecting to 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. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
18. Has known, active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
19. 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. 
20. Has a diagnosis of scleroderma. 
21. Has a known history of allogenic stem cell transplant 
22. Has received a solid organ transplant. 
5.2 
Trial Treatment: Pembrolizumab 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route 
of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Carboplatin 
AUC 2 
QW 
IV infusion 
Weekly 
during 
radiation 
(min 
4 
SOC 

 
PROCEED v_05.05.2021                                                                                                                     pg. 16 
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route 
of 
Administration 
Regimen/Treatment 
Period 
Use 
cycles) 
Paclitaxel 
50mg/m2 
of 
BSA 
QW 
IV infusion 
Weekly 
during 
radiation 
(min 
4 
cycles) 
SOC 
 
Radiotherapy will be initiated within 14 days after the first dose of pembrolizumab. 
Radiation treatment will be administered at a dose of 1.8Gy/fraction to a total dose of 
45Gy. Radiotherapy will be given with concurrent, weekly carboplatin (AUC 2) and 
paclitaxel (50mg/m2 of BSA) as per standard of care. Three cycles of pembrolizumab will 
be administered prior to surgical resection. Pembrolizumab will be given every 3 weeks 
and may be given at the same time as systemic therapy. Three cycles of adjuvant 
pembrolizumab will be administered after surgery. Given the possibility of post-operative 
complications after neoadjuvant chemoradiotherapy and surgery for EGC, we anticipate 
variation in timing of adjuvant pembrolizumab based on physician judgment. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale. 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in 
the Merck Prescribing Information. 
5.2.1.2 Dose Modification (Escalation/Titration/Other) 
AEs associated with pembrolizumab exposure, including coadministration with 
additional compounds, may represent an immunologic aetiology. These immune-related 
AEs (irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications.  Based on existing clinical study data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab/combination treatment, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, 
ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab/combination treatment are provided in Table 4. 
See Section 5.6 for supportive care guidelines, including use of corticosteroids. 
 

 
PROCEED v_05.05.2021                                                                                                                     pg. 17 
 
5.2.1.3 
Dose Modification Guidelines for Drug-Related Adverse Events 
Table 4 Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last study intervention treatment. 
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper. 
 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action 
With 
Pembrolizumab 
Corticosteroid 
and/or 
Other Therapies 
Monitoring and Follow-up 
Pneumonitis 
Grade 2 
Withhold 
•  Administer 
corticosteroids (initial dose 
of 1 to 2 mg/kg prednisone 
or equivalent) followed by 
taper 
•  Add 
prophylactic 
antibiotics for opportunistic 
infections 
•  Monitor participants for signs 
and symptoms of pneumonitis 
•  Evaluate 
participants 
with 
suspected 
pneumonitis 
with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4 
Permanently 
discontinue 
Diarrhea/Colitis 
Grade 2 or 3 
Withhold 
•  Administer 
corticosteroids (initial dose 
of 1 to 2 mg/kg prednisone 
or equivalent) followed by 
taper 
 
•  Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus) 
•  Participants with ≥Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis 
•  Participants 
with 
diarrhea/colitis should be advised 
to drink liberal quantities of clear 
fluids. If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be substituted 
via IV infusion 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
AST 
or 
ALT 
Elevation 
or 
Increased 
Grade 2 a 
Withhold 
•  Administer 
corticosteroids (initial dose 
of 
0.5 
to 
1 mg/kg 
•  Monitor with liver function 
tests (consider weekly or more 
frequently until liver enzyme 

 
PROCEED v_05.05.2021                                                                                                                     pg. 18 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action 
With 
Pembrolizumab 
Corticosteroid 
and/or 
Other Therapies 
Monitoring and Follow-up 
Bilirubin 
prednisone or equivalent) 
followed by taper 
value returned to baseline or is 
stable) 
Grade 3 b or 4 
c 
Permanently 
discontinue 
•  Administer 
corticosteroids (initial dose 
of 1 to 2 mg/kg prednisone 
or equivalent) followed by 
taper 
T1DM 
or 
Hyperglycemia 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of 
β-cell 
failure 
Withhold d 
•  Initiate 
insulin 
replacement 
therapy 
for 
participants with T1DM 
•  Administer 
antihyperglycemic 
in 
participants 
with 
hyperglycemia 
 
•  Monitor 
participants 
for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer 
corticosteroids and initiate 
hormonal replacements as 
clinically indicated 
•  Monitor 
for 
signs 
and 
symptoms 
of 
hypophysitis 
(including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective 
beta-blockers 
(eg, 
propranolol) or thionamides 
as appropriate 
•  Monitor 
for 
signs 
and 
symptoms of thyroid disorders 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 
4 
Continue 
•  Initiate 
thyroid 
replacement hormones (eg, 
levothyroxine 
or 
liothyronine) per standard 
of care 
•  Monitor 
for 
signs 
and 
symptoms of thyroid disorders 
Nephritis: 
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer 
corticosteroids (prednisone 
1 to 2 mg/kg or equivalent) 
followed by taper 
•  Monitor 
changes 
of 
renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 

 
PROCEED v_05.05.2021                                                                                                                     pg. 19 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action 
With 
Pembrolizumab 
Corticosteroid 
and/or 
Other Therapies 
Monitoring and Follow-up 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 2, 3 or 
4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, or 
DRESS 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent 
Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 
Withhold 
or 
discontinue 
based on the 
event e 
Recurrent 
Grade 3 
or 
Grade 4 
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a 
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b 
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 
to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c 
AST/ALT: 
>20.0 
x 
ULN, 
if 
baseline 
normal; 
>20.0 
x 
baseline, 
if 
baseline 
abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d 
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e 
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important 
irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 
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, and/or 

 
PROCEED v_05.05.2021                                                                                                                     pg. 20 
 
holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the PI. The reason for interruption 
should be documented in the patient's study record. 
 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the 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. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Trial Treatment: Radiation Therapy (Below are recommendations but at 
the discretion of the treating physician.). 
Image-guided radiation treatment (IGRT) is recommended for this study. 
5.3.1 Dose Specifications 
5.3.1.1 
Neoadjuvant Chemotherapy 
Carboplatin (AUC 2) and paclitaxel (50mg/m2 of BSA) will be given concurrent, weekly 
with radiation with plan for at least 4 total doses neoadjuvantly per treating medical 
oncologist. Administration will be as per standard of care. 
5.3.1.2 Preoperative IGRT 
Either 3D conformal radiotherapy (3D-CRT) or intensity modulated radiation therapy 
(IMRT)/volumetric arc therapy (VMAT) may be utilized. Recommendations for dose 
volume histogram (DVH) constraints for critical normal structures are at the discretion of 
the treating physician but Section 5.35 provides recommended metrics. 
A prescription dose of 45Gy in 25 daily fractions will be prescribed with recommendation 
to cover 95% of the PTV. 

 
PROCEED v_05.05.2021                                                                                                                     pg. 21 
 
5.3.2 Technical Factors 
Megavoltage photon beams produced by linear accelerators with energies of ≥ 4 MV are 
permitted. 
Image guidance may be achieved using any one or more of the following techniques: 
• Orthogonal 2D kilovoltage (KV) and MV electronic images, e.g., ExacTrac; 
• Linear-accelerator mounted kV and MV conebeam CT images; 
• Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 
 
Any questions regarding IGRT technology should be directed to the PI. 
 
5.3.3 Localization, Simulation, and Immobilization 
Patients should be immobilized in stable and comfortable positions to allow accurate 
repositioning from treatment to treatment and to prevent movement during treatments. A 
variety of immobilization devises may be utilized, including Alpha Cradle, indexed 
wingboard and vac-lock. Radiotherapy treatment plans will be generated after CT 
simulation. Ideally PET/CT simulation will be performed for radiation treatment planning. 
Respiratory motion assessment is recommended and if motion is greater than 1.5cm 
respiratory motion management is advised but at the discretion of the treating physician. 
5.3.4 Treatment Planning/Target Volumes 
The definition of volumes will be in accordance with the ICRU Report #62: Prescribing, 
recording and Reporting Photon Beam Therapy (supplement to ICRU Report #50). 
Gross Tumor Volume (GTV): Gross tumor defined as the primary tumor in the 
esophagus/stomach and grossly involved regional lymph nodes. 
Clinical Target Volume (CTV): The CTV is defined as a 2-4cm superior and inferior 
expansion along the length of the esophagus and stomach and a 1-1.5cm radial expansion 
for the primary and nodal GTV. The superior and inferior expansion should follow the 
contour of the esophagus and stomach. The intent is to extend the margin along the length 
of the esophagus and stomach to provide a margin for coverage of the submucosal 
extension of tumor. The celiac axis may be covered for tumors of the distal esophagus, GE 
junction or stomach. The internal target volumes (ITV) as assessed on the 4D-CT will be 
included in the CTV. Elective nodal coverage is at the discretion of the treating physician. 
Planning Target Volume (PTV): Include CTV and set up uncertainty. Typically PTV 
includes CTV plus 0.5-1cm in all directions. 
Boost PTV: Defined as the GTV with expansion of 1-1.5cm. 

 
PROCEED v_05.05.2021                                                                                                                     pg. 22 
 
5.3.5 Critical Structures 
Radiation dose to normal tissues should be kept within the accepted normal tissue 
tolerances when using standard 1.8Gy fractionation schedules. The following are suggested 
normal tissue parameters: 
Normal Tissue 
Description 
 
 
Lung 
Lung-PTV 
V20 
≤25% 
Heart 
Heart & pericardium 
Mean 
V40 
≤25% 
≤40% 
Kidney 
Combined kidneys 
V20 
≤30% 
Spinal Cord 
Spinal cord 
Max 
50Gy 
Liver 
Liver 
V30 
Mean 
≤33% 
21Gy 
 
5.3.6 Compliance Criteria 
Treatment interruptions should be minimized. Radiation treatment breaks longer than 5 
days will be documented. If radiation treatment break is longer than 5 days there will be 
discussion with PI to consider taking the patient off study. If chemotherapy is held at the 
discretion of the treating medical oncologist, it will be documented but not counted as a 
treatment break 
 
5.3.7 Chemoradiation Therapy Adverse Events 
5.3.7.1 
Acute Adverse Events 
Common chemoradiation adverse events include: anorexia/weight loss, constipation, 
diarrhea, esophagitis, fatigue, nausea/vomiting, dermatitis, hair thinning/alopecia, nerve 
damage, and reduction in blood counts. 
5.3.7.2 
Long-term Adverse Events 
Possible long-term treatment adverse events include esophageal stenosis/stricture, 
difficulty maintaining weight, depressed blood counts, pneumonitis, increased risk of 
cardiovascular disease, myelopathy, renal dysfunction necessitating dialysis, and bowel 
obstruction, perforation or bleeding. 
5.3.8 Trial Treatment: Surgery 

 
PROCEED v_05.05.2021                                                                                                                     pg. 23 
 
5.3.8 Surgical Evaluation 
A surgeon, radiation oncologist and medical oncologist must see any eligible patient prior 
to instituting preoperative therapy. 
Resection of the EGC will occur following combined preoperative chemoradiation and 
pembrolizumab after restaging imaging has confirmed no evidence of metastatic disease 
and patient is medically fit for surgery as per standard of care. 
5.3.9 Postoperative Management 
Post-operative management is at the discretion of the surgical team per standard of care. 
 
5.3.10 Surgical Adverse Events 
Major wound complications, such as secondary operations, re-admissions, and/or invasive 
procedures will be collected based on retrospective review of the patient’s electronic 
medical record.Constitution symptoms related to surgical recovery such as weight loss, 
nausea and vomiting, fatigue, post-operative pain, constipation caused by narcotic 
medication prescribed for pain management both during and after discharge from hospital, 
will not be captured. Anticipated surgical complications specifically, anastomic leak, 
fistula, chylothorax, pneumonia and pericardial effusion will be captured. 
5.4 
Treatment Arm 
An initial safety run-in of 5 patients will be performed to evaluate safety of concurrent 
pembrolizumab and chemoradiotherapy for EGC. If no more than 1 grade 3 or higher 
toxicity is definitely related to concurrent pembrolizumab and observed within 30 days of 
the last dose of neoadjuvant pembrolizumab (i.e. cycle 3) for the fifth patient, then the 
study will continue to accrue.  In the event that more than 1 of the first 5 patients has a 
grade 3 or higher toxicity definitely related to concurrent pembrolizumab, then an 
additional five patients (total 10 patients) will be enrolled with close toxicity assessment. If 
more than 2 grade 3 or higher toxicities definitely related to concurrent pembrolizumab and 
chemoradiotherapy are observed in the 10 patients, then the PI will consider that the safety 
cohort be repeated using a lower dose of radiation with close toxicity assessment. 
Cohort 
Number 
Patients 
Pembrolizumab 
# Grade 3+ toxicities permitted 
1 
5-10 
200 mg every 3 
weeks 
1 
(if more than 1 Grade 3+ toxicity then 
additional 5 patients accrued) 
Expansion 28-33 
200 mg every 3 
weeks 
 

 
PROCEED v_05.05.2021                                                                                                                     pg. 24 
 
Accrual: 38 patients with intent to have 30 evaluable patients (patients who complete 
neoadjuvant treatment and undergo resection) for the primary endpoint. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required.  The investigator should discuss any questions 
regarding this with the Merck Clinical team.  The final decision on any supportive therapy 
or vaccination rests with the investigator and/or the subject's primary physician. 
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phase (including retreatment for post-complete response relapse) of this trial: 
• Immunotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. 
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 section describes other medications that are prohibited in this trial. 
Biological therapy or immunotherapy will remain prohibited beyond the treatment phase 
unless the patient develops metastatic disease. There are no additional prohibited therapies 
during the post-treatment follow-up phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 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 

 
PROCEED v_05.05.2021                                                                                                                     pg. 25 
 
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 despite anti-diarrheals, 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) 

 
PROCEED v_05.05.2021                                                                                                                     pg. 26 
 
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 and as indicated based on 
clinical evaluation) and for clinical signs and symptoms of thyroid disorders. TSH 
will be performed at baseline and prior to administration of subsequent cycles of 
pembrolizumab as per institutional policy. 
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 liothyronine, 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. 

 
PROCEED v_05.05.2021                                                                                                                     pg. 27 
 
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Management of Infusion Reactions: Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 3 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 3 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication 
at 
subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not 
indicated; 
intervention 
not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate 
premedication 
should 
be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief 
interruption 
of 
infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
No subsequent dosing 

 
PROCEED v_05.05.2021                                                                                                                     pg. 28 
 
NCI CTCAE Grade 
Treatment 
Premedication 
at 
subsequent 
dosing 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
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. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
5.6.2 Supportive Care Guidelines for Chemoradiation 
• Corticosteroids will be administered as per standard of care for systemic therapy 
administration. Subjects will be pre-medicated with dexamethasone 8mg po the 
night before, the morning prior to each chemotherapy, and for 2 days after each 
chemotherapy. If a patient is allergic to dexamethasone, a steroid equivalent may be 
used at the discretion of the treating physician. 
Efforts will be made to minimize the use of corticosteroids during chemoradiation for 
symptomatic or supportive management. 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known 
if pembrolizumab has transient adverse effects on the composition of sperm. The Duke 
Contraception policy will be followed. 
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 as per Duke policy. If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject 
should not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if 
the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn). 

 
PROCEED v_05.05.2021                                                                                                                     pg. 29 
 
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. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the PI should any untoward effect occur.  In addition, a subject may be 
withdrawn by the PI 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 withdraws consent. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
The end of treatment and follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject 
will be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by review of electronic medical record until death, 
withdrawal of consent, or the end of the study, whichever occurs first. 

 
PROCEED v_05.05.2021                                                                                                                     pg. 30 
 
5.9 
Subject Replacement Strategy 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 

 
31 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles/Radiotherapy/Surgery 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
Screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
C1 
XRTa 
(5-6 
wk) + 
C2/C3 
Surg. 
C4* 
C5* 
C6* 
Safety 
Follow
-up 
Follow 
Up Visits 
Survival 
Follow-
Up 
Timing (Weeks) 
 
-4 to -1 
Wk 0 
Wk      
1 – 6 
6–20 
wk 
post-
C3/XR
T 
4-12  
wk 
postop 
3 wk 
post-
C4 
3 
wk 
post-
C5 
30 
days 
post-
C6 
Per 
treating 
MD 
discretion 
Every 52 
wk 
Scheduling Window (Days): 
 
-28 to -1 
± 3 
± 3 
± 21 
± 3 
± 3 
± 3 
± 7 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
Study Drug Administrationb 
 
 
X 
X 
 
X 
X 
X 
 
 
 
Chemotherapy Administrationc 
 
 
 
X 
 
 
 
 
 
 
 
Radiotherapy Administrationd 
 
 
 
X 
 
 
 
 
 
 
 
Surgical Resection of Primary Tumor 
 
 
 
 
Xh 
 
 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
X 
Review Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
Focused Physical Examination 
 
 
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 
 
Pregnancy Test – Serum β-HCG (if 
appropriate) 
 
X 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
Xi 
 
 
X 
 
 
 
 
 
 
CBC with Differential 
 
Xi 
X 
X 
X 
X 
X 
X 
 
 
 
Comprehensive Serum Chemistry Panel 
 
Xi 
X 
X 
X 
X 
X 
X 
 
 
 

 
32 
 
Trial Period: 
Screening Phase 
Treatment Cycles/Radiotherapy/Surgery 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
Screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
C1 
XRTa 
(5-6 
wk) + 
C2/C3 
Surg. 
C4* 
C5* 
C6* 
Safety 
Follow
-up 
Follow 
Up Visits 
Survival 
Follow-
Up 
Timing (Weeks) 
 
-4 to -1 
Wk 0 
Wk      
1 – 6 
6–20 
wk 
post-
C3/XR
T 
4-12  
wk 
postop 
3 wk 
post-
C4 
3 
wk 
post-
C5 
30 
days 
post-
C6 
Per 
treating 
MD 
discretion 
Every 52 
wk 
Scheduling Window (Days): 
 
-28 to -1 
± 3 
± 3 
± 21 
± 3 
± 3 
± 3 
± 7 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
TSH 
 
X 
 
X 
 
X 
X 
X 
 
 
 
T3, FT4 
 
X 
 
 
 
 
 
 
 
 
 
ACTH, 
 
X 
 
 
 
 
 
 
 
 
 
Cortisol 
 
X 
 
 
 
 
 
 
 
 
 
LH/FSH 
 
X 
 
 
 
 
 
 
 
 
 
Testosterone 
 
X 
 
 
 
 
 
 
 
 
 
EKG 
 
X 
 
 
 
 
 
 
 
 
 
EUS 
gX 
 
 
 
 
 
 
 
 
 
 
CT CAP or PET/CT for staging 
X 
 
 
 
Xe 
 
 
 
 
X 
 
Archival or Newly Obtained Tissue 
Collection 
 
Xf 
 
 
 
X 
 
 
 
 
 
Correlative Studies Blood Collection 
X 
 
 
X 
X 
preop 
X 
 
 
X 
 
 
 
aPatients will be evaluated at least weekly during radiation treatment including assessment for adverse events. 
bStudy drug is pembrolizumab 
c Chemotherapy is weekly Carboplatin/Paclitaxel as per standard of care 
dRadiotherapy will be administered daily (Monday through Friday) for five-five and a half weeks (25-28 total treatments) 
eRestaging will be performed prior to surgical resection, and may be repeated at the discretion of the treating physician 
fPDL-1 assay testing will be performed on archived or fresh tissue from biopsy 
gEUS for local tumor staging (if ultrasound probe able to traverse tumor). Not required if EUS probe cannot traverse the lesion. 
h Surgical resection will occur 6-20 weeks after chemoradiotherapy. Surgical resection >20 weeks after chemoradiotherapy may be 
allowed at the surgeon’s discretion. 

 
33 
 
 
i Screening labs will be performed within 14 days of treatment initiation 
• *adjuvant systemic therapy is preferred as outlined in the study calendar but timing and administration is at the discretion of 
the 
treating 
medical 
oncologist

 
 
 
 
 
34 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.1 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 and Registration Process 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. After obtaining Informed Consent, eligible patients will be 
enrolled on this trial. Subjects will be issued a subject unique identifying numbers for eligible 
participants. An investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the investigation on 
each subject treated with the investigational product in the study or registered to the study. 
While all study evaluations must be performed by the Investigator as described in Section 
9.0, Study Evaluations and Study Calendar (Section 6.1). This study will use a web based 
data entry system, REDCAP, for data collection. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature 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 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. 

 
 
 
 
 
35 
 
Specifics about the trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor requirements. 
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. Details regarding the disease for which the subject has 
enrolled in this study will be recorded separately. 
7.1.1.4 Concomitant Medications Review 
7.1.1.4.1 Concomitant Medications 
The investigator or qualified designee will record steroid and endocrine related medications, 
including topical steroids, if any, taken by the subject during the trial.  All medications 
related to reportable SAEs 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. 
7.1.2 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. 

 
 
 
 
 
36 
 
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 have performed a complete physical exam during 
the prescreening period. 
7.1.2.3 Focused 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 focused physical exam as clinically indicated prior to 
trial treatment administration. 
7.1.2.4 Vital Signs 
Vital signs will be taken 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 
Staging CT C/A/P or PET/CT will be performed prior to and after completion of neoadjuvant 
radiotherapy, may be repeated at the discretion of the treating physician prior to definitive 
surgical resection. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Fresh tissue collection will be performed prior to treatment initiation (optional endoscopic 
procedure) and at the time of surgery. Blood collection will be performed at 5 predefined 
time points as detailed in the trial flow chart. 
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.  

 
 
 
 
 
37 
 

 
 
 
 
 
38 
 
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 
Total triiodothyronine (T3) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
Free thyroxine (T4) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Adrenocorticotropic Hormone (ACTH) 
Absolute Lymphocyte Count 
(CO2 or bicarbonate) 
 
Cortisol 
 
Uric Acid 
 
 
 
Calcium 
 
Luteinizing hormone (LH)- in women 
 
Chloride 
 
Follicle stimulating hormone (FSH) – in 
women 
 
Glucose 
 
Testosterone- males 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Magnesium 
 
Blood for correlative studies 
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
 

 
 
 
 
 
39 
 
 

 
 
  
40 
 
 
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. After discontinuing 
treatment following assessment of CR, these subjects should return to the site for a safety follow-up visit 
(described in Section 7.1.5.3.1) and then proceed to the follow-up period of the study (described in 
Section 7.1.5.4). 
7.1.4.2 Blinding/Unblinding 
This is an open-label trial. Blinding will not be performed. 
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 
7.1.5.2 Treatment Period 
Patients will be evaluated by the treating radiation oncologist at least once per week while undergoing 
neoadjuvant, 
concurrent 
chemoradiation 
treatment. 
During 
the 
neoadjuvant 
and 
adjuvant 
pembrolizumab therapy, patients will be evaluated at least every three weeks by the treating medical 
oncologist with labs performed as per study flow chart. 
7.1.5.3 Post-Treatment Visits 
After completion of the final cycle of pembrolizumab, patients will be evaluated by the treating medical 
oncologist, radiation oncologist, or surgical oncologist every 3-6 months for the first two years, then 
every 6-12 months for years three to five as per standard of care. 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory safety follow-up visit will be required for subjects who have completed 6 cycles of 
pembrolizumab and 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 

 
 
  
41 
 
 
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 by review of the medical chart. 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
follow-up phase and should be assessed as per discretion of treating oncologist. Every effort should be 
made to collect information regarding disease status until the start of new anti-neoplastic therapy, 
disease progression, death, end of the study.  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 disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject associated with administered of a pharmaceutical product and/or use of a medical procedure, 
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, 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. 
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment must be reported by 
the investigator if they cause the subject to be excluded from the trial, or are the result of a protocol-

 
 
  
42 
 
 
specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, or a 
procedure. 
From the time of treatment 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 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 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before 
intervention allocation/randomization must be reported by the investigator if the participant is receiving 
placebo run-in or other run-in treatment, if the event cause the participant to be excluded from the 
study, or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
• All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator. 
• All AEs meeting serious criteria, from the time of intervention allocation/randomization through 
90 days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. 
• All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days following cessation of study intervention, or 30 days 
following cessation of study intervention if the participant initiates new anticancer therapy must 
be reported by the investigator. 
• Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately to Merck if the event is considered drug-
related. 
 
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in former 
study participants. However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be reasonably related 
to the study intervention or study participation, the investigator must promptly notify Merck. 

 
 
  
43 
 
 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and reported to 
Merck within the time frames as indicated in the table below : 
Table: Reporting Time Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events 
 
Type of Event 
Reporting Time 
Period: 
Consent to 
Randomization/ 
Allocation 
Reporting Time 
Period: 
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Merck: 
 
 
 
 
 
Serious Adverse Event 
(SAE) including Cancer 
and Overdose 
Report if: 
- due to protocol-
specified 
intervention 
- causes exclusion 
- participant is 
receiving placebo 
run-in or other run-
in treatment 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event 
Pregnancy/Lactation 
Exposure 
Report if: 
- due to 
intervention 
- causes exclusion 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event 
Event of Clinical 
Interest (require 
regulatory reporting) 
Report if: 
- due to 
intervention 
- causes exclusion 
Report 
- potential drug-
induced liver 
injury (DILI) 
- require regulatory 
reporting 
Not required 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event 
 
 
 
 
 

 
 
  
44 
 
 
7.2.2 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 5 working 
days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 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 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 

 
 
  
45 
 
 
7.2.4 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.4.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event 
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment, any serious 
adverse event, or follow up to a serious adverse event, including death due to any cause other 
than progression of the cancer under study (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 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 progression 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. 

 
 
  
46 
 
 
SAE reports and any other relevant safety information are to be forwarded on a 
MedWatch form (FDA 3500) to the Merck Global Safety facsimile number:  +1-215-661-
6229 
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. 
7.2.4.2 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 5 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, any ECI, or 
follow up to an ECI, that occurs to any subject must be reported within 5 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 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 5 days 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. 

 
 
  
47 
 
 
7.2.4.3 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 Merck Global Safety within 5 working days either by electronic or 
paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression 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 progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 5 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered 
a SAE. 
 
7.2.5 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. Intensity of all 
adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events v 4.0 (CTCAE) on a five-point scale (grades 1 to 5, Table 6) and reported in 
detail on the CRF.  Any adverse event which changes CTCAE grade over the course of a 
given episode will have each change of grade recorded on the adverse event case report 
forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

 
48 
 
Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 

 
49 
 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken 
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product 
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 

 
50 
 
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.) 

 
51 
 
 
 
7.2.6 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB and investigators in 
accordance with all applicable global laws and regulations. 
8.0 CORRELATIVE/SPECIAL STUDIES 
We will perform immunohistochemistry and flow cytometric analysis in order to find 
markers that correlate with or predict response to neoadjuvant treatment. Whole exome 
sequencing, RNA expression analysis, and T-cell receptor sequencing may also be 
considered to explore expression profiles of tumor neo-antigens, immune modulators, and T 
cell repertoires. Immunohistochemistry and immunofluorescence will be performed on 
optional pretreatment biopsy and surgical resection specimens using standard methodology 
and an automated analyzer. Imaging analysis will be used for quantification. Flow cytometric 
analysis will be performed on peripheral blood samples and tumor specimens to characterize 
the peripheral blood immunophenotype and tumor immune cell infiltrate in patients receiving 
chemoradiotherapy and pembrolizumab.  We will use CD3, CD4, CD8, B220, Foxp3, PD-1, 
Eomes, Ki67, and Granzyme B staining to analyze the tumor lymphocyte population, 
including quantification of the immunoinhibitory Treg population and characterization of 
exhausted versus reinvigorated effector T cells. We will utilize CIBERSORT to characterize 
the tumor immune cell composition.  CIBERSORT is a computational method that analyzes 
RNA expression data within complex tissues to quantify estimated fraction of leukocyte 
subsets, including naïve and memory B cells, CD8+ T cells, resting and activated memory 
CD4+ T cells, natural killer cells, monocytes, macrophage subtypes, resting and activated 
dendritic cells, and neutrophils (31). Flow cytometry, immunohistochemistry, and/or 
immunofluorescence will be employed to assess cell surface expression of MHC-I, PD-1, 
PD-L1, PD-L2, and CTLA-4 in pre-treatment biopsy and surgical resection specimens. Given 
that tumor mutational load correlates with clinical response to anti-PD-1 therapy 
administered in the absence of radiation therapy (15, 30), whole exome sequencing may be 
performed to correlate mutational load with outcomes. Finally, next-generation deep 
sequencing may be used to assess diversity of the T cell receptor repertoire and heterogeneity 
8.1 
Collection, Handling, and Shipping of Specimens 
Additional blood and tumor samples will be collected for research purposes only. Some of 
these research studies are mandatory for study participation and some are optional. The 
optional studies will be performed only on patients who have provided informed consent for 
each individual study. Samples will be transported in compliance with current regulatory 
guidelines for transport of biological specimens. 
 
8.1.1 Tumor Samples (optional) 
Paraffin-embedded samples from initial tumor biopsy will be assessed for PDL-1 expresssion 
using an house testing platform. Fresh tumor biopsies via endoscopic procedure at study 

 
52 
 
entry are optional for patients who have provided written consent for this separate procedure. 
Fresh tissue from surgical resection specimen will be processed and stored in the Duke 
biorepository. 
8.1.2 Blood Samples 
Blood samples will be analyzed via flow cytometry for the presence of PD-1 expressing T 
cells as well as for the proportion of circulating regulatory T cells (Tregs) and myeloid-
derived suppressor cells (MDSCs). Other immune cell populations may also be explored.  
Plasma may also be analyzed for cytokines and genetic alterations in cell free DNA related to 
tumor immunology and cancer biology. Please see Table below for complete blood sample 
collection schedule. Three acid citrate dexatrose (ACD) and 2 ethylenediamine tetraacetic 
acid (EDTA) will be obtained at the following time points: 
Time points for blood sample collections 
Pre-treatment 
After consent is signed, prior to first study drug administration 
On-treatment 
Week 3 of chemoradiation +pembrolizumab 
On-treatment 
Post- Cycle 3, prior to surgical resection 
On-treatment 
After surgery, Pre-Cycle 4 
Post-treatment 
30 days post-Cycle 6 
 
8.2 
Correlative Studies 
The following correlative studies will be performed using PBMCs and tumor tissues 
collected from the patients included in the study: 
 
The planned Correlative Science (CS) studies for this Phase II clinical trial will focus on 
comprehensive immune profiling of the pre- and post-treatment tumor microenvironment 
(TE) as well as baseline and longitudinal Peripheral blood mononuclear cells (PBMCs) 
samples in an attempt to identify both baseline signatures that predict which patients might 
benefit from neoadjuvant pembrolizumab plus concurrent chemoradiotherapy as well as 
pharmacodynamic signatures that could provide mechanistic insights regarding therapeutic 
responses. Given the past difficulties in the identification of anti-PD-1 signatures in the 
peripheral circulation (i.e. PBMC), special emphasis will be placed on immune profiling the 
TE. The principal profiling platform to be used in these studies will be highly standardized, 
polychromatic flow cytometry assays that have been developed by the Duke Immune 
Profiling Core (DIPC) specifically for monitoring immune signatures in the context of 
immune checkpoint blockade trials. 
 

 
53 
 
The 3 proposed immune profiling panels for this trial are depicted below, and include: 1) a 
12-color ‘Exhaustion Panel’, 2) a 12-color ‘Tumor Reactive T Cell Panel’, and 3) a 14-color 
regulatory T cell (Treg) and monocytic myeloid-derived suppressor cells (m-MDSC) panel. 
Each of these established panels can also serve as a base for inclusion of additional 
phenotypic markers of interest. Instrumentation within DIPC includes a 4-laser BD SORP 
LSRII analyzer (19-parameter capacity), a 5-laser BD SORP LSRFortessa analyzer (21-
parameter capacity), and a 5-laser BD SORP LSRFortessa X50 analyzer (46-parameter 
capacity). This later instrument with 5 high powered lasers, each serving a decagon 
composed of 10 tunable detectors, is capable of highly efficient high dimension profiling, 
and includes a ‘microfluidics console’ that is ideally suited for comprehensive analyses of 
samples with limited cellular content such as occasional TE specimens. ‘Reportables’ for all 
the immune profiling analyses will include single parameter frequencies (62 for the 
‘exhaustion’ panel; 54 for the ‘tumor reactive’ panel; and 73 for the ‘Treg and MDSC’ panel) 
in addition to frequencies of selected co-expression markers. 
 
 

 
54 
 
 
In addition to the 3 proposed phenotyping panels above, a fourth ‘Intracellular Cytokine 
Staining’ (ICS) panel will be included to measure the frequency and relative 
polyfunctionality of T cell reactivities against highly conserved tumor associated antigens 
(TAA).  Based on the expression of TAA by the individual patient’s pre-treatment tumor, 
PBMC and TE samples will be stimulated with TAA peptide pools consisting of 15-mers 
with 11 amino acid overlaps in the presence of a transport inhibitor. The antigen-driven T 
cell response will be assessed by determining the frequencies of CD4+ and CD8+ T cells 
staining positive for intracellular IFN-γ, IL-2, TNF-α, granzyme B, and expression of 
CD107a. Using Boolean gating, the relative polyfunctionality of the anti-TAA responses can 
be delineated. 
The proposed Correlative Science studies for this Phase II protocol will test the following 
hypotheses: 
1) 
Neoadjuvant pembrolizumab with concurrent chemoradiotherapy and adjuvant 
pembrolizumab will produce higher frequencies of activated T cells in PBMC 
and TE than standard of care chemoradiotherapy alone. 
2) 
Enrolled 
patients 
with 
an 
immunologically 
activated 
(‘hot’) 
tumor 
microenvironment (TE) at baseline will derive greater therapeutic benefit from 
neoadjuvant pembrolizumab therapy than those with a non-activated (‘cold’) TE. 
• Baseline TE containing >20% CD8+ cells co-expressing CTLA-4 and 
PD-1 will constitute an immunologically activated TE 
3) 
Enrolled patients with PDL-1+ tumors will derive greater therapeutic benefit 
than patients with PDL-1- tumors. 
4)  Clinical Response(s) to therapy will be accompanied by an increase in the 
frequency and polyfunctionality of anti-TAA T cell responses in PBMC and TE. 
 
9.0 STUDY EVALUATIONS AND STUDY CALENDAR 
9.1 
Screening Studies 
The following procedures will be performed during the screening period: 
• Informed consent 
• History/demographics updated within 2 weeks prior to patient enrollment 
• Documentation of cancer 
• CBC with differential 
• Comprehensive Serum Chemistry Panel 
• T3, FT4, and TSH 
• Urinalysis 
• Serum β–HCG or urine pregnancy test for women of childbearing potential 
• Blood for research studies (PBMCs) will be collected (pre-treatment) after study 
consent is signed 
• Optional Tumor Biopsy (pre-treatment) after study consent is signed 

 
55 
 
• Staging imaging (CT CAP or PET/CT) to confirm no evidence of metastatic disease 
• EUS for local tumor staging (if ultrasound probe able to traverse tumor). Not required 
if EUS probe cannot traverse the lesion. 
• EKG within 30 days prior to first study drug administration. 
 
The screening period can be up to 30 days prior to first study drug administration (Day 1 
Cycle 1). Laboratory baseline evaluations are to be conducted within 14 days prior to first 
administration of study drug. Radiologic imaging must be done within 45 days prior to first 
study drug administration. 
 
9.2 
On Study Evaluations 
Visits will occur with the treating medical oncologist at each pembrolizumab treatment visit 
(i.e. every 3 weeks during Cycles 1 – 3 and Cycles 4 – 6) from study initiation. The 
following procedures will be performed during the pembrolizumab treatment period: 
• Physical exam, including weight, vital signs, ECOG performance status 
• Administration of study drug 
• Recording of adverse events 
• Relevant laboratory evaluations, WBC, Hgb, Plt, ANC, Cr, K, Ca, ALT, AST, Total 
Bilirubin, alkaline phosphatase, TSH 
• Blood for research studies (PBMCs) will be collected at week 3 of chemoradiation, 
prior to surgery, and prior to cycle 4 and at safety follow up visit 
• Disease assessments will be performed at after completion of neoadjuvant 
chemoradiation and then at the treating physicians discretion 
 
Visits will occur with the treating radiation oncologist once weekly during the five week 
radiation treatment period.  The following procedures will be performed during the radiation 
treatment period: 
• Physical exam, including weight, vital signs, ECOG performance status 
• Recording of adverse events 
 
A visit with the operating surgeon will typically occur within four-eight weeks of completing 
chemoradiotherapy to assess treatment-induced toxicity and determine optimal timing for 
surgical resection. Additional postoperative visits by the surgeon will occur as per treating 
physician’s discretion. 
 
Subsequent follow-up visits will occur approximately every 3-6 months for the first two 
years after treatment, every 6-12 months during years three to five as per discretion of 
treating physicians.  These visits may alternate among the medical oncologist, radiation 
oncologist, and surgeon.  The following will be performed during this post-treatment period: 
• Physical exam, including weight, vital signs, ECOG performance status 
• Recording of adverse events (up to 90 days after last dose of pembrolizumab) 
• CT CAP or PET/CT 
 

 
56 
 
9.3 
Off Study Evaluation 
Final visit is to be performed at the time (or within 30 days +/- 14 days) of removal from the 
study if adjuvant therapy is administered. Off study evaluations will include: 
• Physical exam: height, weight vital signs, ECOG performance status 
• Recording of adverse events (for unresolved adverse events, patients should be 
monitored for 30 days following the last dose of study drug) 
 
Patients who complete study treatment should be followed for local recurrence, distant 
recurrence, progression free and overall survival every 6 months by retrospective review of 
the patient’s chart or by phone call. 
 
10.0 STATISTICAL ANALYSIS PLAN 
10.1 Statistical Analysis Plan 
The primary objective of this one-arm Phase II trial is to test whether neoadjuvant 
chemoradiotherapy combined with Pembrolizumab followed by surgical resection has a 
pathologic complete response (pCR) rate that is significantly larger than the historical control 
pCR rate observed with standard of care (neoadjuvant radiotherapy followed by surgical 
resection). A historical pCR rate of 0.23 (van Hagen, 2012) was observed in 161 patients. An 
accrual rate of about 12 patients per year is expected in this trial. While the planned statistical 
design requires no more than 30 patients (30 months of accrual), the trial could accrue as 
many as 38 patients (36 months of accrual) in order to replace patients who withdraw before 
surgery. Thus, the length of the trial could be as long as 41 months (i.e., 36 months of accrual 
plus 5 months for the last patient to be evaluated for response). 
A two-stage design will be used to test the null hypothesis that the true pCR rate is ≤ 0.30 
against the alternative hypothesis that the true pCR rate is ≥ 0.50. This design will allow the 
trial to stop early to accept the null hypothesis. If there are no more than 4 responders (27%) 
in the first 15 evaluable patients, the trial will stop to accept the null. Otherwise, an 
additional 15 evaluable patients will be accrued. The null will be rejected only if at least 13 
(43%) or more of the 30 patients respond. The significance level and power of this design are 
0.08 and 0.81, respectively. The probability of early termination under the null and 
alternative hypotheses is 0.56 and 0.06, respectively. The observed pCR rate will be 
estimated with its exact 80% confidence interval. 
 
Secondary Objective 1 is to estimate the safety of the study treatment. Toxicity by type and 
grade will be tabulated. Toxicity rates of interest will be calculated with their 80% 
confidence intervals. Only 2 Grade+3 toxicities of any type will be tolerated in the first ten 
accrued patients. If and when a third Grade 3+ toxicity is observed in the first ten patients, a 
dose reduction in radiation will be considered. 
 
Exploratory Objective 1 is to estimate the association between pCR rate and selected 
predictors of response. Using categorical predictors of clinical interest, pCR rates with their 
80% confidence intervals will be presented according to the level of the predictors. 

 
57 
 
Exploratory Objective 2 is to estimate the distribution of time to local recurrence (TTLR), 
time to distant recurrence (TTDR), progression free survival (PFS), and overall survival 
(OS). Local recurrence will be defined as the time from enrollment to local recurrence; 
distant recurrences will be ignored and deaths will be censored.  TTDR will be defined 
analogously. PFS will be defined as the time from enrollment to local recurrence, distant 
recurrence, or death due to any cause, whichever comes first. OS is defined as the time from 
enrollment to death due to any cause. The Kaplan Meier method will be used to estimate 
these four distributions. 
10.1.1 Interim Analysis to Monitor Safety 
After the first 5 eligible patients have been accrued to the study, an analysis will be 
performed to assess acute treatment-related toxicity. If more than 1, grade 3 or greater 
toxicities is definitely related to concurrent pembrolizumab and chemoradiotherapy are 
observed, then an additional five patients will be added to this treatment arm. If no issues 
concerning for safety are observed within 30 days of the last dose of neoadjuvant 
pembrolizumab (cycle 3) for the fifth patient, then the study will continue to accrue. Patients 
accrued prior to the interim analysis will be evaluated for the primary endpoint. 
11.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
11.1 Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
11.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 

 
58 
 
11.3 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. 
11.4 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. 
11.5 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. 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Confidentiality 
All patient data will be captured and maintained in a study specific database with password 
protected access. Data is entered using an assigned patient identification number. The data 
provided to those reviewing the results, for example the study statistician will include the 
patient identification numbers, but will not include patient identifiable data. The research 
samples obtained in this study will only be sent using the patient identification number which 
can only be linked to the patient at a given institution by the treating physician. All 
documentation that contains personal health information that may include patient identifiable 
information will be maintained at the site to preserve patient confidentiality. 
 
12.2 Compliance with Financial Disclosure Requirements 
By signing this protocol, the investigator agrees to provide to the Sponsor accurate financial 
information to allow the Sponsor to submit complete and accurate certification and disclosure 
statements as required by U.S. Food and Drug Administration regulations (21 CFR Part 54). 

 
59 
 
The 
investigator 
further 
agrees 
to 
provide 
this 
information 
on 
a 
Financial 
Disclosure/Certification Form that is provided by Merck Sharp & Dohme Corp., a subsidiary 
of Merck & Co., Inc. This requirement also extends to sub investigators. The investigator 
also consents to the transmission of this information to Merck Sharp & Dohme Corp., a 
subsidiary of Merck & Co., Inc., in the United States for these purposes. This may involve 
the transmission of information to countries that do not have laws protecting personal data. 
 
12.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; 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 study. 
 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations Sponsored by Merck is attached. The investigator 
also agrees to allow monitoring, audits, Institutional Review Board/Independent Ethics 
Committee review, and regulatory agency inspection of trial-related documents and 
procedures and provide for direct access to all study-related source data and documents. 
 
The investigator agrees not to seek reimbursement from subjects/patients, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor. 
 
The Investigator shall prepare and maintain complete and accurate study documentation in 
compliance with Good Clinical Practice standards and applicable federal, state, and local 
laws, rules and regulations; and, for each subject/patient participating in the study, provide all 
data, and upon completion or termination of the clinical study submit any other reports to the 
sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor. 
 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the investigator’s site upon request for 
inspection, copying, review, and audit at reasonable times by representatives of the Sponsor 
or any regulatory agencies. The investigator agrees to promptly take any reasonable steps that 
are requested by the Sponsor as a result of an audit to cure deficiencies in the study 
documentation and worksheets/case report forms. 
 
International Conference of Harmonization Good Clinical Practice guidelines (Section 4.3.3) 
recommend that the investigator inform the subject’s primary physician about the subject’s 
participation in the trial if the subject has a primary physician and if the subject agrees to the 
primary physician being informed. 
 
According to European legislation, a Sponsor must designate a principal or coordinating 
investigator (CI) to review the report (summarizing the study results) and confirm that to the 
best of his/her knowledge the report accurately describes conduct and results of the study. 

 
60 
 
The Sponsor may consider one or more factors in the selection of the individual to serve as 
the CI (e.g., thorough understanding of clinical trial methods, appropriate enrollment of 
subject/patient cohort, timely achievement of study milestones, availability of the CI during 
the anticipated review process). 
 
The investigator will promptly inform the Sponsor of any regulatory agency inspection 
conducted for this study. 
 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred, or if any proceeding for debarment is pending or, to the 
best of the investigator’s knowledge, threatened. 
 
In the event the SPONSOR prematurely terminates a particular trial site, the SPONSOR will 
promptly notify that site’s IRB/IEC. 
 
12.4 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. 
12.5 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written 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 study. 
 
12.6 Data Management 
All patient data will be captured and maintained in a study-specific database with password-
protected access (REDCAP). Data is entered using an assigned patient identification number.  
The data provided to those reviewing the results, for example the study statistician, will 
include the patient identification numbers, but will not include patient identifiable data. 
 
The research samples obtained in this study will only be sent using the patient identification 
number, which can only be linked to the patient by the study team. All documentation that 
contains personal health information that may include patient identifiable information will be 
maintained at the site to preserve patient confidentiality. 

 
61 
 
 
Access to the password-protected study website will be limited to individuals involved in the 
clinical trial: overall Study PI, research nurses, and data managers responsible for this trial. 
Adverse Events reporting will be performed as outlined in Section 7. 
 
 
This clinical research study will be monitored both internally by the PI and institutionally by 
the Duke Cancer Institute (DCI).  In terms of internal review the PI will continuously 
monitor and tabulate adverse events.  Appropriate reporting to the Duke University Medical 
Center IRB will be made.  If an unexpected frequency of Grade III or IV events occur, 
depending on their nature, action appropriate to the nature and frequency of these adverse 
events will be taken.  This may require a protocol amendment, dose de-escalation, or 
potentially closure of the study.  The PI of this study will also continuously monitor the 
conduct, data, and safety of this study to ensure that: 
Interim analyses occur as scheduled; 
Stopping rules for toxicity and/or response are met; 
Risk/benefit ratio is not altered to the detriment of the subjects; 
Appropriate internal monitoring of AEs and outcomes is done; 
Over-accrual does not occur; 
Under-accrual is addressed with appropriate amendments or actions; 
Data are being appropriately collected in a reasonably timely manner. 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved 
Data and Safety Monitoring Plan.  Briefly, protocol review begins with an initial review by 
the Cancer Protocol Committee (CPC), which assesses the ethics and safety of the protocol.  
Documentation of these assessments will be maintained.  Formal, independent monitoring 
will be conducted by the DCI Monitoring Team after the first 3 subjects are enrolled, 
followed by annual monitoring of 1-3 subjects until the study is closed to enrollment and 
subjects are no longer receiving study interventions that are more than minimal risk.  DCI 
Monitoring Team reports and additional data/safety/toxicity reports submitted by the PI will 
be reviewed by the Safety Oversight Committee (SOC) on an annual basis.  Additional 
monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns.  Monitoring visits may also be 
initiated upon request by DUHS and DCI Leadership, CPC, SOC, a sponsor, an investigator, 
or the IRB. 
The Duke School of Medicine Office of Audit, Risk and Compliance (OARC) office may 
conduct confidential audits to evaluate compliance with the protocol and the principles of 

 
62 
 
GCP.  The PI agrees to allow the OARC auditor(s) direct access to all relevant documents 
and to allocate his/her time and the time of the study team to the OARC auditor(s) in order to 
discuss findings and any relevant issues. 
OARC audits are designed to protect the rights and well-being of human research subjects. 
OARC audits may be routine or directed (for cause). Routine audits are selected based upon 
risk metrics generally geared towards high subject enrollment, studies with limited oversight 
or monitoring, Investigator initiated Investigational Drugs or Devices, federally-funded 
studies, high degree of risk (based upon adverse events, type of study, or vulnerable 
populations), Phase I studies, or studies that involve Medicare populations. Directed audits 
occur at the directive of the IRB or an authorized Institutional Official. 
OARC audits examine research studies/clinical trials methodology, processes and systems to 
assess whether the research is conducted according to the protocol approved by the DUHS 
IRB. The primary purpose of the audit/review is to verify that the standards for safety of 
human subjects in clinical trials and the quality of data produced by the clinical trial research 
are met. The audit/review will serve as a quality assurance measure, internal to the 
institution. Additional goals of such audits are to detect both random and systemic errors 
occurring during the conduct of clinical research and to emphasize “best practices” in the 
research/clinical trials environment. 
 
12.6.1.1 
Database Access 
This study uses REDCAP, a web-based data entry system for electronic data capture (EDC). 
All patient registrations and Case Report Forms (CRFs) will be entered electronically via the 
study website. 
12.6.1.1 Enrolling a Patient 
A signed informed consent document(s) will be obtained prior to entry into the study. Patients 
who consent and are being evaluated for eligibility should be tracked on the site screening log. 
Following consent and verification of eligibility, patients will be registered in the study database. 
Please note that only patients who meet all eligibility criteria will be registered in the study 
database. 
 
Each enrolled patient will automatically be assigned a unique patient identification number 
following registration in the study database. 
 
12.6.1.1 Data Entry 
Required eCRFs should be submitted electronically within 10 working days of the required visit. 
Serious Adverse Events (SAEs) should be entered into the database as soon as possible and no 
later than 5D days after site PI was initially informed of the SAE. 

 
63 
 
13.0 APPENDICES 
13.1 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. 
 
13.2 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) 
Adverse events not listed on the CTCAE should be graded as follows: 

 
64 
 
CTC Grade 
Equivalent To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily 
activity 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated although this 
could improve the overall well-being or symptoms of the 
patient 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment 
or medical intervention is indicated in order to improve the 
overall well-being or symptoms; delaying the onset of 
treatment is not putting the survival of the patient at direct 
risk. 
Grade 4 
Life threatening 
or disabling 
An immediate threat to life or leading to a permanent mental 
or physical conditions that prevents work or performing 
normal daily activities; treatment or medical intervention is 
required in order to maintain survival. 
Grade 5 
Death 
AE resulting in death 
 

 
65 
 
 
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