Clinical trial NCT02918162
Conditions: Gastric Cancer Adenocarcinoma of the Gastroesophageal Junction
Keywords: pembrolizumab adenocarcinoma gastric cancer Locoregional gastric adenocarcinoma Locoregional GE junction adenocarcinoma
Sponsor: Gulam Manji
Start date: 2017-11-25; Completion date: 2023-02-28
Enrollment: 49 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a non-randomized, multi-site, open-label trial of pembrolizumab and chemotherapy in subjects with gastric or gastroesophageal (GE) junction adenocarcinoma. The purpose of this study is to determine and evaluate the efficacy of combination therapy with immune checkpoint blockade and chemotherapy used in the perioperative period in eradicating micrometastatic disease; and to compare paired tissue and serum samples (pre-treatment and post-treatment) from individually treated patients to explore the immune effects of combination therapy and predictors of response.

Detailed description:
Gastric cancer is one of the most common cancers worldwide. Surgical resection is the primary treatment for gastric cancer but most patients present with locally advanced disease and recurrence is common after surgery. Many patients (35%) will have early recurrence within 6-9 months of surgery indicating the need for more aggressive upfront therapy in these subjects. In addition, the majority of patients will ultimately have recurrence and 5 year survival rates are 35-40% despite aggressive therapy.

The ability to combine immunotherapy with pembrolizumab gives the potential to increase therapeutic options while continuing standard of care chemotherapy. The particular use of maintenance therapy may delay or eliminate the growth of residual micrometastatic disease and lead to durable disease control. Additionally, this study provides the foundation for substantial correlative work to define tumor and patient characteristics that may predict for response to pembrolizumab in gastric cancer.

The initial primary outcome of Disease Free Survival (DFS) was changed to pathologic complete response rate (pCR) on November 24, 2020, at which time no formal data analysis had been preformed.

Arms: arm 1: All study subjects will receive standard of care chemotherapy regimen for 3 cycles prior to and 3 cycles following surgery in combination with Pembrolizumab with an additional cycle of Pembrolizumab (4 total) in the pre-operative period. Additionally subjects will complete 12 months of maintenance Pembrolizumab (14 additional doses to complete 17 post-operative cycles) following completion of post-operative chemotherapy.

Standard of care combination chemotherapy regimen has a 21-day cycle.
Interventions: intervention 1: Pembrolizumab intervention 2: Standard of care chemotherapy regimen
Intervention descriptions: intervention 1: Pembrolizumab dosed IV at 200mg every 21 days per cycle. intervention 2: Standard regimen containing at least a platinum and Fluorouracil (5-FU) agent (per National Comprehensive Cancer Network guidelines) - such as Doublet or Triplet chemotherapy with capecitabine, oxaliplatin, and epirubicin (optional) (21 day cycle). Epirubicin can be excluded at the discretion of the treating physician.

Example:

Oxaliplatin dosed IV at 130 mg/m2 every 21 days per cycle. Capecitabine dosed orally at 625mg/m2 twice a day daily.

Protocol documents:
Prot_SAP_000.pdf: 
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CUMC IRB#: AAAQ9871 
Version Date: Version 1.9; 10 AUG 2021 
TITLE: A Phase II study of chemotherapy and immune checkpoint blockade with 
Pembrolizumab in the perioperative and maintenance treatment of locoregional gastric 
or GE junction adenocarcinoma. 
SPONSOR: 
Gulam Manji, MD., PhD.,  
Columbia University Medical Center 
Coordinating Center: 
Columbia University Medical Center/ 
NewYork-Presbyterian 
Principal Investigator: 
Gulam Manji, MD., PhD. 
161 Fort Washington Ave 
New York, NY 10032 
Telephone: (212) 305-7115 
Email address: gam2140@cumc.columbia.edu 
Collaborating Institution 
Weill Cornell Medical College/ 
NewYork-Presbyterian 
Co-Principal Investigator: 
Manish A. Shah, MD 
1305 York Avenue, Room Y1247 
New York, NY 10021 
Telephone: 646-962-2547 
Fax: 646-962-1607 
Email address: mas9313@med.cornell.edu 
Collaborating Institution 
Washington University in St. Louis 
Co-Investigator: 
Haeseong Park, MD 
660 S. Euclid Ave., Room 8056 
St. Louis, MO 63110 
Telephone: 314-362-5740  
Fax: 314-362-7086 
Email address: haeseongpark@wustl.edu 
Collaborating Institution 
Rhode Island Hospital/Lifespan Cancer Institute 
Co-Investigator: 
Alexander Raufi, MD 
164 Summit Ave. Fain building 3rd floor 
Providence, RI 02906 
Telephone: 401-793-2920 
Fax: 401-793-7603 
Email address: ARaufi2@Lifespan.org 
NCT02918162


 
 
 
 
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IND NUMBER: 
 
 
 
 


 
 
 
 
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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 9 
1.1 
PROTOCOL SYNOPSIS ..................................................................................... 10 
2.0 
TRIAL DESIGN........................................................................................................ 12 
2.1 
Trial Design ........................................................................................................... 12 
2.2 
Trial Diagram ........................................................................................................ 13 
3.0 
Objectives and hypotheses ....................................................................................... 14 
3.1 
Primary Objective & Hypothesis ........................................................................ 14 
3.2 
Secondary Objectives & Hypotheses ................................................................... 14 
3.3 
Exploratory Objectives & Hypotheses ................................................................ 14 
4.0 
BACKGROUND & RATIONALE .......................................................................... 14 
4.1 
Background ........................................................................................................... 14 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 15 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 17 
4.1.3 Ongoing Clinical Trials ....................................................................................... 17 
4.2 
Rationale ................................................................................................................ 18 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 18 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 19 
4.2.3 Rationale for Endpoints ...................................................................................... 21 
5.0 
METHODOLOGY ................................................................................................... 24 
5.1 
Entry Criteria ........................................................................................................ 24 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 24 
5.1.2 Subject Inclusion Criteria.................................................................................... 24 
5.1.3 Subject Exclusion Criteria .................................................................................. 25 
5.2 
Trial Treatments ................................................................................................... 27 


 
 
 
 
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5.2.1 Dose Selection/Modification .............................................................................. 27 
5.2.2 Timing of Dose Administration .......................................................................... 30 
5.2.3 Trial Blinding/Masking ....................................................................................... 32 
5.3 
Randomization or Treatment Allocation ............................................................ 32 
5.4 
Stratification .......................................................................................................... 32 
5.5 
Concomitant Medications/Vaccinations ............................................................. 32 
5.5.1 Acceptable Concomitant Medications ................................................................ 32 
5.5.2 Prohibited Concomitant Medications.................................................................. 32 
5.6 
Rescue Medications & Supportive Care ............................................................. 33 
5.6.1 Supportive Care Guidelines ................................................................................ 33 
5.6.2 Supportive Care Guidelines for Chemotherapy Agents ...................................... 36 
5.7 
Diet/Activity/Other Considerations ..................................................................... 37 
5.7.1 Diet ...................................................................................................................... 37 
5.7.2 Contraception ...................................................................................................... 37 
5.7.3 Use in Pregnancy ................................................................................................ 38 
5.7.4 Use in Nursing Women ....................................................................................... 39 
5.8 
Subject Withdrawal/Discontinuation Criteria ................................................... 39 
5.8.1 Discontinuation of Study Therapy after CR ....................................................... 40 
5.9 
Subject Replacement Strategy ............................................................................. 40 
5.10 
Clinical Criteria for Early Trial Termination ................................................... 41 
5.11 
Inclusion of Women and Minorities .................................................................... 41 
6.0 
TRIAL FLOW CHART ........................................................................................... 43 
7.0 
TRIAL PROCEDURES ........................................................................................... 46 
7.1 
CUMC Research Participant Registration ......................................................... 46 
7.1.1 CPDM Central Registration Procedures: ............................................................ 46 


 
 
 
 
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7.2 
Trial Procedures ................................................................................................... 47 
7.2.1 Administrative Procedures .................................................................................. 48 
7.2.2 Clinical Procedures/Assessments ........................................................................ 50 
7.2.3 Laboratory Procedures/Assessments .................................................................. 52 
7.2.4 Other Procedures ................................................................................................. 54 
7.2.5 Visit Requirements .............................................................................................. 54 
7.3 
Assessing and Recording Adverse Events .......................................................... 56 
7.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor-Investigator and to Merck ..................................................................... 57 
7.3.2 Reporting of Pregnancy and Lactation to the Sponsor-Investigator and to 
Merck .................................................................................................................. 57 
7.3.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 58 
7.3.4 Evaluating Adverse Events ................................................................................. 60 
7.3.5 Sponsor-Investigator Responsibility for Reporting Adverse Events .................. 64 
7.3.6 Reporting Process ............................................................................................... 65 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 65 
8.1 
Statistical Analysis Plan Summary ..................................................................... 65 
8.1.1 Primary Endpoint ................................................................................................ 65 
8.1.2 Secondary Endpoint ............................................................................................ 66 
8.1.3 Exploratory and Ancillary Studies ...................................................................... 66 
8.2 
Statistical Analysis Plan Details ........................................................................... 66 
8.2.1 Efficacy Endpoints .............................................................................................. 66 
8.2.2 Safety Endpoints ................................................................................................. 67 
8.2.3 Statistical Methods for Safety Analysis .............................................................. 67 
8.2.4 Analysis Populations ........................................................................................... 67 
8.2.5 Measurement of Effect ........................................................................................ 67 


 
 
 
 
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9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 69 
9.1 
Investigational Product ........................................................................................ 69 
9.2 
Packaging and Labeling Information ................................................................. 70 
9.3 
Clinical Supplies Disclosure ................................................................................. 70 
9.4 
Storage and Handling Requirements .................................................................. 70 
9.5 
Returns and Reconciliation .................................................................................. 70 
10.0 
ADMINISTRATIVE/ Data Reporting AND REGULATORY DETAILS .......... 71 
10.1 
Data Collection ...................................................................................................... 71 
10.2 
Data Reporting ...................................................................................................... 71 
10.3 
Data and Safety Monitoring Committee ............................................................. 71 
10.4 
Quality Control and Quality Assurance ............................................................. 72 
10.5 
Confidentiality ....................................................................................................... 73 
10.6 
Source Documents ................................................................................................. 73 
10.7 
Case Report Forms ............................................................................................... 73 
10.8 
Records Retention ................................................................................................. 73 
10.9 
Ethical Considerations ......................................................................................... 74 
10.9.1 Institutional Review Board or Ethics Committee Approval ............................... 74 
10.10 Study Finances ...................................................................................................... 74 
10.10.1 
Conflict of Interest ....................................................................................... 74 
10.10.2 
Subject Stipends or Payments ...................................................................... 74 
10.11 Compliance with Trial Registration and Results Posting Requirements ........ 74 
11.0 
Protection of Human Subjects ................................................................................. 75 
12.0 
Publication Plan ........................................................................................................ 75 
13.0 
APPENDICES ........................................................................................................... 76 
13.1 
ECOG Performance Status .................................................................................. 76 


 
 
 
 
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13.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 76 
13.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 76 
13.4 
Guidelines for Affiliate Institutions in Multicenter Studies .............................. 76 
14.0 
List of references ....................................................................................................... 85 
 
 
 


 
 
 
 
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LIST OF TABLES 
Table 1   
Adequate Organ Function Laboratory Values 
24 
Table 2   
Trial Treatment 
27 
Table 3   
Dose modifications for Trial Medications 
28 
Table 4   
Dose Modification Guidelines for Drug-Related Adverse Events for 
Pembrolizumab 
29 
Table 5  
Infusion Reaction Treatment Guidelines 
36 
Table 6   
Study Flow Chart 
43 
Table 7   
Laboratory Tests 
53 
Table 8      Evaluating Adverse Events 
61 
Table 9      Product Descriptions 
70 
 


 
 
 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Perioperative chemotherapy and pembrolizumab in locally advanced 
gastric cancer 
Trial Phase 
Phase II 
Clinical Indication 
Gastric or Gastroesophageal Junction Adenocarcinoma 
Trial Type 
Interventional 
Type of control 
No Treatment Control (historical control) 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded Open-Label 
Treatment Groups  
Single Cohort: Standard of care combination peri-operative chemotherapy 
plus Pembrolizumab with Pembrolizumab maintenance.  
Number of trial subjects 
28 evaluable  
Estimated enrollment period 
18 months 
Estimated duration of trial 
We estimate that the trial will require 36 months from the time the first 
subject signs informed consent until the last subject completes the final 
treatment. It will take an estimated 18 months to complete enrollment of 
all subjects. 
Duration of Participation 
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through final contact. After a screening 
phase, eligible subjects will be enrolled on the trial and will begin 
chemotherapy and pembrolizumab on Cycle 1 Day 1. Treatment will 
continue for 12 weeks and then be paused for surgical planning and 
surgical resection. Subjects will resume therapy with Cycle 5 Day 1 
following surgical recovery which is estimated to be between 6-10 weeks 
following surgery. Once subjects resume on Cycle 5 Day 1, they will 
continue pembrolizumab treatment every 3 weeks for 17 cycles total.  
Treatment will continue unless there is documented disease progression or 
recurrence following surgery, unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, Investigator’s 
decision to withdraw the subject, subject withdraws consent, pregnancy of 
the subject, noncompliance with trial treatment or procedure requirements, 
subject receives 17 cycles of study medication, or administrative reasons 
requiring cessation of treatment.  
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 or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier). 
All subjects will be followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study. 
Estimated average length of 
treatment per patient 
16 months 
 
 
 
 


 
 
 
 
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1.1 
PROTOCOL SYNOPSIS 
Title 
Phase II study of combination chemotherapy and immune checkpoint 
blockade with Pembrolizumab in the perioperative and maintenance 
treatment of locoregional gastric or GE junction adenocarcinoma. 
Short Title 
Perioperative chemotherapy and pembrolizumab in locally advanced 
gastric cancer (Merck Internal Reference: MISP 52339) 
Protocol Number 
AAAQ9871 
Phase 
Phase II 
Methodology 
Single arm, multi-center, Phase II study with interim safety analysis 
Study Duration 
30 months (for efficacy results) 
Study Centers 
Columbia University Medical Center, New York; Weill Cornell 
Medical Center, New York; Washington University in St. Louis, St. 
Louis; Rhode Island Hospital/Lifespan Cancer Institute, Providence, 
Rhode Island 
Objectives 
Primary Objective: 
1. To evaluate the efficacy of combination therapy with immune 
checkpoint blockade and chemotherapy as determined by the 
pathologic complete response rate (pCR).  Pathological 
complete response is defined as no invasive disease within an 
entirely submitted and evaluated gross lesion, and 
histologically negative nodes. 
Secondary Objectives: 
2. To determine the efficacy of combination therapy with 
immune checkpoint blockade and chemotherapy by overall 
response rate (ORR), and used in the perioperative period in 
eradicating micrometastatic disease as measured by disease 
free survival (DFS) and overall survival. 
3. To compare paired tissue and serum samples (pre-treatment 
and post-treatment) from individually treated patients to 
explore the immune effects of combination therapy and 
predictors of response as determined by IHC, flow cytometry, 
and genomic analysis of tumor and immune cells  
Exploratory Objective: 
1. To determine if pathologic complete response (pCR) rate 
correlates with recurrence free survival (RFS) 
 


 
 
 
 
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Number 
of 
Subjects 
There will be an estimated 38 patients enrolled in this protocol. We 
estimate that at least 28 subjects will proceed to surgery and be 
evaluable for the primary outcome of pCR. All subjects will be 
available for the secondary analysis of ORR, DFS, and OS.  
Diagnosis 
and 
Main 
Inclusion 
Criteria 
Locoregional gastric or GE junction adenocarcinoma 
Primary Inclusion Criteria: 
- 
T2 or greater disease or N1 
- 
Patient suitable for surgical resection 
- 
ECOG 0-1 
Primary Exclusion Criteria: 
- 
Metastatic disease (Stage 4 disease) 
- 
Previous treatment for gastric cancer 
- 
Active infection 
- 
Active autoimmune disease 
Study 
Product, 
Dose, 
Route, 
Regimen 
Pembrolizumab dosed IV at 200mg every 21 days per cycle. 
Doublet or Triplet chemotherapy with Capecitabine, oxaliplatin, and 
epirubicin (optional) (21 day cycle). Epirubicin can be excluded at 
the discretion of the treating physician. 
Duration 
of 
administration 
21 day cycles of combination chemotherapy and pembrolizumab: 
Perioperative Treatment: 3 cycles prior to surgery and 3 cycles 
following surgery. Subjects will receive an additional cycle of 
pembrolizumab alone prior to surgery (4th cycle).  
Maintenance Treatment: Subjects will receive an additional 
maintenance period following surgery which consists of up to 17 
additional cycles of single agent pembrolizumab following 
completion of combination therapy. 
Reference therapy 
Not applicable- single arm. 


 
 
 
 
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Statistical 
Methodology 
The primary hypothesis of this study is that combination therapy 
including immunotherapy and chemotherapy will result in increased 
efficacy compared to chemotherapy alone. This will be evaluated 
based on the primary outcome of pathologic complete response 
(pCR), which is defined as no invasive disease within an entirely 
submitted and evaluated gross lesion, and histologically negative 
nodes as determined by an independent pathologist at Columbia 
University (T0N0). We will enroll an estimated 38 subjects to allow 
for at least 28 evaluable subjects. This Phase II study will have 80% 
power to detect an increase in pCR rate from 3% to 15% with a one-
sided alpha of 0.05.  
A key secondary efficacy outcome is disease free survival (DFS). 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a non-randomized, multi-site, open-label trial of pembrolizumab and chemotherapy in 
subjects with gastric or gastroesophageal junction adenocarcinoma. Up to 38 subjects may be 
enrolled in a single cohort, for a sample of 28 evaluable subjects, to assess the efficacy of 
combination therapy with standard peri-operative chemotherapy in resectable gastric or GE 
junction adenocarcinoma. The trial was initiated at 2 sites and two additional sites were 
subsequently added to increase enrollment.  
All study subjects will receive standard of care chemotherapy for 3 cycles prior to and 3 cycles 
following surgery in combination with Pembrolizumab with an additional cycle of 
Pembrolizumab (4 total) in the pre-operative period. Additionally, subjects will complete 12 
months of maintenance Pembrolizumab (14 additional doses to complete 17 post-operative 
cycles) following completion of post-operative chemotherapy. The primary efficacy endpoint 
will be pathologic complete response (pCR) rate  among all enrolled subjects. Recurrence or 
disease progression will be determined based on RECIST 1.1 and investigator assessment.  
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlines in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0.(As referened in Appendix 13.2) 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring. Serious adverse events and Events of Clinical Interest (ECI) will be collected for 
90 days after the end of treatment or 30 days after the end of treatment if the subject initiates 
new anticancer therapy, whichever is earlier. Subjects who discontinue treatment for reasons 
other than disease recurrence will have post-treatment follow-up for disease status until disease 
recurrence, withdrawing consent, or becoming lost to follow-up. All subjects will be contacted 
by telephone for overall survival until death, withdrawal of consent or the end of the study, 
whichever comes first. 


 
 
 
 
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The primary objectives of the trial are to determine the efficacy of addition of pembrolizumab 
(200mg fixed dose Q3W) to standard of care peri-operative therapy and as maintenance 
therapy as measured by pathological complete response (pCR) at the time of resection. 
Secondary objectives include assessment of disease free survival,, overall survival (OS), 
response rate (ORR), safety and tolerability of combination and maintenance therapy in this 
clinical setting. Additional secondary objectives include overall survival (OS), and duration of 
response (DOR) in all subjects and those with PD-L1 positive tumors. Exploratory objectives 
are planned to assess the relationship between candidate efficacy/resistance biomarkers and 
anti-tumor activity of pembrolizumab and by comparing baseline tissue measurements as well 
as biological response measures. 
 
All subjects will be required to provide adequate tumor tissue from baseline for evaluation of 
PD-L1 expression and additional immunological profiling. In addition, all subjects will be 
required to submit adequate tumor tissue at the time of resection (unless they achieve 
pathological or near pathological complete response). A biopsy is also requested at the time of 
recurrence, but will not be required.  
 
This study will be conducted in conformance with Good Clinical Practices. 
 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outline in the Trial Flow Chart – Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
 
2.2 
Trial Diagram 
 


 
 
 
 
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3.0 OBJECTIVES AND HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
1. Objective: To determine the efficacy of combination therapy with immune checkpoint 
blockade and chemotherapy in subjects with resectable gastric adenocarcinoma as determined 
by the pathologic complete response rate (pCR).. 
Hypothesis:  We hypothesize that PD-1 blockade will lead to immune activation and enhance 
the efficacy of chemotherapy in patients with locally advanced gastric cancer.  This will lead 
to an improved pathological response (as assessed by complete pathologic response rate). 
3.2 
Secondary Objectives & Hypotheses 
1. Objective: To determine the impact of combination immune therapy and chemotherapy on 
disease free survival (DFS), overall survival (OS),immune activation, and tumor response in 
gastric adenocarcinoma as measured by changes in tumor immune profile following neo-
adjuvant therapy. 
Hypothesis: We hypothesize that combination chemotherapy and pembrolizumab will 
improve ORR, DFS, OS, and enhance immune activation and lead to increased immune 
infiltration and tumor death in the peri-operative period.   
2. Objective: To assess the safety of combination chemotherapy and immune therapy 
including maintenance immune therapy following surgery in gastric adenocarcinoma.   
Hypothesis:  We hypothesize that maintenance therapy with pembrolizumab will be safe and 
feasible following surgical resection and will control growth of micrometastasis and delay 
recurrence of gastric cancer.  
3.3 
Exploratory Objectives & Hypotheses 
Objective: To identify tumor and patient characteristics that predict response and correlate 
with long term outcomes following treatment with combination Pembrolizumab and 
chemotherapy. 
Hypothesis:  We hypothesize that baseline markers of immune activation such as Tumor 
Infiltrating Lymphocytes and CD8+ lymphocytes will correlate with response to 
pembrolizumab and that responders to pembrolizumab will have distinct tumor immune 
phenotype as determined by immunohistochemistry compared to non-responders. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
In addition to the rationale outlined in the subsequent sections, refer to the Investigator’s 
Brochure (IB)/approved labeling for more detailed background information on MK-3475 
(pembrolizumab). 


 
 
 
 
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4.1.1 Pharmaceutical and Therapeutic Background 
4.1.1.1 Gastric and GE junction Adenocarcinoma  
Gastric cancer is one of the most common cancers worldwide with high incidence in China, 
Japan, and Korea. Although relatively less common in North America, it is estimated to cause 
11,000 deaths in the United States in 20141. Surgical resection is the primary treatment for 
gastric cancer but most patients present with locally advanced disease and recurrence is 
common after surgery. Systemic chemotherapy has been shown to reduce the rates of 
recurrence and prolong survival in surgically resected patients. Because of the high risk of 
recurrence with surgical resection alone, the current standard of care is to treat with 
combination therapy incorporating chemotherapy in addition to surgery. On the basis of the 
pivotal MAGIC trial2, one commonly utilized standard of care incorporates perioperative 
chemotherapy with 3 cycles of chemotherapy prior to surgery and 3 cycles following resection. 
Despite improvement in survival with chemotherapy, the majority of patients are not cured of 
their cancer using this approach and long term survival (5 years) following surgery and 
chemotherapy remains below 50%. New therapies are needed to produce improved and durable 
responses. 
 
4.1.1.2 Neoadjuvant chemotherapy and outcomes in gastric cancer:  
The use of neoadjuvant therapy prior to planned surgical resection may increase the likelihood 
of achieving a complete resection (R0), improve surgical outcomes and enable the delivery of 
systemic chemotherapy prior to complete surgical recovery. This approach is the current 
standard of care for the treatment of resectable gastric cancer. The tumor response to 
neoadjuvant therapy is predictive of improved outcomes3 and pathologic complete response 
(pCR) is a predictor of improved survival for gastric and GE junction adenocarcinoma.4 
Despite this, the current regimen of systemic chemotherapy for 9-12 weeks prior to surgery 
rarely results in pathologic complete response. Unlike other studies using radiotherapy in 
which pCR is seen at higher levels (predominantly in GE junction and esophageal tumors), in 
chemotherapy trials there are low rates of pCR. In the pivotal MAGIC trial there were no 
reported pCR2 and in the large multicenter FNLCC/FFCD trial (12 weeks of pre-op chemo) 
the pCR rate was only 3%5.  
 
4.1.1.3 Immune checkpoint therapy: 
In the last few years it has become clear that cancers are recognized by the immune system, 
which can suppress and even eliminate malignant clones, resulting in substantial patient 
benefit, and, in some cases, long term response. Anti-tumor immunity can be enhanced by 
antibody-mediated blockade of coinhibitory molecules such as CTLA-4 or PD1. These 
checkpoint-blocking antibodies have shown significant clinical activity in a variety of tumor 
types including, melanoma, RCC and NSCLC6.  
 
The most promising agents are the antibodies targeting the PD1 or its ligand, PD-L1. PD1 is 
expressed on broad subsets of immune cells and is upregulated by activated T lymphocytes in 
the tumor microenvironment.7 PD1 has two known ligands, PD-L1 and PD-L2. PD-L1 and to 
a lesser extent PD-L2 are expressed on human gastric cancer8, and in many malignancies 


 
 
 
 
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expression of PD-L1 has been correlated with prognosis. Thus interrupting the PD-1/PD-L1 
interaction could be an effective anticancer therapy by blunting inhibition of immune 
responses, thereby facilitating cytotoxic T cell responses against the tumor. Pembrolizumab is 
an anti-PD-1 antibody that received initial FDA approval in September 20149. We propose 
utilizing this novel antibody in combination with chemotherapy in the perioperative treatment 
of locoregional gastric cancer.  
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades10.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies11-14.  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)15.  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 cells16.  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 tumors17-19.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
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This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a mono-therapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of IFN-ɣ, granzyme B and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector T-
cell function in vivo20,21. Experiments have confirmed the in vivo efficacy of PD-1 blockade 
as a mono-therapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (see the Investigator’s Brochure [IB]). 
 
Clinical trials have demonstrated efficacy in patients with advanced melanoma, non –small 
cell lung cancer, head and neck cancer, bladder cancer and gastric adenocarcinoma. 
 
4.1.3 Ongoing Clinical Trials 
Preliminary interim data is available from a cohort of gastric adenocarcinoma patients studied 
in trial KN012. KEYNOTE-012 trial is a multi-cohort phase 1b study of which one cohort 
enrolled subjects with recurrent or metastatic gastric or GEJ adenocarcinoma that expressed 
PD-L1 (≥1% by immunohistochemistry). This cohort enrolled 39 patients (19 from Asia and 
20 outside Asia), 67% of whom had received 2 or more prior chemotherapy lines. The primary 
efficacy endpoint was objective response rate (ORR). Despite the heavily pre-treated patient 
population, Pembrolizumab monotherapy demonstrated an interim ORR of 33% by RECIST 
v.1.1 per investigator review (95% confidence interval (CI) (19.1%, 50.2%); all partial 
responses). The interim disease control rate (DCR) was 41% (95% CI (25.6%, 57.9%). ORR 
was similar in patients from Asia and outside of Asia, while the DCR was numerically higher 
in Asia. Responses were observed across all lines of treatment. It should be noted that in the 
non-Asia group, patients had less prior therapy relative to the Asian patients, and that ORR in 
later line patients (≥3L) was higher in the Asian group (1 PR/7 patients in the non-Asia group, 
4 PR/13 patients in the Asia group). As of the data cutoff date of 14 Nov 2014, the median 
duration of response was 24 weeks (6 months). Based on preliminary data there appears to be 
a correlation between response and degree of PD -L1positivity22. 
 


 
 
 
 
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In these gastric cancer patients in KN012, single agent pembrolizumab at 10 mg/kg Q2W was 
generally well tolerated, with the type, severity and frequency of adverse events similar to that 
observed in other indications (see the IB for information about adverse events in other 
indications). There was 1 death reported in the gastric cancer cohort. This patient had adverse 
events of tracheomalacia (Grade 3) and hypoxia (Grade 5). The investigator considered the 
Grade 5 hypoxia to be related to study treatment. 
 
Early Data from the FLOT4-AIO Trial: 
The results of the phase 2 part of the open-label, randomized phase 2/3 FLOT4-AIO trial 
demonstrated an increase in pathologic complete regression (response) with the combination 
of neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT) as compared to 
epirubicin, cisplatin, and fluorouracil or capecitabine ECF/ECX23. The primary endpoint for 
the phase 2 part of the study was proportion of patients with pathological complete regression 
which was defined as the proportion of patients with pathological complete regression over the 
total number of patients evaluated centrally by the study pathologist. Pathologic complete 
regression was defined according to the Becker regression criteria which estimates the 
percentage of vital tumor cells in relation to the macroscopically identifiable tumor bed. 
Pathologic complete regression is defined as no residual tumor cells. This study reported, 
a significantly higher proportion of patients achieving a pathological complete regression in 
patients receiving FLOT compared to those receiving ECF/ECX (20 [16%; 95% CI 10.3–23.0] 
of 128 patients in the FLOT group vs 8 [6%; 2.8–11.3] of 137 patients in the ECF/ECX group; 
p=0.02) 
FLOT + Pembro Trial: 
The KEYNOTE-585 (NCT03221426) is a global, multicenter, randomized, double-blind, 
Phase III study comparing perioperative chemotherapy (cisplatin plus 5-fluorouracil or 
cisplatin plus capecitabine or 5-flurouracil plus docetaxel plus oxaliplatin [FLOT]) with 
pembrolizumab to chemotherapy with placebo. The planned sample size is approximately 800 
patients and the primary endpoints are overall survival (OS), event-free survival (EFS) and 
pathologic complete response (pCR). PathCR rate is defined as the percentage of participants 
having a pathCR. PathCR is defined as no invasive disease within an entirely submitted 
and evaluated gross lesion, and histologically negative nodes. 
 
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
This is a Phase 2 study of combination standard of care chemotherapy plus pembrolizumab 
with the addition of maintenance pembrolizumab in subjects with resectable gastric or 
gastroesophageal junction adenocarcinoma. It will be conducted in a single cohort at multiple 
sites and will include subjects who are appropriate for peri-operative chemotherapy and 
surgical resection. Despite aggressive therapy and extensive surgery, the majority of these 


 
 
 
 
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subjects will have recurrence of disease. Many subjects (35%) will have early recurrence 
within 6-9 months of surgery indicating the need for more aggressive upfront therapy in these 
subjects. In addition, the majority of patients will ultimately have recurrence and 5 year 
survival rates are 35-40% despite aggressive therapy.  
Attempts at increasing the dose or duration of chemotherapy are limited due to increasing 
toxicity. The ability to combine immunotherapy with pembrolizumab gives the potential to 
increase therapeutic options while continuing standard of care chemotherapy. The particular 
use of maintenance therapy may delay or eliminate the growth of residual micrometastatic 
disease and lead to durable disease control. Additionally, this study provides the foundation 
for substantial correlative work to define tumor and patient characteristics that may predict for 
response to pembrolizumab in gastric cancer. This study will enroll all appropriate subjects 
regardless of PD-L1 status, but this will be checked in the baseline and surgical specimens of 
all subjects. In addition, we will analyze blood and tumor biomarkers including emerging 
immunological profiling, whole genome and protein analysis to identify changes within a 
specific tumor and predictors of response. Additionally, in gastric cancers PD-L1 and PD-L2 
overexpression have recently been associated with EBV- positive tumors24 and we will assess 
whether this  correlates with response in the current study.   
4.2.2 Rationale for Dose Selection/Regimen/Modification  
The underlying rationale for this study is to combine standard of care chemotherapy in the dose 
and schedule that would normally be used and to assess the addition of pembrolizumab for 
both efficacy and safety. 
GE junction and gastric cardia adenocarcinomas in which the treating physician plans to utilize 
neo-adjuvant chemoradiotherapy regimens will not be eligible for this study.  
4.2.2.1 Rationale for Pembrolizumab Dosing 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested 
in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to 
test for initial tumor activity.  Recent data from other clinical studies within the MK-3475 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
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A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed 
for other antibodies and would support both body weight normalized dosing or a fixed dose 
across all body weights.  MK-3475 has been found to have a wide therapeutic range based on 
the melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative 
to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
4.2.2.2 Rationale for Chemotherapy Dosing and Modifications 
For combination chemotherapy dosing we will employ standard of care chemotherapy 
regimens without deviation from routine regimens. The two large randomized studies 
demonstrating benefit of peri-operative chemotherapy utilized different regimens. The most 
common regimens are based on the MAGIC trial which utilized a 3 drug regimen of Epirubicin, 
Cisplatin, and 5-FU. This regimen has proved difficult to tolerate and subsequent Phase 3 
studies have demonstrated the non-inferiority of utilizing Oxaliplatin or Capecitabine in a 
similar 3 drug regimen25. The FFCD trial utilized a 2 drug regimen of cisplatin and infusional 
5-FU. Current guidelines and practice consider several 2 drug options as long as they utilize a 


 
 
 
 
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platinum agent with a 5-FU agent, though some centers continue to utilize 3 drug 
combinations.  
For this study, the objective is to test the addition of pembrolizumab to standard of care therapy 
and thus it will be up to the investor’s choice to determine the optimal starting regimen as long 
as this is a standard regimen containing at least a platinum and 5-FU agent (with guidance from 
NCCN guidelines). Epirubicin will be allowed if cardiac function is adequate as defined in this 
study.   
4.2.2.3 Rationale for Combination Chemotherapy and Pembrolizumab 
One of the objectives of this study is to assess the benefit of combination therapy in improving 
efficacy in gastric cancer. Based on current knowledge about toxicity profiles and multiple 
ongoing completed clinical trials, it is expected that there will be limited overlapping toxicities 
between these two modalities. However, the safety and tolerability of this combination and 
impact on surgical outcomes will be closely monitored   in this study.  
Preclinical data in various animal models has identified a potential role for chemotherapy in 
modulating the immune microenvironment and potentiating the effect of immune checkpoint 
blockade therapy. In this regard, oxaliplatin has shown particular impact on increasing CD8+ 
T cell infiltration26 and in a colon cancer animal model, oxaliplatin was effective than other 
chemotherapies in inducing tumor regression with checkpoint blockade27. We will test this 
provocative hypothesis with the use of this agent in the current protocol.   
 
4.2.3 Rationale for Endpoints 
Rational for Primary Endpoint of Complete Pathological Response 
As cancer therapies improve, robust and durable clinical responses are becoming more 
common. Neoadjuvant chemotherapy, given prior to surgical resection, is utilized more 
frequently and has become a standard of care for patients with resectable gastric cancer. To 
account for this, the 8th edition of American Joint Committee on Cancer (AJCC) gastric cancer 
TNM staging system has incorporated ypTNM so that the extent of downstaging may be 
quantified. Pathological complete response (pCR), defined as the absence of invasive/in situ 
cancer after treatment, had been an uncommon occurrence in solid tumors until recently. There 
is strong data in breast, rectal and bladder cancer, showing that achieving pCR after 
neoadjuvant chemotherapy confers a better overall and disease-free survival28-31. In 2014, the 
FDA released guidelines on the use of pCR as an endpoint in neoadjuvant treatment of high-
risk early-stage breast cancer. The use of pCR as a surrogate endpoint in gastric cancer has 
also garnered support. In the early 2000’s several studies were able to demonstrate that 
histologic tumor regression grades correlated with patient prognosis after neoadjuvant 
chemotherapy. For example Becker et al showed in thirty-six patients with gastric carcinoma 
treated with the combination of etoposide, doxorubicin, and cisplatin that tumor regression 
correlated significantly with survival (P = 0.01)32. Several more recent retrospective reviews 
and meta-analyses have also shown a correlation between pCR and survival after neoadjuvant 
chemotherapy in gastric and gastroesophageal junction cancer33-36. Pathological complete 


 
 
 
 
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response (pCR) for this study is defined as no invasive disease within an entirely 
submitted and evaluated gross lesion, and histologically negative nodes (T0N0). The 
submitted specimens will be reviewed by an independent designated pathologist at 
Columbia University. For samples for which a consensus is not reached, the sample will be 
sent for independent review to either Washington University or Brown University for review 
and the results discussed for a final determination. 
Efficacy Endpoints 
 
The primary efficacy objective of this study is to evaluate anti-tumor activity of 
pembrolizumab in combination with chemotherapy in down staging disease as determined by 
the pathologic complete response rate (pCR), the rate of pathologic complete response at the 
time of surgery following 12 weeks of initial therapy.  
Additional efficacy endpoints will be assessed, most notably the ability of this 
combination to eradicate micro-metastatic disease and prevent recurrence following 
complete resection of localized gastric or GE junction adenocarcinoma. This will be 
assessed by measuring time to disease recurrence or death (recurrence free survival) as 
measured from the time of trial initiation. Safety Endpoints 
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in combination with chemotherapy in subjects with resectable gastric cancer. 
The primary safety analysis will be based on subjects who experienced toxicities as defined by 
CTCAE 4.0 criteria Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received pembrolizumab, including serious adverse events 
(SAEs) and events of clinical interest (ECIs). 
 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune –related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 7.3.3.2. 
 
Biomarker Research and Exploratory Endpoints 
As an exploratory clinical endpoint, analysis will be performed to determine if pathologic 
complete response (pCR) rate correlates with recurrence free survival (RFS). 
 
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued. For example, tumor and blood samples (including serum and plasma) from 
this study may undergo proteomic, genomic, metabolomics, and transcriptional analyses. 
This research may evaluate factors important for predicting responsiveness or resistance to 
pembrolizumab therapy and other immunologic targets. 
 


 
 
 
 
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Assays may include but are not be limited to the following: 
 
Immunohistochemistry 
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to 
explore the relationship between PD-L1 expression and response to treatment with 
pembrolizumab (this is a secondary objective of the trial). Other exploratory 
biomarkers (e.g. PD-1 expression, markers of T-cell phenotype) may also be evaluated.  
 
Transcriptional Analyses 
As potential exploratory analysis messenger RNA (mRNA) expression profiling in 
archival material (biopsy specimens, peripheral blood) will be completed to assess 
expression of approximately 500 genes and attempt to define a gene set critical for 
clinical response to pembrolizumab. The hypothesis to be tested is that pembrolizumab 
induces responses in tumors that reflect an inflamed/ immune phenotype based on gene 
expression signatures capturing PD -L1 & interferon gamma transcriptional programs. 
Global profiling will also be pursued. Expression of individual genes related to the 
immune system may also be evaluated such as immune signatures and critical cytokines 
(e.g., IL-10). MicroRNA profiling may also be pursued in serum samples. 
 
Proteomic analysis 
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and 
released into the blood. Enzyme-linked immunoassay can measure PD-L1 in serum and 
correlate this expression with response to pembrolizumab therapy, as well as levels of 
PD-L1 IHC or protein in the tumor. Blood would be a less invasive component from 
which to measure PDL1 protein biomarker. In addition to this specific protein 
biomarker, both tissue and blood derivatives can be subjected to proteomic profiling 
studies using a variety of platforms that could include but are not limited to 
immunoassay, Liquid Chromatography/Mass Spectrometry. This approach could 
identify novel protein biomarker that could aid in subject selection for pembrolizumab 
therapy. 
 
Gene Analyses 
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or can detect the presence of specific T-cell clones within the tumor 
microenvironment or in the peripheral blood. There is a potential that the hypermutated 
state and/or increased T-cell clonality may correlate with response to pembrolizumab 
therapy, and/or that the converse, ‘hypomutated’ state or lack of dominant T-cell clones 
may correlate with non-response. 
 
In addition, understanding genetic determinants of drug response is an important 
endeavor during medical research. This research will evaluate whether genetic 
variation within a clinical trial population correlates with response to the treatment(s) 
under evaluation. If genetic variation is found to predict efficacy or adverse events, the 
data might inform optimal use of therapies in the subject population. 
 


 
 
 
 
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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male/Female subjects with gastric or gastroesophageal junction adenocarcinoma of at least 
18 years of age will be enrolled in this trial. 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have previously untreated localized gastric or GE junction adenocarcinoma as defined 
by T2 or greater primary lesion or the presence of any positive nodes- N+(clinical 
nodes) without evidence of metastatic disease. 
2. Plan to proceed to surgery following peri-operative chemotherapy based on standard 
staging studies per local practice.  
3. Be willing and able to provide written informed consent/assent for the trial. The subject 
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research. In 
cases of partial impairment, impairment that fluctuates over time, or complete 
impairment due to dementia, stroke, traumatic brain injury, developmental disorders 
(including mentally disabled persons), serious mental illness, and delirium, a subject 
may be enrolled if the subject’s legally authorized representative consents on the 
subject’s behalf. 
4. Be  18 years of age on day of signing informed consent. 
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior 
to initiation of treatment on Day 1.   
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
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 
≤1.5 X upper limit of normal (ULN) OR 


 
 
 
 
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Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
 
≥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 OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Have a 2D Echocardiogram with left ventricular ejection fraction  45% in order to 
receive epirubicin, if epirubicin is planned. Subjects with inadequate EF or other 
contraindication can proceed on study without the use of Epirubicin. 
9. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
11. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 


 
 
 
 
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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. The use of physiologic doses of corticosteroids (prednisone 10 mf or 
equivalent) may be approved after consultation with the Sponsor.  
3. Has a known history of active TB (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
 
5. Has had any prior chemotherapy, targeted small molecule therapy, or radiation therapy 
for their current diagnosis.  
6. Has a known additional malignancy that is progressing or requires active treatment 
within 3 years from registration. 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. Subjects with a history of prior malignancy diagnosed and 
treated greater than 3 years form registration may be considered with consultation of 
the primary investigator.  
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
8. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
9. Has known history of prior pneumonitis requiring treatment with steroids, or any 
evidence of active, non-infectious pneumonitis. 
10. Has an active infection requiring systemic therapy which is not expected to have 
resolved by Cycle 1 Day 1 dosing. 
11. Has a history or current evidence of any condition (e.g. known deficiency of the 
enzyme dihydropyrimidine dehydrogenase [DPD]), therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 


 
 
 
 
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14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor-investigator staff directly involved with 
this trial, unless prospective IRB approval (by chair or designee) is given allowing 
exception to this criterion for a specific subject. 
 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 
5.2 
Trial Treatments 
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 
Oxaliplatin 
130 mg/m2 
Q3W 
IV infusion 
Day 1 of each 3 week 
chemo cycle 
Combination 
agent 
Capecitabine 
(Xeloda) 
625mg/m2 
BID, 
day 
1-21 
PO 
administration 
Day 1-21 of each 3 
week chemo cycle 
Combination 
agent 
Epirubicin 
50mg/m2 
Q3W 
IV infusion 
Day 1 of each 3 week 
chemo cycle 
Combination 
agent 
 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
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.   


 
 
 
 
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Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual. Preparation and administration of the chemotherapy agents used in Cohort 
2 should be completed as per the approved product label. See Sections 5.2.2.2 –5.2.2.4 for 
general recommendations for administration. 
 
Body surface area (BSA) in m2 should be calculated per local guidance. 
  
5.2.1.2 Dose Modification (Escalation/Titration/Other) 
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be used 
to grade the severity of adverse events. 
If appropriate, the Investigator may attribute each toxicity event to any of the individual 
chemotherapy agents used or pembrolizumab alone in the combination arms and use stepwise 
dose modifications according to Table 3. Pembrolizumab dose reductions are not permitted. 
Pembrolizumab treatment may be interrupted or discontinued due to toxicity. 
 
If a dose level reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Dose modifications are always based on the previous cycle. 
 
Subjects may have up to 2 dose level reductions per chemotherapy agent throughout the course 
of the study, as described in Table 3 with the exception of Epirubicin. If further toxicity occurs 
or the criteria for resuming treatment are not met, the subject must be discontinued from 
chemotherapy treatment. Of note, in the event a subject is discontinued from chemotherapy 
treatment, the subject may still be eligible for continued treatment with pembrolizumab (Dose 
Level -3 in Table 3). Refer to Table 4, and Table 5 for dose modification guidelines for adverse 
events for pembrolizumab; other chemotherapy will be modified per institutional standards 
and package labeling. If a subject experiences several toxicities and there are conflicting 
recommendations, follow the most conservative dose adjustment recommended (dose 
reduction appropriate to the most severe toxicity). 
 
Reduction or with-holding of one chemotherapy agent and not the other agent is appropriate 
if, in the opinion of the Investigator, the toxicity is definitely related to one of the study 
treatments. If, in the opinion of the Investigator, the toxicity is related to the combination of 
two chemotherapy agents, both treatments should be reduced (if applicable), interrupted or 
discontinued according to recommended dose modifications. If the toxicity is related to the 
combination of three agents, all three agents should be reduced or held according to the 
recommended dose modifications. 
 
Exceptional circumstances to following the dose modification tables below may be considered 
after consultation with the Sponsor Investigator. 
 
Table 3 Dose modifications for Trial Medications 
Drug 
Starting Dose Dose Level - 1 
Dose Level - 2 
Dose Level -3 


 
 
 
 
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Pembrolizumab 200 mg fixed 
dose 
Dose 
reductions 
are not permitted 
Dose reductions 
are not permitted 
Dose reductions are 
not permitted 
Oxaliplatin 
130 mg/m2 
110 mg/m2 
90 mg/m2 
Discontinue 
Capecitabine 
(Xeloda) 
625mg/m2 
BID 
500 mg/m2 BID 
375 mg/m2 BID 
Discontinue 
Epirubicin 
50mg/m2 
40 mg/m2 
discontinue 
N/A 
 
Capecitabine treatment may be shortened to 14 days at any currently treated dose level at the 
discretion of the treating physician based on toxicity assessment.  Epirubicin may be excluded 
from the initial treatment regimen at the discretion of the treating physician, or the starting 
dose may be reduced to 40 mg/m2 (dose level -1), at the discretion of the treating physician.   
If a toxicity is not otherwise specified, investigators should refer to the label or local standard 
of care for dose adjustments. At the Investigator’s discretion, dose modification according to 
Table 3 is allowed for intolerable Grade 2-3 toxicities that are not specified in the tables below. 
These dose modification decisions must be documented in the subject’s study records. 
 
5.2.1.2.1 Dose Modification for Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 4 below. Pembrolizumab will 
be permanently discontinued for any severe or Grade 3 (grade 2 for pneumonitis) drug-related 
AE that recurs or any life-threatening event. See Section 5.6 for supportive care guidelines, 
including use of corticosteroids. 
Table 4 Dose Modification Guidelines for Drug-Related Adverse Events for Pembrolizumab 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, 
ALT, 
or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) 
or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 


 
 
 
 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued 
while 
thyroid 
replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose; Refer to Table 5 Infusion 
Reaction Treatment Guidelines Error! Reference source not found.for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
5.2.1.2.2 Dose Modifications for Chemotherapy 
Standard of care chemotherapy will be utilized in this protocol and modifications are allowed 
based on guidance detailed in Table 3 at the discretion of the treating investigator and per 
standard package instructions. Permanent discontinuation of any agent should be considered 
for any severe or life-threatening event.  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor-Investigator. The reason 
for interruption should be documented in the patient's study record. 
5.2.2 Timing of Dose Administration 
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Cycle 1 Day 1: 
Study treatment with pembrolizumab must be administered on Day 1 Cycle 1, after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0), 
followed by oxaliplatin and capecitabine.  Chemotherapy may be administered up to 3 days 
after the scheduled Day 1 of each cycle due to administrative reasons. 
Cycle 2 Onwards: 
 
Study treatment with pembrolizumab, followed by oxaliplatin and capecitabine, may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle for administrative 
reasons. It is not required that pembrolizumab is given on the same day as IV chemotherapy, 
but it must be administered before IV chemotherapy is administered in each cycle.   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study treatment (e.g., elective surgery, unrelated medical events, subject 
vacation, and/or holidays). Subjects may restart study treatment as soon as clinically 
appropriate at the Investigator discretion, and not exceeding 3 weeks from the interrupted 
dosing. Discussion with the Sponsor-Investigator must occur if the Investigator determines a 
subject cannot restart study medication within 3 weeks. The reason for interruption must be 
documented in the subject's study record. 
Surgical Resection 
Should occur 4-6 weeks following the last chemotherapy dose.  Tissue will be collected for 
correlative studies.  
 
Post-operative therapy 
Should begin 6-10 weeks following resection.  The dose of chemotherapy can be adjusted 
down 1 level or omitted at the treating physician’s discretion.  Pembrolizumab may be 
administered without chemotherapy in the post-operative setting.   
 
 
5.2.2.1 Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.2.2 Chemotherapy Administration  
All sites will administer pembrolizumab in combination with epirubicin (when appropriate), 
oxaliplatin and capecitabine as the combination chemotherapy regimen. Administration of 
oxaliplatin and epirubicin (when appropriate) should begin on Day 1 of each three week cycle, 


 
 
 
 
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as detailed in Table 3 and the Trial Flow Chart (Section 6.0). Administration of capecitabine 
should begin on Day 1 of each three week cycle following administration of oxaliplatin, as 
detailed in Table 3 and the Trial Flow Chart (Section 6.0). Please refer to the product label for 
additional guidance on administration procedures for oxaliplatin, capecitabine, and epirubicin. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor-Investigator, investigator and subject will 
know the treatment administered. 
5.3 
Randomization or Treatment Allocation 
Subjects participating in this trial will be allocated by non-random assignment. 
5.4 
Stratification 
No stratification based on age, sex, or other characteristics will be used in this trial. 
5.5 
Concomitant Medications/Vaccinations 
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. However, the decision to 
continue the subject on trial therapy or vaccination schedule requires the mutual agreement of 
the investigator, the Sponsor-Investigator and the subject. 
 
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 


 
 
 
 
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 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor-
Investigator. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  


 
 
 
 
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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 


 
 
 
 
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o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 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 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 


 
 
 
 
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Table 5 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) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
5.6.2 Supportive Care Guidelines for Chemotherapy Agents 
Pre-infusion supportive care is permitted including administration of corticosteroids per 
NCCN or institutional guidelines.  
Please refer to the product label or local standards of care for additional supportive measures 
for all chemotherapy agents (oxaliplatin, capecitabine, epirubicin).  
 


 
 
 
 
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5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
 Single method (one of the following is acceptable): 


 
 
 
 
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• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
 Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
5.7.3 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-Investigator and to 
Merck without delay and within 24 hours to the Sponsor-Investigator and within 2 working 


 
 
 
 
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days to Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor-Investigator 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. 
5.7.4.1 Pembrolizumab 
It is unknown whether pembrolizumab is excreted in human milk. 
 
5.7.4.2 Oxaliplatin 
It is unknown whether oxaliplatin is excreted in human milk.  
5.7.4.3 Capecitabine 
Lactating mice given a single oral dose of capecitabine excreted significant amounts of 
capecitabine metabolites into the milk. It is not known whether capecitabine is excreted in 
human milk. Subjects receiving capecitabine should not breast-feed. 
 
5.7.4.4 Epirubicin 
It is unknown whether epirubicin is excreted in human milk, however other anthracyclines are 
known to be excreted in breast milk. Subjects receiving epirubicin should not breast-feed. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor-Investigator 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.  
Even if a subject discontinues trial treatments, they will be encouraged to continue to 
participate in collection of data regarding the endpoints, including DFS and OS. 
A subject must be discontinued from the trial treatments for any of the following reasons: 


 
 
 
 
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 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression or recurrence 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 12 months of uninterrupted treatment with pembrolizumab following 
surgical resection or 17 administrations of study medication, whichever is later. 
Note: 12 months of study medication is calculated from the date of first dose following 
surgical resection.  
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (TRIAL 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 or recurrence, withdrawing consent or becoming lost 
to follow-up. After documented disease progression each subject will be followed by telephone 
for overall survival until death, withdrawal of consent, or the end of the study, whichever 
occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
As this is a maintenance trial following complete resection of the primary tumor, it is 
anticipated that all subjects will continue on therapy for the duration of the post-operative 
period (52 weeks) even in the absence of disease and even in the event of pathological CR at 
the time of surgery. 
5.9 
Subject Replacement Strategy 
A subject who discontinues from the trial will not be replaced unless the subject discontinued 
prior to receiving any doses of study medication. 


 
 
 
 
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5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
5.11 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 Males 
 Total 
Hispanic or Latino 
4 
+ 5 
= 9 
Not Hispanic or Latino 
13 
+ 16 
= 29 
Ethnic Category:  
Total of all subjects 
(17) 
+ (21) 
= (38) 
Racial Category 
 
American Indian or Alaskan Native 0 
+ 0 
= 0 
Asian 
3 
+ 3 
= 6 
Black or African American 
2 
+ 4 
= 6 
Native Hawaiian or other Pacific 
Islander 
0 
+ 0 
= 0 
White 
12 
+ 14 
= 26 


 
 
 
 
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Racial Category:  
Total of all subjects 
(17) 
+ (21) 
= (38) 


 
 
 
 
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6.0 TRIAL FLOW CHART 
Table 6 Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cycles a (3 weeks per cycle) 
Maintenance 
Period 
End of Treatment and Post-
Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening  
Visit 1 
1 
2  
3 
4 
Surgical 
Period 
 
5 
6 
7 
8+ 
(to maximum 
17 
cycles 
post-op) 
End 
of 
Treatment 
(last dose) or 
Dis-
continuation 
Safety 
Follow-up 
(30 
days 
from 
last 
dose) 
Survival 
Follow-
Up 
(phone) 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
± 7 
Every 12 
weeks  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent for FBR b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
12- Lead ECG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
2-D Echo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Ht (V1 only), Wt & Vital Signs (T/P/BP/RR) X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Trial Treatment Administration 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
IV Chemotherapy Administration c 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
Q12 wks 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
Q12 wks 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 


 
 
 
 
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Trial Period: 
Screening 
Phase 
Treatment Cycles a (3 weeks per cycle) 
Maintenance 
Period 
End of Treatment and Post-
Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening  
Visit 1 
1 
2  
3 
4 
Surgical 
Period 
 
5 
6 
7 
8+ 
(to maximum 
17 
cycles 
post-op) 
End 
of 
Treatment 
(last dose) or 
Dis-
continuation 
Safety 
Follow-up 
(30 
days 
from 
last 
dose) 
Survival 
Follow-
Up 
(phone) 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
± 7 
Every 12 
weeks  
Pregnancy Test – Urine or Serum β-HCG d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential  
X 
X e 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panel  
X 
X e 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
X 
 
X 
 
X 
 
X 
 
X 
Xf  
X 
X 
 
Efficacy Measurements 
Tumor Imaging 
X 
 
 
 
X g 
 
X h 
 
 
X i 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival 
or 
Newly 
Obtained 
Tissue 
Collection 
X 
 
 
 
 
Xj 
 
 
 
 
 
 
X k 
Correlative Studies Blood Collection 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 


 
 
 
 
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Trial Period: 
Screening 
Phase 
Treatment Cycles a (3 weeks per cycle) 
Maintenance 
Period 
End of Treatment and Post-
Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening  
Visit 1 
1 
2  
3 
4 
Surgical 
Period 
 
5 
6 
7 
8+ 
(to maximum 
17 
cycles 
post-op) 
End 
of 
Treatment 
(last dose) or 
Dis-
continuation 
Safety 
Follow-up 
(30 
days 
from 
last 
dose) 
Survival 
Follow-
Up 
(phone) 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
± 7 
Every 12 
weeks  
a. Unless otherwise specified, assessments/procedures are to be performed prior to dose administration on Day 1 of each cycle. 
b. Informed consent for the optional Future Biomedical Research (FBR) samples must be obtained before DNA sample is collected.  
c. Refer to Section 5.2.2 regarding window for timing of dose administrations. 
d. For women of reproductive potential, a negative pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  
e. Laboratory screening tests should be repeated prior to cycle 1 day 1 if the screening labs were performed more than 14 days prior to study treatment.  
f. Labs will be collected every other cycle during the maintenance period.  
g. First imaging assessment will be performed between at week 11  (+/- 14 days) from study initiation.  
h. Second imaging assessment will be performed post-operatively prior to resumption of therapy. 
i. Subsequent imaging will be performed every 12 weeks (+/- 7 days) from the timing of the initial post-op imaging test (second imaging assessment).  
j. Surgical specimens will be evaluated for pathological response for primary end point analysis. 
k. There will be an optional tumor biopsy at the time of disease recurrence. 
 


 
 
 
 
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7.0 TRIAL PROCEDURES 
7.1 
CUMC Research Participant Registration  
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
Obtain informed consent, by following procedures defined in section 7.2.1.1.1, General 
Informed Consent, along with applicable institutional policies and federal regulations. 
Only Investigators/Research personnel properly trained and delegated to consent subjects for 
this protocol will participate in the consenting process. Furthermore, properly 
delegated/trained Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a 
protocol specific Eligibility Checklist for each subject enrolled on the study, in addition to 
providing the relevant source documentation confirmation subject eligibility. 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of 
study treatment. 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST 
(excluding holidays and weekends). Same day patient registrations (and after hour 
registrations) will be accommodated on a case by case basis provided that the study team has 
expressed all time sensitive registration concerns/cases in a timely manner to the Central 
Registration Office.  
7.1.1 CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to 
the CPDM Central Registration Office via an email to CPDMRegistration@columbia.edu or 
fax to 212.305.5292, with the subject line “AAAQ9871 Pending Subject Registration Request 
(PHI)”.  Upon receipt, applicable subject information as well as a “pending eligibility” status 
will be entered into HICCC’s institutional database.  This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for 
all pending registration submissions are as follows: 
 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
 
The completed/signed IRB approved HIPAA Authorization form 
 
Completed/signed CPDM ICF checklist 
 
Completed/signed HICCC personal census form 
 
Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 


 
 
 
 
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 
The completed/signed study specific Eligibility Checklist  (signed by an Physician level 
Investigator) 
 
Copies of source documentation necessary for each item to be verified on the CPDM 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent 
process information, along with providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms (e.g., positive 
investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 
Please note: subject line of email or fax should include the protocol number followed by: 
“Complete Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will 
be verified by a qualified Central Registration Registrar. If any questions arise during the 
review process, queries in the form of emails will be addressed to the applicable study team 
personnel for clarification prior to enrollment. .All applicable finalized registration/eligibility 
information will then be entered into HICCC’s institutional CTMS database by the Central 
Registration Registrar.  Upon completion, an official subject registration notification email will 
be sent to the PI/research team which will include eligibility/enrollment status, as well as 
subject ID information.  Protocol therapy may not be initiated prior to receipt of this 
notification from the Central Registration Office. 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office 
in a manner analogous to the procedures noted above. Applicable source documentation will 
be required within the corresponding submissions. 
7.2 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor-
Investigator 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. 


 
 
 
 
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7.2.1 Administrative Procedures 
7.2.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject or each subject’s 
legally acceptable representative prior to participating in a clinical trial. 
7.2.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable state laws and federal 
regulations. 
7.2.1.2 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.  
7.2.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   


 
 
 
 
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7.2.1.4 Prior and Concomitant Medications Review 
7.2.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.2.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.1.4.2. 
7.2.1.5 Disease Details and Treatments 
7.2.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.2.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.2.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
7.2.1.6 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation. Each subject will 
be assigned only one screening number. Screening numbers must not be re-used for different 
subjects. 
Any subject who is screened multiple times will retain the original screening number assigned 
at the initial screening visit.  
 


 
 
 
 
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7.2.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses in the post-operative setting require consultation between the 
investigator and the Sponsor-Investigator and written documentation of the collaborative 
decision on subject management. Any delay in resumption of study related therapy beyond 12 
weeks from surgery will also be reviewed in consultation between the investigator and 
Sponsor-Investigator.  
 
Administration of trial medication will be witnessed by the investigator and/or trial staff while 
the subject is in the treatment center. Administration of chemotherapy including oral and IV 
chemotherapy will be administered as per standard practice without additional verification.  
 
7.2.2 Clinical Procedures/Assessments 
7.2.2.1 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 13.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
Please refer to section 7.3 for detailed information regarding the assessment and recording of 
AEs.   
7.2.2.2 Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed as specified in the Trial Flow Chart. For 
cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to dosing 
on Day 1 of each treatment cycle. 
After the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs. 
 
 
7.2.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 


 
 
 
 
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7.2.2.4 12-Lead Electrocardiogram 
A standard 12-lead ECG will be performed using local standard procedures once at screening. 
Clinically significant abnormal findings should be recorded as medical history. Additional time 
points may be performed as clinically necessary. 
 
Please note that the ECHO is only required for patients receiving Epirubicin. 
 
7.2.2.5 2-D Echocardiogram 
A standard 2-dimensional Echocardiogram (TTE) will be performed using local standard 
procedures once at screening to assess left ventricular ejection fraction (EF) to determine 
eligibility for Epirubicin chemotherapy. Additional Echocardiograms will be conducted during 
therapy and as clinically necessary as described in the Trial Flow Chart. 
7.2.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 13.1) at screening, 
prior to dosing on Day 1 of each treatment cycle (except Cycle 1) and at discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.2.2.7 Tumor Imaging and Assessment of Disease 
Tumor imaging may be performed by computed tomography (CT) including PET/CT 
(preferred) or magnetic resonance imaging (MRI), but the same imaging technique, 
acquisition, and processing parameters should be used in a subject throughout the trial. If 
PET/CT was used initially it is not required to use PET/CT for each subsequent tumor imaging 
assessment, CT is sufficient.  
 
Imaging tests will be reviewed locally and tumors will be quantified utilizing RECIST 1.1. All 
treatment decisions will be made locally by the treating Investigator’s radiographic assessment 
of disease.  
7.2.2.7.1 Baseline Tumor Imaging 
To meet screening criteria, subjects do not require measurable disease on imaging. However, 
if subjects have a lesion quantifiable according to RECIST 1.1 criteria, this will be utilized to 
assess disease response (RR).  
Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality and performed within 28 days prior to the first dose of 
study treatment. 
 
7.2.2.7.2 Tumor Imaging During Trial   
The first on-study imaging assessment will be performed 11 weeks after Cycle 1 Day 1 (78 
days +/- 14 days) and will be used to assess response to chemotherapy and eligibility for 
surgery. Imaging may be conducted prior to Cycle 4 dosing (of Pembrolizumab) if clinically 
indicated as assessed by local routine practice. Subsequent imaging will be performed 


 
 
 
 
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following surgical resection and will begin within 7 days of Cycle 5 day 1 (first post-operative 
cycle) which is expected to not be later than 8 weeks from the time of surgery ( 65 days +/- 14 
days). Beginning from the first post-operative scan, subsequent tumor imaging will be 
performed every 12 weeks (+/- 7 days).  
Imaging should continue to be performed until whichever one of the following occurs first: 
 disease progression limiting a subject from surgical resection 
 recurrence of disease following surgical resection 
 completion of study treatment 
 withdrawal of consent 
 death 
 end of study 
Imaging should follow calendar days and not be delayed for any dose interruptions that may 
occur (except for delays post-operatively).  
7.2.2.7.3 Assessment of Disease- RECIST 1.1 and irRECIST 
The primary endpoints in this study are recurrence free survival and pathologic surgical 
response, and not tumor response based on RECIST. In addition due to the neo-adjuvant nature 
of the study, it is not expected to have confirmatory scans of response prior to surgery. Thus 
all responses will be unconfirmed and we do not anticipate using irRECIST measurements.  
7.2.2.8 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Tumor tissue sample may be collected in either formalin solution or FFPE block is acceptable. 
A fine needle aspirate (FNA) or cytologic specimen will not be acceptable.  
Details regarding time points for collection of tumor tissue are outlined in the Study Flow Chart 
–Section 6.0. 
 
7.2.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below  
7.2.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.   


 
 
 
 
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Table 7  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


 
 
 
 
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Laboratory tests for screening should be performed within 14 days of dosing for eligibility. If 
performed more than 72 hours prior to Cycle 1 Day 1 they should be repeated on Cycle 1 Day 
1 prior to the first dose of treatment for treatment decisions but not for eligibility. After Cycle 
1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. Results of 
standard tests must be reviewed by the investigator or qualified designee per local treating 
guidelines and found to be acceptable prior to each dose of trial treatment.  
7.2.4 Other Procedures 
7.2.4.1 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 7.3 - Assessing and Recording 
Adverse Events.   
7.2.4.2 Blinding/Unblinding 
This is an open label trial; there is no blinding for this trial. 
7.2.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.2 - Trial Procedures. 
7.2.5.1 Screening 
Within 28 days prior to expected start of therapy, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Visit requirements 
are outlines in Section 6.0 – Trial Flow Chart. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following: 
 
 For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment. 
 Biopsy collections may be collected up to 42 days prior to the first dose of trial 
treatment as presented in Section 5.1.1. 
 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 
 


 
 
 
 
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7.2.5.2 Treatment Period 
As described in Section 6.0- Trial Flow Chart, the study treatment period is divided into the 
pre-operative period, the post-operative combination period, and the maintenance period. 
7.2.5.2.1 Pre-operative Treatment Period 
This will begin on Cycle 1 Day 1 and as outlines will include 4 cycles of therapy. The first 3 
cycles will consist of combination chemotherapy and Pembrolizumab and the 4th cycle will 
consist of study treatment alone with Pembrolizumab. Based on previous studies it is 
anticipated that subjects will proceed to surgery between 4-6 weeks following completion of 
perioperative chemotherapy (completion of cycle 3). The pre-operative treatment period will 
complete once a subject proceeds to surgical exploration. 
All subjects will remain on study if they have received a single dose of study medication, even 
if they did not complete the full course of pre-surgical chemotherapy or combination therapy.  
7.2.5.2.2 Post-operative Treatment Period 
All subjects who have received at least 1 dose of pre-surgery study medication will be included 
in the post-treatment therapy. Subjects will be re-evaluated by the treating Investigator between 
4-8 weeks post-operatively per local practice. It is anticipated that the majority of subjects will 
be deemed appropriate to begin chemotherapy within 8 weeks of surgery but subjects may be 
delayed at the discretion of the treating physician. The decision to modify chemotherapy (to 
omit or dose reduce agents) will also be at the discretion of the treating physician and will be 
documented in the patient record. If delay in post-operative chemotherapy is anticipated 
beyond 9 weeks, subjects may begin therapy with Pembrolizumab alone and add chemotherapy 
with subsequent cycles. No subject will receive more than 3 cycles of chemotherapy following 
surgery.  
Disease assessment with CT (or MRI) will be performed prior to initiation of Cycle 5 Day 1 
(within 14 days). The first dose of Pembrolizumab after surgery will be Cycle 5 Day 1 and all 
subsequent dosing will be based on this date.  
7.2.5.2.3 Maintenance Treatment Period 
Subjects will continue receiving study drug with Pembrolizumab for up to 17 cycles post-
operatively with 21 day cycles. The first 3 cycles will be scheduled to be administered with 
chemotherapy and 14 subsequent cycles will be given with Pembrolizumab alone. If a subject 
is not deemed appropriate for chemotherapy (per treating physician) that subject will  begin 
Pembrolizumab alone and may receive chemotherapy subsequently for up to 3 cycles per 
standard practice. Chemotherapy does not need to be given on the same day as Pembrolizumab 
(if delayed) but all cycles will follow Pembrolizumab dosing. During this treatment period, 
subjects will continue receiving disease assessment with imaging at 12 week intervals.  


 
 
 
 
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7.2.5.3 Post-Treatment Visits 
7.2.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.   
7.2.5.3.2 Survival Follow-up 
Once a subject experiences confirmed disease progression or completes 17 cycles of post-
operative therapy, the subject moves into the survival follow-up phase and should be contacted 
by telephone every 12 weeks to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first.  
7.3 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  


 
 
 
 
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All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome. 
7.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor-Investigator 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).   
 any standard treatment is any dose >/= 20% over the prescribed dose. 
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
Overdoses of chemotherapy agents (oxaliplatin, capecitabine, epirubicin), will be managed in 
accordance with the respective product label. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor-Investigator and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
7.3.2 Reporting of Pregnancy and Lactation to the Sponsor-Investigator 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. 


 
 
 
 
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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 through 120 days 
following cessation of the investigational product, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor-Investigator and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.3.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.3.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is an other important medical event  
 Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 8 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment allocation, any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study that occurs to any subject 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, 


 
 
 
 
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including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study whether or not related to the Merck product, must be reported within 24 hours to the 
Sponsor-Investigator and within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
7.3.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor-Investigator and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor-Investigator and within 2 working days to Merck 
Global Safety if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor-Investigator and within 24 
hours to Merck Global Safety. 
Events of clinical interest for this trial include: 


 
 
 
 
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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-Investigator, 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.  
7.3.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor-Investigator and to 
Merck, unless there is evidence suggesting a causal relationship between the drug and the 
event. Any such event will be submitted to the Sponsor-Investigator within 24 hours and to 
Merck Global Safety within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor-Investigator will monitor 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 2 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. 
 
7.3.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


 
 
 
 
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Table 8     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-Investigator 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-
Investigator and to Merck within 2 working days.. 


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


 
 
 
 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to 
Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the investigational product; or (3) the trial is a single-dose drug trial); or (4) Investigational 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) 
Investigational 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-INVESTIGATOR AS PER 
DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with 
Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, 
there 
is 
a 
reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR 
the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 


 
 
 
 
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7.3.5 Sponsor-Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
7.3.5.1 IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an 
unanticipated problem posing risk to subjects or others must be submitted to the IRB within 
one week (5 business days) following the occurrence of the unanticipated problem or the 
principal investigator’s acquiring knowledge of the unanticipated problem  in accordance with 
IRB policy. Additionally, the sponsor-investigator will submit a summary of all Unanticipated 
problems that occurred since the beginning of the study at the time of continuing review. 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Regulatory binder. 
7.3.5.2 FDA Notification by Sponsor-Investigator 
The Columbia University Medical Center Sponsor-Investigator, as holder of the IND, will be 
responsible for all communication with the FDA. Columbia University Medical Center 
Principal Investigator will report to the FDA, regardless of the site of occurrence, any adverse 
event that is serious, unexpected and there is evidence to suggest a causal relationship between 
the drug and the adverse event. These must be reported to the FDA and any affiliate sites as 
soon as possible, but in no case later than 15 calendar days after the sponsor determines that 
the information qualifies for reporting.  The Sponsor-Investigator will also submit an IND 
annual report to the FDA in accordance with 21.CFR 312.33. 
The Columbia University Medical Center Sponsor Investigator must report to the FDA and 
any affiliate site investigators as follows:  
 Any unexpected fatal or life-threatening event must be reported as soon as possible, 
but no later than 7 calendar days after the sponsor investigator initial receipt of the 
information 
 Any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies, whether or not conducted under an IND, and 
whether or not conducted by the sponsor-investigator, that suggest a 
significant risk in humans exposed to the drug  must be reported as soon as 
possible but no later than 15 calendar days after the sponsor-investigator 
determines that the information qualifies for reporting 
 Any findings from animal or in vitro testing whether or not conducted under 
an IND, and whether or not conducted by the sponsor-investigator, that 
suggest a significant risk in humans exposed to the drug  must be reported 
as soon as possible but no later than 15 calendar days after the sponsor-
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 Any clinically important increase in the rate of a serious suspected adverse 
reactions  over that listed in the protocol or Investigator Brochure 
 Expected SAEs and AEs will be included in the IND Annual Reports. 
Follow-up information to a safety report should be submitted as soon as the relevant 
information is available.  However, if the results of a sponsor’s investigation show that an 
adverse drug experience not initially determined to be reportable are so reportable, the sponsor 
investigator must report such experience as soon as possible, but no later than 15 calendar 
days after the determination is made. 
 
All other serious unexpected experiences associated with the use of the study treatment will 
be reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
7.3.6 Reporting Process 
Adverse events may be submitted on FDA Form 3500A, the HICCC DSMC Serious Adverse 
Event Reporting Form, or in a narrative format.  
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
8.1.1 Primary Endpoint 
The primary endpoint for this study is pathological complete response (pCR) defined as no 
invasive disease within an entirely submitted and evaluated gross lesion, and histologically 
negative nodes (T0N0). The primary hypothesis of this study is that combination induction 
and maintenance therapy including immunotherapy and chemotherapy will result in increased 
efficacy compared to historical use of chemotherapy alone. This will be achieved by comparing 
the pathological complete response (pCR) rate at the time of surgery following 3 cycles of pre-
operative chemotherapy (with 4 cycles of pembrolizumab) to historical controls. Previous 
studies have reported low rates of pCR following neoadjuvant therapy with chemotherapy 
alone for gastric cancer (3% in the FNCLCC and FFCD study5 and 0% reported in the MAGIC 
study2). Although this is an uncommon finding this novel combination and increase pre-op 
dosing may increase the pCR rate to 15% or more. Assuming that 28 out of the 38 patients will 
be evaluable for pCR, we estimate that with 28 patients we will have 80% power to detect an 
increase in pCR rate from 3% to 15% with a one-sided binomial test with an actual alpha of 
0.05.  We reject the null that the pCR rate is 3% or less if 3 or more out of the 28 patients 
respond.    


 
 
 
 
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8.1.2 Secondary Endpoint 
The secondary endpoints are ORR, DFS and OS.  DFS is defined as time from Cycle 1 Day 1 
treatment administration to the first documented event of: disease progression, disease 
recurrence following surgery (preferably biopsy proven), or death- whichever occurs first. 
Overall Survival (OS): time from Cycle 1 Day 1 treatment administration to death due to any 
cause. 
The secondary hypothesis of this study is that combination therapy with immune checkpoint 
blockade and chemotherapy used in the perioperative period will eradicate micrometastatic 
disease and improve disease free survival (DFS). 
8.1.3 Exploratory and Ancillary Studies 
Gene expression profiles and IHC will be quantified as continuous variables and results will 
be compared between baseline and surgical specimens (pre therapy and post 12 weeks of 
combination therapy). We expect that some samples will be inadequate for analysis but 
anticipate 35 paired specimens. With 35 paired samples of pre and post specimens, we will 
have 80% power to detect a change of 0.50 standard deviation with a two-sided alpha of 0.05.  
We will analyze changes in immune profiles between subjects (prior to and after treatment) 
using paired t-tests or non-parametric test if the data is not normally distributed.  Moreover, 
we will compare immune profiles (using presence of TILs and PD-L1 expression among other 
measurements) between those who have a good response (defined as pathCR, or 24 month 
DFS) to those who do not have a good response.  Given that we expect a small number of 
patients with pathCR, we will compare the data descriptively using summary statistics such as 
mean, median and ranges.   
8.2 
Statistical Analysis Plan Details 
8.2.1 Efficacy Endpoints 
Pathologic complete response (pCR): The number and proportion of subjects with pCR will be 
reported along with the exact binomial confidence interval.  We reject the null that the pCR 
rate is 3% or less if 3 or more out of the 28 patients achieve pCR.  
Disease Free Survival (DFS) and Overall Survival (OS): The Kaplan-Meier method will be 
used to evaluate all time to event endpoints.  Median DFS and OS will be estimated and 
reported with 95% confidence intervals.  Moreover, we will report the estimated DFS at 24 
months with 95% confidence intervals.   
Overall Response Rate (ORR): The number and proportion of subjects with initial RECIST 
1.1 measurable disease who have complete response (CR) or partial response (PR) at any time 
will be reported along with the exact binomial confidence interval.   


 
 
 
 
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8.2.2 Safety Endpoints 
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in combination with chemotherapy in subjects with gastric cancer. The 
primary safety analysis will be based on subjects who experienced toxicities as defined by 
CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades experienced 
by subjects who have received pembrolizumab, including serious adverse events (SAEs) and 
events of clinical interest (ECIs). 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 7.3.3.2.  
8.2.3 Statistical Methods for Safety Analysis 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs. Count and percentage of treatment 
related AEs will be provided. Confidence interval for rate of AE of clinical interest will be 
estimated using Exact method based on binomial distribution. 
8.2.4 Analysis Populations 
All subjects who received at least one dose of study treatment will be included in the primary 
and secondary efficacy and safety analysis.  
8.2.5 Measurement of Effect 
8.2.5.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with Pembrolizumab. 
Evaluable for primary outcome (pCR):  
All subjects who receive a single dose of study medication and are eligible will be considered 
evaluable for the primary outcome of pCR.  Patients who discontinue treatment prior to surgery 
due to reasons other than eligibility (e.g. disease progression, toxicity, or physician discretion) 
will be considered as not having achieved pCR.  For secondary analysis, we will consider not 
evaluable those who do not have a pathology report for determination of pCR or discontinue 
treatment prior to surgery due to reasons other than disease progression and toxicity for the 
estimation of pCR rate.   
Evaluable for secondary outcome (RR, DFS, or OS): All subjects who receive a single dose of 
study medication will be included in the assessment of ORR, DFS, or OS.  


 
 
 
 
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Evaluable for objective response: All patients included in the study must be assessed for 
response to treatment if they have measurable disease at baseline.  
8.2.5.2 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis 
for nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers 
by clinical exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements.  It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 


 
 
 
 
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recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up.  
8.2.5.3     Response Criteria 
8.2.5.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase. Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal Investigator). 
Disease recurrence: is defined as PD (as above) or appearance of a new lesion following 
surgical resection. Evidence of recurrence will generally require biopsy confirmation and the 
time of recurrence will be the time that biopsy is positive. In situations in which a biopsy is not 
feasible or recommend by the treating physician or is declined by the subject, the evidence of 
recurrence will be confirmed by the review panel (or Principal Investigator).  
8.2.5.4 Response Review 
All responses will be reviewed by an expert independent of the study at the study’s completion. 
All imaging will be stored at Columbia NYP. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 


 
 
 
 
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investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 9. 
Table 9     Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-Investigator 
and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the 
label text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 


 
 
 
 
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10.0 ADMINISTRATIVE/ DATA REPORTING AND REGULATORY DETAILS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.3 
(Adverse Events: List and Reporting Requirements).  The Data Safety Monitoring Plan is 
described in Section 10.3. 
10.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be 
built into the CTMS for data entry. The system has full auditing capabilities which is web-
based and housed on a server in a fully HIPAA compliant server room with restricted access 
and video camera monitoring.  All users must login with their own application username and 
password.  Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials.  Users are only able 
to see study information if they are indicated as study personnel in our electronic IRB system. 
Users are limited to access based on the role assigned in their corresponding protocol.  Subject 
data is entered directly into the system, which (in the case of Columbia subjects) confirms the 
correct identity of patients via an interface with the electronic medical patient index.  Staff with 
the appropriate IRB defined roles can run reports within the system for reporting purposes. 
10.2 
Data Reporting 
Case Report Forms will be completed for each subject enrolled into the clinical study through 
the CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory 
data entered on the corresponding CRFs are complete, accurate and authentic. 
10.3 
Data and Safety Monitoring Committee 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol will adhere to the policies of the currently approved 
HICCC Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and 
CUMC-IRB policy and guidelines.  The committee is chair is appointed by the HICCC 
Director. The committee consists of HICCC faculty and staff with expertise in oncology, 
research pharmacy, research nursing, and data management. The DSMC convenes twice a 
month to review patient safety and the conduct of the trial. The PI will submit data and safety 
monitoring reports to the DSMC at a frequency to be determined by the DSMC based on risk 
to the subjects. 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB. 
All study data reviewed and discussed during these meetings will be kept confidential.  
For multicenter research, the principal investigator will assure that there is a mechanism in 
place to distribute the report to all participating investigators for submission to their local IRB.  
The report will document that a review of data and outcomes across all centers took place on 
a given date.  It will summarize the DSMC’s review of the cumulative toxicities reported from 


 
 
 
 
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all participating sites without specific disclosure by treatment arm.  It will also inform site 
investigators of the study the DSMC’s conclusion with respect to progress or need for 
modification of the protocol.   
10.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be 
conducted periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  
Additionally, the Compliance Oversight Committee of the IRB at Columbia University 
Medical Center may audit the study at any time per institutional policies and procedures. The 
Sponsor-investigator and Columbia University Medical Center will permit direct access of the 
study monitors and appropriate regulatory authorities to the study data and to the corresponding 
source data and documents to verify the accuracy of this data. 
A risk-based approach will be used by the Compliance Core to determine the frequency, 
number of subject charts, and data elements to be monitored. The Compliance Coordinator will 
review the study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, 
statistical endpoints (e.g., stopping rules), etc. for the full DSMC membership at the regularly 
scheduled meetings.   
 
Internal On-site Monitoring: 
 
 
Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
remote clinical sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 
The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
The Compliance Coordinator will communicate with the site coordinator/Site Principle 
Investigator to schedule the monitoring visit and arrange for access to study materials and 
documentation. 
 
The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 
first subject is enrolled and throughout the life of the study to ensure that the study is being 
conducted in accordance with the protocol, GCP, applicable federal and local regulations, and 
per all applicable SOPs. The Compliance Coordinator is responsible to notify the PI and 
CRNP/CRN/CRC of upcoming monitor visits and convey what information and 
documentation will be required for the visit(s).  The Compliance Coordinator is responsible 
for verifying that informed consent is properly obtained, eligibility is met (via the central 
registration process), and all study procedures are conducted according to the study protocol. 
The Compliance Coordinator will also verify that the data reported in the CRF’s accurately 
reflect source documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to local IRB and HICCC 
DSMC requirements. The Compliance Coordinator will issue queries and ensure resolution 
in a timely and efficient manner.  The Compliance Coordinator will also monitor for 
applicable regulatory compliance and research pharmacy compliance (if applicable) and 
communicate any deficiencies as appropriate. 


 
 
 
 
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10.5 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (e.g., that the subject is alive) 
at the end of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator and study staff will have access to the file. 
10.6 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
10.7 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  
10.8 Records Retention 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 
CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies 
whether or not any subjects were enrolled in the study. 
If the research is FDA regulated, records should be retained for at least two years after approval 
of the investigational agent by FDA; if it is not approved, records should be retained at least 
two years after the study is terminated and FDA is notified (note the additional requirement 
below for clinical research studies);  


 
 
 
 
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Clinical records, including consent forms that document clinical intervention or clinical 
diagnostic procedure research-related procedures, must be retained in medical records by the 
institution for at least seven years, per CUMC and NYP policy which is based on state law. 
10.9 
Ethical Considerations 
10.9.1 Institutional Review Board or Ethics Committee Approval 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated.  The study 
will be conducted in accordance with FDA, applicable national and local health authorities, 
and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case, the IRB 
must be updated at least once a year.  The Principal Investigator must also keep the IRB 
informed of any significant AEs. 
Investigators are required to promptly notify their respective IRB of all adverse drug reactions 
that are both serious and unexpected.  This generally refers to SAEs that are not already 
identified in the Investigator’s Brochure and that are considered possibly or probably related 
to the molecule or study drug by the investigator.  Some IRBs may have other specific AE 
requirements to which investigators are expected to adhere.  Investigators must immediately 
forward to their IRB any written safety report or update provided by Genentech (e.g., IND 
safety report, Investigator’s Brochure, safety amendments and updates, etc.). 
10.10 Study Finances 
10.10.1Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the Columbia University Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved prior 
to participation in this study.  All CUMC investigators will follow the University conflict of 
interest policy. Other investigators will be required to follow conflict of interest policies at 
their respective institutions.  
10.10.2 Subject Stipends or Payments 
No payments will be made to study subjects. 
10.11 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-Investigator 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 


 
 
 
 
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conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.     
11.0 
PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be obtained before commencement 
of this study.  
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study. This consent form will be submitted with the protocol for review and approval by 
the IRB for the study.  The formal consent of a subject, using the IRB-approved consent form, 
must be obtained before that subject is submitted to any study procedure.  This consent form 
must be signed by the subject or legally acceptable surrogate, as outlined in the IRB approved 
protocol, and the investigator-designated research professional obtaining the consent.  
12.0   PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will 
be published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. The study drug manufacturers reserve the right to 
review all manuscripts prior to submission for publication. 
 


 
 
 
 
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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) 
13.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
 
* As published in the European Journal of Cancer27. 
13.4 Guidelines for Affiliate Institutions in Multicenter Studies 
1. Multi-site Communication: 
The CPDM Office at CUMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial.  The CPDM Office 
will coordinate, at minimum, regularly scheduled conference calls with affiliate sites.  
The following issues will be discussed, as appropriate:  
 Enrollment information  


 
 
 
 
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 Cohort updates (e.g., DLTs) 
 Adverse events (e.g., new adverse events and updates on unresolved adverse events and 
new safety information) 
 Protocol violations 
 Other issues affecting the conduct of the study 
 
2. New Protocol Distribution, IRB Submission, Modifications, and Annual Renewals 
 Protocol specific documents are distributed to affiliate sites once CUMC IRB approval 
has been obtained.  
 The affiliate site must submit a draft of site specific revisions to protocol and/or consent 
form documents for review and approval by the sponsor-investigator prior to 
submission to the local IRB. Draft documents should be sent to the study specific email 
address. The site will be provided confirmation that they are approved to submit to their 
local IRB.  
 Protocol amendments must be approved by the affiliate site’s local IRB within 90 days 
of distribution to the site by the sponsor-investigator.  
 
3. Regulatory Documents: 
Prior to Site Initiation: 
Sponsor-Investigator will ensure that proper requests are made of sites and that the following 
documentation is collected, prior to the initiation of an affiliate site.   
 CV of PI, Co-I’s and other research staff listed on FDA 1572 (signed and dated 
copy within 2 years) 
 Medical Licenses of PI and Co-I’s (current copy) 
 Human subjects training certificates for PI and Co-I’s 
 CLIA/Laboratory  Certifications for Local Laboratories listed on FDA 1572 
 Local Laboratory Director’s CV and License 
 Local Laboratory Reference Ranges  
 IRB roster or statement of compliance 
 FDA Form 1572, if applicable (wet ink originals required) 
 Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 
Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper requests 
are made of sites and that the following documentation is collected throughout the course of 
the study. 
 IRB approval letters for all protocol modifications and all renewals 
 IRB-approved consent forms 


 
 
 
 
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 Current IRB roster, if statement of compliance is not provided as part of site 
initiation  
 FDA Form 1572, if applicable as updates are required 
 Updated investigator and site information where relevant (e.g., CV, medical 
licensure and Financial Disclosure for new sub-investigator, local laboratory 
information) 
Regulatory documents may be sent to Q9871@columbia.edu or to the following address if wet 
ink originals are required: 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
 
4. Site activation 
Columbia University will schedule a site initiation visit once IRB approval has been submitted 
from the affiliate site.  
5. Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process:  
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to 
any administration of study drug/intervention/local institution registration.  Please see 
instructions below: 
1. Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate 
Institution CRN and/or CRC is required to submit the following documents to the 
coordinating center’s designee (CUMC’s study specific Clinical Research Coordinator 
or Clinical Research Nurse).  The coordinating center’s designee will review the 
documents for accurateness, and subsequently submit the documents to the CPDM 
Central Registration Office via email at Q9871@columbia.edu (or via fax at 
212.305.5292), with a request to register the patient “pending eligibility.” The title of 
the email should read, “AAAQ9871 Pending Subject Registration Request (PHI)”.  The 
following documents should be submitted with the pending registration request, as 
applicable: 
a. Redacted Completed/signed IRB approved/stamped Informed Consent Forms, 
including additional study ICFs (e.g., tissue, DNA, etc.), as applicable 
b. Redacted Signed HIPAA (or institutional equivalent) 
c. MCT CPDM Velos Note to File form  
2. The Affiliate Institution’s investigator/research nurse/data manager/coordinator must 
contact the coordinating center’s designee (CUMC’s study specific Clinical Research 


 
 
 
 
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Coordinator or Clinical Research Nurse) via telephone or email to communicate the 
following: 
 Notify of pending registration request  
 Confirm method of registration request submission (email or fax) 
 Communicate expected time-line of registration request submission (e.g., same day, 
next day, within the hour, etc.) 
3. To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study 
specific designee: 
 A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
 Copies of redacted source documentation necessary for each item to be verified on the 
CUMC specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) capturing the consent process information, along with 
providing 
source 
documentation 
of 
any 
other 
items 
needed 
for 
screening/eligibility that are not captured in other source document forms. (e.g., 
positive investigator statements of unique eligibility items not captured via 
other direct source documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 Please note: subject line of email or fax should include the following: “AAAQ9871 
Complete Subject Registration Request (PHI)”. 
4. Upon receipt of the above mentioned documents, the designated study specific Clinical 
Research Coordinator will review all documents and verify patient eligibility.  If any 
questions arise during the review process, queries in the form of emails will be addressed 
to the applicable affiliate site study team personnel for clarification prior to enrollment.  
Upon verification, the CUMC study specific designee will then forward all documents to 
the CPDM Central Registration Office for central registration (as described above). The 
CPDM Central Registration Registrar will review all applicable documents and 
communicate to the CUMC study specific designee in order to clarify any items.  The 
CUMC study specific designee will communicate with the applicable site study team 
personnel for additional clarifications necessary prior to enrollment. 
5. Upon receipt of the subject registration notification email, the CUMC study specific 
designee will forward the notification email (which will include the study specific patient 
ID) to the affiliate site’s Principal Investigator, Consenting Professional, and applicable 
research personnel.  This notification should be filed in the patient research binder 
accordingly. Protocol therapy may not be initiated prior to receipt of this notification from 
the coordinating center. 


 
 
 
 
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6. All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration 
Office in a manner analogous to the procedures noted above. Applicable source 
documentation will be required within the corresponding submissions. 
 
6. Protocol Deviation/Subject Waiver request for Affiliate Sites: 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for 
review and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained 
from all entities prior to implementation at the Affiliate site.  If a prospective protocol deviation 
request is submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC 
approval(s) and correspondence and CUMC IRB eligibility deviation approval letter(s) should 
be forwarded to the Affiliate site for documentation. The Affiliate site is also required to obtain 
prospective local IRB approval as per institutional policies/procedures prior to implementing 
the proposed deviation and registering/enrolling the subject via CUMC Central Registration. 
All documents and determinations must be clearly documented in the study subject’s medical 
record, research chart and regulatory binder, as described. 
 
7. Guidelines for Affiliate Site Monitoring  
 
On-Site MCT Monitoring:  
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
Affiliate sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
a. The study Monitoring Visit Log will be completed and signed by the monitor 
and the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first 
subject is enrolled at the Affiliate site and throughout the life of the study to ensure that 
the study is being conducted in accordance with the protocol, GCP, applicable federal 
and local regulations, and per all applicable SOPs. The Compliance Coordinator is 
responsible to notify the participating site PI and CRNP/CRN/CRC of upcoming 
monitor visits and convey what information and documentation will be required for the 
visit(s).  The Compliance Coordinator is responsible for verifying that informed 
consent is properly obtained, eligibility is met (via the central registration process), and 
all study procedures are conducted according to the study protocol. The Compliance 
Coordinator will also verify that the data reported in the CRF’s accurately reflect source 
documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to Coordinating Center, 
local IRB and HICCC DSMC requirements. The Compliance Coordinator will issue 
queries and ensure resolution in a timely and efficient manner.  The Compliance 
Coordinator will also monitor for applicable regulatory compliance and research 
pharmacy compliance (if applicable) and communicate any deficiencies as appropriate. 


 
 
 
 
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4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being 
made available (if applicable) and before any subjects are enrolled on a study at the 
Affiliate site. 
 
MCT Remote Monitoring:  
 When necessary (due to logistical constraints), Affiliate sites will be monitored 
remotely by a designated Compliance Coordinator. Sites will be informed of this 
remote monitoring process on a site by site basis. 
 Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory 
level, as well as a clinical data/source documentation review level. 
 Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure 
email for all subjects enrolled at Affiliate sites. Timelines for submission procedures 
will be defined on a case by case basis.   
 The Compliance Coordinator will review all submitted redacted source documents 
against the data entered on the protocol specific CRFs. The Compliance Coordinator 
will issue queries when/if necessary. 
 The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
 The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance 
regarding: 
a. Informed consent procedures 
b. Eligibility criteria 
c. Protocol specific treatment compliance 
d. Protocol specific toxicity/outcome documentation/compliance 
e. Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on 
study, follow-up) 
f. Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, INDSR 
submissions, etc). 
g. Required specimen submissions (e.g., tissue specimens, research blood 
specimens, etc.) 
h. Pharmacy accountability records 
i. Adherence to the CRF submission timeframes to CUMC (within the protocol 
specified timeframes) 
 Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and 
Affiliate sites after each remote monitoring review. Reports will include information 
regarding data submission timeliness/accuracy, protocol adherence items, query 
resolution status, regulatory status, and overall Affiliate site performance. These 
reports will be generated by the Compliance Coordinator and reviewed with the 
Compliance Core Manager prior to dissemination. 
 


 
 
 
 
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8. Dose Level Determinations: 
 
The sponsor-investigator will review enrollment for each dose level cohort during the regularly 
scheduled conference call with the affiliate sites.  
The dose level for newly enrolled subjects will be determined by the study statistician upon 
notification that a subject has signed informed consent to participate in the study. The assigned 
dose level for any subject to begin study treatment will be communicated to the affiliate site 
along with the determination by Central Registration that the subject is eligible for enrollment 
in the study.  
If a Dose Limiting Toxicity (DLT) is identified in a subject, the affiliate site must notify the 
sponsor-investigator via email at the study specific email address within 1 business day of 
identification. The lead site will communicate that a DLT has been experienced within 1 
business day.  
 
9. Adverse event reporting 
Sponsor reporting: Notifying participating investigators at affiliate sites of adverse events 
It is the responsibility of the study sponsor to notify all affiliate sites, in a written IND safety 
report, of any adverse event associated with the use of the drug that is both serious and 
unexpected, as well as any finding from tests in laboratory animals that suggest a significant 
risk for human subjects.  Additionally, sponsors are also required to identify in IND safety 
reports all previous reports concerning similar adverse events and to analyze the significance 
of the current event in light of the previous reports. 
Serious Adverse Event Reporting 
Each participating investigator is required to abide by the reporting requirements set by 
Columbia University Medical Center. The study must be conducted in compliance with FDA 
regulations, local safety reporting requirements, and reporting requirements of the principal 
investigator. 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence 
using the SAE Report Form. In the event that the participating investigator does not become 
aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), 
the participating investigator is to report the event within 24 hours after learning of it and 
document the time of his or her first awareness of the adverse event. Report serious adverse 
events by telephone, email or facsimile to: 
Gulam Manji, MD., PhD. 
161 Fort Washington Ave 
New York, NY 10032 
Telephone: 212 305 0592 
Email address: gam2140@cumc.columbia.edu 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 


 
 
 
 
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event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow- up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, and whether the subject continued or withdrew from study 
participation or if study drug was interrupted or discontinued. 
 
If the SAE is not previously documented in the Investigator’s Brochure for the study drug 
(new occurrence) and is thought to be related to the investigational agent, the sponsor-
investigator may urgently require further information from the investigator for reporting to 
Health Authorities. 
Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the Columbia University Medical Center Overall 
Principal Investigator on the toxicity Case Report Forms. 
Reporting to the Institutional Review Board (IRB) and the Data and Safety Monitoring 
Committee: 
All Unanticipated Problems (UPs) will be reported to the CUMC IRB.  SAEs not constituting 
UPs will reported to the HICCC DSMC.   
Each affiliate site will be responsible for safety reporting to their local IRB.  Investigators are 
responsible for complying with their local IRB’s reporting requirements, though must submit 
the required reports to their IRB no later than 7 calendar days following the occurrence of the 
UP or the Principal’s Investigator’s acquiring knowledge of the UP.  Copies of each report and 
documentation of IRB notification and receipt must be included in the regulatory binder. 
Expected AEs must be reported at the time of continuing review of a protocol. 
Guidelines for Processing IND Safety Reports  
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies 
to notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. The CUMC Principal 
Investigator will review all applicable IND Safety Reports and has the responsibly for 
forwarding the IND Safety Reports to the Affiliate Institutions. The Affiliate Institution 
investigators are to review, send a copy to their IRB according to their local IRB’s policies and 
procedures, and file a copy with their regulatory documents. All Affiliate site INDSR 
submissions, along with IRB acknowledgment (per local policies and procedures) are to be 
forwarded to CUMC for placement within the trial master file. 
Reporting to Hospital Risk Management 


 
 
 
 
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Affiliate Site investigators will report to their local Risk Management Office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
10.  Confidentiality 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each new 
subject being assigned the next sequential number (e.g., 04-10). All sites will be required to 
enter their data in the Velos eResearch, the Clinical Trial Management System used for all 
Cancer-related clinical research at CUMC. All users must login with their own application 
username and password.  Users off campus must first access the Virtual Private Network with 
their assigned campus username and password and then use their application credentials.   
Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations.  
Except when required by law, study information shared with persons and organizations outside 
of Columbia University Medical Center must not identify the patient by name, social security 
number, address, telephone number, or any other direct personal identifier. 
If the results of this research project are published or presented at a scientific or medical 
meeting, the patient not be identified. Otherwise, all results will be kept confidential and will 
not be divulged (except as required by law) without permission.  
11. Data Reporting Plan 
Columbia University Medical Center (CUMC) is deeply committed to research integrity and 
strong credibility when it comes to the discovery of new treatment concepts, implementation 
of new clinical research techniques, and acceptance of its researcher's findings by the medical 
establishment. In accord with these ethics, CUMC encourages and supports its investigators in 
the sharing of final research data and/or details of newly developed clinical treatments. 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and 
state laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy 
of patients who participate in clinical trials. The data can be made available for continuing 
review by federal agencies upon request and for ongoing study safety reviews by the Principal 
Investigator, Statistician, Data Safety and Monitoring Board (DSMC), and, in other instances, 
the CUMC IRB. 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or 
transferred to other collaborators.  Prior to transfer, the data collected must comply with, and 
must be limited by, the CUMC's guidelines for Protecting the Rights and Privacy of Human 
Subjects.   
12. Data Acquisition and Submission 


 
 
 
 
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Informed consent, including HIPPA authorization, must be obtained on all subjects prior to 
their participation. Always keep the original signed and dated consent form, with the redacted 
source documents and eligibility checklist. Velos eResearch will be used as the electronic 
clinical trials and data management system. Affiliate sites will enter data directly into Velos 
eResearch via customized case report forms for the study. The research staff will generate 
reports from Velos eResearch to ensure timely submission of data by affiliate sites. This 
resource allows for the timely analysis of particular data sets for safety analysis. 
13. Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.   
 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the 
study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which 
it is being investigated; or, if no application is to be filed or if the application is not approved 
for such indication, until 2 years after the investigation is discontinued and FDA is notified. 
 
14.0 
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