Clinical trial NCT03342937
Conditions: Gastric Cancer Esophagus Cancer
Keywords: pembrolizumab XELOX gastric cancer
Sponsor: Duke University
Start date: 2018-01-11; Completion date: 2023-02-06
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be conducted in two stages: 1) safety validation and 2) dose expansion

1. Safety Validation Cohort: The first portion of the study will preliminarily establish the tolerability of the combination of pembrolizumab, oxaliplatin and capecitabine. Five (5) subjects will be enrolled and their safety data after 21 days of treatment will be reviewed before additional subjects are enrolled. Subjects on this portion of the study will only be enrolled at the Duke Cancer Institute.
2. Dose Expansion Cohort: The second portion of the study (ie. phase II) will enroll 30 subjects. In the dose expansion cohort, the first cycle will be modified to allow one week of pembrolizumab monotherapy before starting capecitabine and oxaliplatin (XELOX) chemotherapy, which will allow analysis of biomarkers related to pembrolizumab. Subjects on this portion of the study will be enrolled at the Duke Cancer institute and select external collaborating institutions.

The primary objective of this trial is to describe the progression free survival (PFS) associated with the combination of pembrolizumab, oxaliplatin and capecitabine (pembrolizumab +XELOX) in all patients with previously untreated metastatic esophagogastric adenocarcinoma.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Oxaliplatin+Capecitabine+Pembrolizumab
Intervention descriptions: intervention 1: For each cycle: Oxaliplatin 130 mg/m2 IV on Day1, Capecitabine 825 or 1000 mg/m2 PO, BID Days on Days1-14, Pembrolizumab 200 mg IV on Day 1.

This study has 2 parts:

1. Safety validation part: all Cycles are 21 days in length.
2. Dose Expansion part: Cycle 1 is 28 days in length. Cycle 2 and beyond are 21 days.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine 
in the First Line Treatment of Patients with Gastro-esophageal Cancer 
(KeyLARGO) 
 
 
Trial: NCT03342937 
 
 
Protocol 
 
March 30, 2022 
 


 
 
 
 
 
 
A Single Arm, Phase II Study of  
Pembrolizumab, Oxaliplatin, and Capecitabine  
in the First Line Treatment of Patients  
with Gastro-esophageal Cancer  
(KeyLARGO) 
 
 
 Lead Principal Investigator:   
Hope Uronis, MD 
Duke Univeristy Medical Center 
10 Bryan Searle Drive 
Seeley Mudd Building 
DUMC Box 2823 
Durham, NC 27710 
 
Supported by:  
Merck & Co. 
 
 
 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to 
initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from the 
coordinating site and sponsor is required for disclosure otherwise. 


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PROTOCOL VERSIONS  
 
Version Number 
Version Date 
Version 1.0/ Initial 
07-April-2017 
Version 2.0 
30-November-2017 
Version 3.0 
31-July-2018 
Version 4.0 
07-November-2018 
Version 5.0 
06-January-2020 
Version 6.0 
06-July-2020 
Version 7.0 
26-May-2021 
Version 8.0 
02-February-2022 
Version 9.0 
30-March-2022 
 
 
 
 
 
 
 


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SPONSOR CONTACT INFORMATION 
 
Lead Principal Investigator (PI): 
Hope Uronis, MD 
Duke Univeristy Medical Center 
10 Bryan Searle Drive 
Seeley Mudd Building 
DUMC Box 2823 
Durham, NC 27710 
Phone: 919-668-1861 
Fax: 919- 668-3037 
Pager: 919-684-8111 
Email: hope.uronis@duke.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNPOSIS  
Title 
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO) 
Objectives 
Primary Objective 
1. To describe the progression free survival (PFS) associated with the combination of 
pembrolizumab, oxaliplatin and capecitabine (pembro+XELOX) in all patients with previously 
untreated metastatic esophagogastric adenocarcinoma. 
Secondary Objectives 
1. To describe the safety and tolerability of the combination of pembro+XELOX in patients with 
metastatic esophagogastric adenocarcinoma. 
2. To describe the response rate (RR) and overall survival (OS) of the combination of 
pembro+XELOX in patients with previously untreated metastatic esophagogastric 
adenocarcinoma. 
Exploratory Objectives 
1. To explore the changes in CD8 and PDL1 expression in tumor tissue related to 
pembrolizumab treatment.  
2. To explore other changes in tissue and blood based biomarkers and their correlation with 
clinical outcomes. 
3. To explore changes in immune cells and biomarkers in those who completed treatment and 
remain in complete response. 
 
Patient Population 
Histologically and/or cytologically documented and radiographically measurable (by RECIST 
1.1) adenocarcinoma of the esophagus or stomach (HER2 negative) that is 
metastatic/recurrent and not amenable to potentially curative treatment (e.g., inoperable 
metastatic or locally recurrent disease).  HER2 positive patients would be considered eligible 
only if there is a contraindication to Herceptin. 
Study Design 
The study will be conducted in two stages: 1) safety validation and 2) dose expansion. 
1. Safety Validation Cohort: The first portion of the study will preliminarily establish the 
tolerability of the combination of pembrolizumab, oxaliplatin and capecitabine. Five (5) 
patients will be enrolled and their safety data after 21 days of treatment will be 
reviewed before additional patients are enrolled. Subjects on this portion of the study 
will only be enrolled at the Duke Cancer Institute. 


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2. Dose Expansion Cohort: The second portion of the study (ie. phase II) will enroll 30 
patients. In the dose expansion cohort, the first cycle will be modified to allow one 
week of pembrolizumab monotherapy before starting capecitabine and oxaliplatin 
(XELOX) chemotherapy, which will allow analysis of biomarkers related to 
pembrolizumab. Subjects on this portion of the study will be enrolled at the Duke 
Cancer Institute and select external collaborating institutions. 
Number of Subjects 
In the Safety Validation Cohort, 5 evaluable subjects will be enrolled.  
In the Dose Expansion Cohort, 30 evaluable subjects will be enrolled. 
A total of 35 evaluable subjects will be accrued to this study to assess the efficacy, safety and 
tolerability of the combination of pembrolizumab, oxaliplatin and capecitabine. 
Estimated Length of Study Participation 
Estimated duration of subject enrollment is 12 months.   
Patients will continue to receive study treatment until they experience unacceptable drug-
related toxicity or disease progression. The maximum duration of treatment for pembrolizumab 
will be up to two years. The duration of treatment for XELOX will be until unacceptable drug-
related toxicity or disease progression.  
Subjects who discontinue study treatment for any reason (e.g., toxicity) other than disease 
progression should be followed until documented disease progression or start of a new anti-
cancer therapy.  All subjects will be followed for survival until death, loss to follow-up, or study 
completion.   
Study completion is 3 years after the last subject starts study drug regimen. 
Study Drug Regimen 
In the Safety Validation Cohort, the cycle length is 21 days. Patients will receive 
pembrolizumab and oxaliplatin on day 1 of each cycle.  Capecitabine will be taken twice per 
day on days 1-14 of each cycle.  Patients will continue to receive study treatment until they 
experience unacceptable drug-related toxicity or disease progression.  
In the Dose Expansion Cohort (ie. phase II), the first cycle of treatment, referred to as 
‘biomarker cycle,’ will be modified to allow assessment of biomarkers related to 
pembrolizumab; the length will be 28 days.  Patients will receive pembrolizumab monotherapy 
on Cycle 1 Day 1. Treatment with oxaliplatin and capecitabine will begin on Cycle 1 Day 8; 
capecitabine will be dosed for 14 days (ie. Days 8-21), followed by one week off drug (ie. Days 
22-28).  Cycle 2 will start on Day 29 of study (ie. 28 days after pembrolizumab monotherapy 
and 20 days after start of capecitabine and oxaliplatin). For cycles 2 and beyond, the cycle 
length is 21 days, with a treatment window of +/-3 days allowed for day 1.  Patients will receive 
pembrolizumab and oxaliplatin on day 1 of each cycle. Capecitabine will be taken twice per 
day on days 1-14 of each cycle.  Patients will continue to receive study treatment until they 
experience unacceptable drug-related toxicity or disease progression.  


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For both cohorts, patients will continue to receive study treatment until they experience 
unacceptable drug-related toxicity or disease progression. The maximum duration of treatment 
for pembrolizumab will be up to two years (35 cycles). The duration of treatment for 
capecitabine and oxaliplatin will be until unacceptable drug-related toxicity or disease 
progression. Patients who complete 35 cycles of therapy and have complete response or 
prolonged stable disease may also elect to end therapy with capecitabine, after a discussion 
with their treating physician. 
Study Assessments 
Toxicity will be assessed at every visit using NCI-CTCAE version 4.0.  Safety assessments will 
be performed weekly during the first cycle, then every three weeks thereafter.  Safety 
assessments will include vital signs, ECOG performance status, medical history, physical 
examination, review of concomitant medications, CBC with differential, and chemistries with 
liver function tests.  Symptom management and supportive care will be provided as clinically 
indicated to ensure optimal patient care.  After discontinuation of study treatment, subjects will 
have safety assessments 30 days after the last dose of study drug. All subjects will then be 
followed by telephone or medical record review for survival.   
Tumor Assessments 
Restaging scans and blood tumor markers will be repeated every three cycles.  Tumor 
response will be assessed using RECIST 1.1 and irRC. 
Correlative Studies 
The association between biomarker expression and clinical outcomes will be explored with the 
following blood and tumor tissue specimen collections and specified time points from all 
subjects: 
 
Tumor Tissue. If available, archived FFPE tumor samples will be obtained from all subjects 
at baseline and at end of study. In the biomarker cycle (ie. Cycle 1) of the Dose Escalation 
Cohort, pre-treatment (up to 1 week before starting treatment) and on-treatment (prior to 
start of oxaliplatin and capecitabine) tumor biopsies will be completed on patients who 
have lesions amenable to safe biopsy.  Subjects in the Dose Escalation Cohort who are 
not amenable to safe biopsy will only have blood based biomarker collections in the 
biomarker cycle (ie. Cycle 1).   
 
Circulating Immune Cells. Subjects will have peripheral blood mononuclear cells (PBMC) 
collected at baseline, at the end of monotherapy lead-in on Day 8 (biomarker cycle of Dose 
Expansion Cohort only), at end of first cycle of combination therapy on Day 29 (biomarker 
cycle of Dose Expansion Cohort only), at first restaging, at disease progression or off 
treatment and complete responders on long term follow-up. 
 
Circulating Proteins. Subjects will have plasma collected at baseline, at the end of 
monotherapy lead-in on Day 8 (biomarker cycle of Dose Expansion Cohort only), at end of 
first cycle of combination therapy on Day 29 (biomarker cycle of Dose Expansion Cohort 
only), at every restaging, at progression or off treatment, at off treatment follow-up, and 
complete responders on long term follow-up.    
 
Pharmacogenomics. Subjects will have whole blood collected at baseline. 


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TABLE OF CONTENTS 
 
1.0  INTRODUCTION .............................................................................................................. 11 
1.1 
Background ............................................................................................................. 11 
1.2 
Study Drugs ............................................................................................................ 12 
1.2.1 
Pembrolizumab ................................................................................................. 12 
1.2.1.1 
Pharmaceutical and Therapeutic Background .............................................. 13 
1.2.1.2 
Preclinical and Clinical Trial Experience ....................................................... 14 
1.2.1.3 
Safety Profile ................................................................................................ 16 
1.2.1.4 
Dose Selection ............................................................................................. 19 
1.2.2 
Oxaliplatin ......................................................................................................... 20 
1.2.3 
Capecitabine ..................................................................................................... 23 
1.3 
Study Rationale ....................................................................................................... 25 
 
2.0  OBJECTIVES ................................................................................................................... 26 
2.1 
Primary Objective .................................................................................................... 26 
2.2 
Secondary Objectives ............................................................................................. 26 
2.3 
Exploratory Objectives ............................................................................................ 26 
 
3.0  STUDY DESIGN .............................................................................................................. 27 
3.1 
Study Description .................................................................................................... 27 
3.2 
Safety Validation ..................................................................................................... 28 
3.2.1 
Dose Limiting Toxicity ....................................................................................... 28 
3.3 
Dose Expansion Cohort .......................................................................................... 28 
 
4.0  SUBJECT SELECTION ................................................................................................... 29 
4.1 
Inclusion Criteria ..................................................................................................... 29 
4.2  
Exclusion Criteria .................................................................................................... 29 
4.3 
Inclusion of Women and Minorities.......................................................................... 31 
 
5.0  STUDY ASSESSMENTS ................................................................................................. 31 
5.1 
Screening Period ..................................................................................................... 31 
5.2 
Treatment Period .................................................................................................... 32 
5.3 
Follow-up Period ..................................................................................................... 33 
5.4 
Laboratory Assessments ......................................................................................... 34 
5.5 
Adverse Event Assessment .................................................................................... 34 
5.6 
Tumor Assessments ................................................................................................ 34 
5.6.1 
RECIST version 1.1 .......................................................................................... 34 
5.6.2  
Immune-Related Response Criteria .................................................................. 35 
5.7 
Subject Discontinuation ........................................................................................... 36 
 
6.0  STUDY DRUGS ............................................................................................................... 37 
6.1 
Treatment Compliance and Study Drug Accountability ........................................... 37 
6.2 
Pembrolizumab ....................................................................................................... 37 
6.2.1 
Storage and Handling ....................................................................................... 38 
6.2.2 
Administration ................................................................................................... 38 
6.3 
Oxaliplatin ............................................................................................................... 38 


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6.3.1    
Storage and Handling ....................................................................................... 39 
6.3.2 
Administration ................................................................................................... 39 
6.4 
Capecitabine ........................................................................................................... 40 
6.4.1    
Storage and Handling ....................................................................................... 40 
6.4.2 
Administration ................................................................................................... 40 
6.5 
Concomitant Medications/Vaccinations ................................................................... 41 
6.5.1 
Acceptable Concomitant Medications ............................................................... 41 
6.5.2 
Prohibited Concomitant Medications ................................................................. 41 
 
7.0  DOSE MODIFICATION AND TOXICITY MANAGEMENT ............................................... 42 
7.1 
Dose Modifications .................................................................................................. 42 
7.1.1 
Pembrolizumab Dose Modifications  ................................................................. 43 
7.1.2 
XELOX Dose Modifications ............................................................................... 45 
7.2  
Toxicity Management .............................................................................................. 52 
7.2.1  
Pneumonitis ...................................................................................................... 52 
7.2.2  
Diarrhea/Colitis.................................................................................................. 52 
7.2.3  
Diabetes 
Mellitus 
53 ...................................................................................................................... 57 
7.2.4  
Hypophysitis ...................................................................................................... 53 
7.2.5  
Hyperthyroidism or Hypothyroidism .................................................................. 53 
7.2.6  
Hepatic .............................................................................................................. 53 
7.2.7  
Renal Failure or Nephritis ................................................................................. 54 
7.2.8  
Infusion Reactions ............................................................................................. 54 
 
8.0  CORRELATIVES ............................................................................................................. 56 
8.1 
Tumor Tissue Biomarkers ....................................................................................... 56 
8.2 
Circulating Immune Cells (PBMC) ........................................................................... 56 
8.3 
Protein Multiplex Arrays (Plasma) ........................................................................... 57 
8.4 
Pharmacogenomics (Whole Blood) ......................................................................... 57 
8.5 
Future Use of Patient Samples ............................................................................... 57 
    8.6     Correlative Collaborations…………….…………………………………………………..57 
    8.6.1   Duke-Personalis Collaboration ................................................................................ 57 
    8.6.2   Duke-Olink Collaboration…………………………………………………………………58 
9.0  STATISTICAL ANALYSIS ................................................................................................ 60 
9.1 
General Analysis Considerations ............................................................................ 60 
9.1.1  
Primary Endpoint ............................................................................................... 59 
9.1.2  
Secondary Endpoints ........................................................................................ 60 
9.1.3  
Exploratory Endpoints ....................................................................................... 61 
 
10.0  SAFETY…….. ............................................................................................................... 61 
10.1 
Adverse Events ....................................................................................................... 61 
10.2 
Serious Adverse Events .......................................................................................... 62 
10.3 
Events of Clinical Interest ........................................................................................ 64 
10.4 
Other Safety Considerations ................................................................................... 64 
10.4.1 
Pregnancy and Lactation .................................................................................. 65 
10.4.2 
Medication Overdose and Error ........................................................................ 65 
 


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11.0  ADMINISTRATIVE RESPONSIBILITIES… .................................................................... 65 
11.1 
Institutional Review Board/Independent Ethics Committee ..................................... 65 
11.2 
Protocol and Protocol Revisions ............................................................................. 65 
11.3  Protocol Deviations and Violations .......................................................................... 65 
11.4 
Informed Consent .................................................................................................... 66 
11.5 
Source and Study Documentation ........................................................................... 67 
11.6 
Case Report Forms ................................................................................................. 68 
11.7 
Monitoring and Audits/Inspections .......................................................................... 68 
11.8 
Study Closeout ........................................................................................................ 69 
11.9 
Records Retention................................................................................................... 69 
 
12.0  REFERENCES.. ............................................................................................................. 71 
 
Appendix A.  RECIST 1.1 ....................................................................................................... 72 
Appendix B.  Immune-Related Response Criteria .................................................................. 78 
Appendix C.  ECOG Performance Status ............................................................................... 79 
Appendix D.  Study Calendar ................................................................................................. 80 
Appendix E.  Laboratory Tests ............................................................................................... 82 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
INTRODUCTION 
1.1 
Background 
Gastric cancer is the fourth most common cancer worldwide, with over 700,000 confirmed deaths 
annually1. In the United States, approximately 21,000 new cases are registered annually2.  At 
presentation, nearly 50% of patients diagnosed with gastric or gastro-esophageal cancer have 
unresectable disease that is locally advanced or metastatic. Life expectancy in this setting is 
unfortunately short, usually less than nine months.  
Chemotherapy is the main treatment option for patients with advanced disease, and chemotherapy has 
been shown to prolong survival and improve symptoms compared to best supportive care alone3.  
Traditional first line options include the doublet of capecitabine and cisplatin.  This doublet has been 
used as the consensus international standard for two recently reported phase III studies: (1) 
capecitabine/cisplatin +/- trastuzumab for HER2 positive gastro-esophageal cancer (ToGA trial)4, and 
(2) capecitabine/cisplatin +/- bevacizumab (AVAGAST trial)5.  Two triplet regimens are also considered 
standard options.  One of these regimens includes docetaxel, cisplatin, and 5-FU (DCF regimen), which 
was found to have superior outcomes compared to CF alone (TAX 325 trial)6.  A second triplet regimen 
includes epirubicin, cisplatin and 5-FU (ECF regimen), a combination that was found to be superior to 
multiple doublets in a meta-analysis7.  In the REAL-2 study, a variation of ECF known as EOX was 
shown to be non-inferior, with a modest trend for superior activity and tolerability8.  EOX replaces 
cisplatin with oxaliplatin and 5-FU with capecitabine (Xeloda®).  These triplet regimens, however, are 
often poorly tolerated, which is why the doublet of capecitabine/oxaliplatin is often used as a first line 
treatment for advanced gastric cancer in the United States. This combination is considered “preferred” 
by the NCCN Gastric Cancer Guideline committee17. 
Cancers have genetic and epigenetic alterations that may be detectable by the immune system. The 
endogenous immune response to such alterations provides an attractive anti-tumor strategy by which 
to target cancers. However, tumors develop multiple resistance mechanisms and can also actively 
evade immune destruction.  One mechanism by which tumors can survive is by escaping endogenous 
“immune checkpoints” that are involved in terminating immune responses following antigen stimulation. 
Programmed death ligand 1 and 2 (PD-L1 and PD-L2) are ligands for PD-1, a co-inhibitory receptor on 
T cells, and the interaction between PD-L1 and PD-1 inhibits T-cell proliferation, cytokine production, 
and cytolytic activity.  PD-1 expression in CD4+ and CD8+ T cells from the peripheral blood of patients 
with gastric cancer is higher than that from CD4+ and CD8+ T cells from normal controls; this increased 
expression has been related to disease progression9. PD-L1 expression is present in many human 
tumors (e.g., lung, ovarian, melanoma, and colon carcinoma); elevated PD-L1 expression results in 
tumor cell evasion of the host’s immune system and a worse prognosis10-13. Blockade of this axis has 
been shown to induce durable tumor regression and prolonged stabilization of disease in patients with 
advanced cancers, including non-small cell lung cancer (NSCLC), melanoma, and renal cell cancer10.  
Pembrolizumab (MK-3475) is the first humanized monoclonal anti-PD-1-antibody, FDA-approved in 
September 2014 for the treatment of advanced or unresectable melanoma refractory to other therapies.  
In the KEYNOTE-001 phase Ib study evaluating pembrolizumab as monotherapy in 411 patients with 
advanced melanoma, the estimated one-year overall survival was 69% for all patients, 74% for 
ipilimumab-naïve patients, and 65% for ipilimumab-refractory patients. The median progression-free 
survival was 5.5 months, and the median overall survival has not yet been reached. Of the patients who 


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responded to pembrolizumab, 88% had ongoing responses at a median follow-up of 12 months, and 
some patients receiving pembrolizumab have been on treatment for more than two years. The most 
common adverse events of any grade were fatigue (36%), pruritis (24%), rash (20%), diarrhea (16%), 
and arthralgia (16%). The most common grade 3 or 4 treatment-related adverse event reported was 
fatigue (2%), but no specific adverse event affected more than 1-2% of patients, and only 4% of patients 
discontinued treatment due to a drug-related side effect. Taken together, pembrolizumab is an anti-PD-
1 antibody with a favorable side effect profile that has utility in patients with advanced melanoma, 
including in ipilimumab-refractory patients. Despite this efficacy, not all melanoma patients respond to 
pembrolizumab and only a subset of patients with other solid tumors respond to PD-1/PD-L1 axis 
inhibition. Therefore, molecular biomarkers of response to PD-1/PD-L1 inhibition are still urgently 
needed.  
1.2 
Study Drugs 
1.2.1 Pembrolizumab 
The programmed cell death 1 (PD-1) pathway represents a major immune control switch, which may 
be engaged by tumor cells to overcome active T-cell immune surveillance. Pembrolizumab 
(KEYTRUDA®, MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of 
the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 
and its ligants, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). 
This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and 
ultimately immune rejection. 
Merck, Sharp & Dohme Corporation, a subsidiary of Merck & Co., Inc. (Merck), is studying 
pembrolizumab for various oncology indications. Overall, as of 03-Mar-2016, 16,496 patients have been 
treated in the pembrolizumab development program, of which approximately 9833 patients have been 
exposed to pembrolizumab in Merck sponsored clinical trials (approximately 6713 subjects received 
pembrolizumab monotherapy, approximately 876 subjects received pembrolizumab in combination with 
one or more other chemotherapy or biologic agents, and approximately 2244 subjects received 
comparator treatment alone). As of the various data cutoff dates for the KEYTRUDA® Investigator 
Brochure (IB) Version 13 dated17-Feb-2017, pembrolizumab monotherapy and combination therapy 
have been administered to subjects with hematologic malignancies and solid tumors, in a total of 49 
ongoing, Phase 1, 2, and 3 clinical trials sponsored by Merck. 
On 04-Sep-2014 the United States (US) Food and Drug Administration (FDA) granted accelerated 
approval to KEYTRUDA® for treatment of patients with advanced or unresectable melanoma who are 
no longer responding to other drugs. KEYTRUDA® is the first approved drug that blocks PD-1. 
KEYTRUDA® is intended for use following treatment with ipilumumab (IPI), a type of immunotherapy. 
For melanoma patients whose tumors express a gene mutation called BRAF V600, KEYTRUDA® is 
intended for use after treatment with IPI and a BRAF inhibitor, a therapy that blocks activity of BRAF 
gene mutations. The recommended dose of KEYTRUDA® is 2 mg/kg administered as an intravenous 
(IV) infusion over 30 minutes every 3 weeks (Q3W). 
On 22-Jul-2015 the European Commission (EC) approved KEYTRUDA® for the treatment of advanced 
(unresectable or metastatic) melanoma in adults. The EC approval of KEYTRUDA® was based on data 
from 3 clinical studies (KEYNOTE [KN]001, KN002, and KN006) conducted in more than 1,500 first-line 
and previously-treated patients with advanced melanoma. KEYTRUDA® received EC regulatory 
approval based on Phase 3 data that showed it as the first and only anti-PD-1 therapy to provide a 
statistically superior survival benefit as a monotherapy compared to IPI, the current standard of care for 
advanced melanoma. This approval allowed marketing of KEYTRUDA® in all 28 EU member states at 


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the approved dose of 2 mg/kg Q3W. With the EC decision, KEYTRUDA® is now approved in more than 
35 countries for the treatment of advanced melanoma. 
On 02-Oct-2015 the US FDA granted accelerated approval for KEYTRUDA® to treat patients with 
advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other 
treatments and with tumors that express a protein called PD-L1. KEYTRUDA® is approved for use with 
a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 
expression in non-small cell lung tumors. The FDA-approved dose of KEYTRUDA® is 2 mg/kg Q3W. 
On 18-Dec-2015, the US FDA expanded the label to include the approval of KEYTRUDA® for the 
treatment of patients with unresectable or metastatic melanoma. This expansion now includes the initial 
treatment of patients with unresectable or metastatic melanoma with pembrolizumab. The FDA-
approved dose of KEYTRUDA® is 2 mg/kg Q3W. 
On 29-Jul-2016 the EC approved KEYTRUDA® for patients with locally advanced or metastatic NSCLC, 
at a dose of 2 mg/kg Q3W, in patients whose tumors express PD-L1 and who have received at least 1 
prior chemotherapy regimen. Patients with EGFR or ALK positive tumor mutations should also have 
received approved therapy for these mutations prior to receiving KEYTRUDA®. The EC approval allows 
marketing of KEYTRUDA® in all 28 EU member states. The approval is based on findings from KN010, 
a pivotal study which showed KEYTRUDA® significantly improved overall survival (OS) compared to 
standard of care chemotherapy. 
On 05-Aug-2016 the US FDA approved KEYTRUDA®, at a fixed dose of 200 mg Q3W, for the treatment 
of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease 
progression on or after platinum-containing chemotherapy. Under the FDA’s accelerated approval 
regulations, this indication for KEYTRUDA® is approved based on tumor response rate and durability 
of response. For HNSCC patients, PD-L1 testing is not needed prior to use of KEYTRUDA®. The FDA-
approved dose of KEYTRUDA® is 200 mg Q3W. 
On 28-Sep-2016, Japan approved KEYTRUDA® for the treatment of radically unresectable melanoma 
in adults. The approved dose of KEYTRUDA® is 2 mg/kg Q3W. 
Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA® both as 
a monotherapy and in combination with other therapies across more than 30 tumor types and enrolling 
more than 16,000 patients. Immune-related adverse events (irAEs) are expected based on the nature 
of the compound, its mechanism of action, and reported experience with immunotherapies that have a 
similar mechanism of action. 
1.2.1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies.  In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-
4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (PD-L1 and/or PD L2).  The structure of murine PD-1 has been resolved.  PD-1 and family 


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members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  
Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells 
as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues 
as well as in various tumors.  Both ligands are type I transmembrane receptors containing both IgV- 
and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-
cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment 
of patients with unresectable or metastatic melanoma and disease progression following ipilumumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. 
1.2.1.2 
Preclinical and Clinical Trial Experience 
For complete study information, refer to the current Pembrolizumab Investigator’s Brochure (IB).   
Non-Clinical Toxicology Summary 
In the 1-month and 6-month toxicology study in cynomologus monkeys, pembrolizumab, intravenously 
administered once a week and once every other week respectively up to a dose of 200mg/kg, resulted 
in no adverse treatment-related effects. In tissue cross-reactivity studies of pembrolizumab in human 
and monkey tissues, the expected on-target staining of mononuclear leukocytes membranes was 
demonstrated in both species. Off-target cross-reactivity staining was also noted in both species but 
was limited to the cytoplasm of various cell types/tissues and the stroma (extracellular connective tissue 
matrix), and was considered related to experimental methodological artifacts, i.e. tissue processing for 
IHC, which are well recognized limitations of tissue cross-reactivity studies and, thus not considered 
toxicologically relevant.  
There was no impact seen on male or female fertility based on evaluation of the Cynomolgus monkeys 
used in the 1-month and 6-month studies. Reproductive risk assessment was performed using a 
literature-based approach. In light of the identified potential risk related to inhibition of the PD-1 pathway, 
no reproductive or developmental toxicity studies were conducted with pembrolizumab. Therefore, 


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inclusion of women of childbearing potential in clinical trials should be in accordance with the study 
protocol and applicable regulatory guidance (e.g., ICH M3(R2): Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals). 
 
Clinical Trial Summary 
As of the data cutoff dates for Version 13 (17-Feb-2017) of the Pembrolizumab Investigator’s Brochure, 
pembrolizumab monotherapy and combination therapies have been administered to approximately 
9833 subjects, with hematologic malignancies and solid tumors, in Merck sponsored trials. 
Clinical Pharmacology 
The PK profile of pembrolizumab, with low clearance and limited volume of distribution, is typical for 
therapeutic antibodies. Exposure to pembrolizumab is approximately linear in the dose range of clinical 
relevance (1 to 10 mg/kg and at 200 mg). Furthermore, pembrolizumab has a low potential fo eliciting 
the formation of ADAs. 
Efficacy 
For this Pembrolizumab IB (Version 13, 17-Feb-2017), efficacy data are available for a total fo 1572 
melanoma subjects treated with pembrolizumab in KN001, KN002, and KN006; 1529 subjects with 
NSCLC treated with pembrolizumab in KN001 and KN010; and 174 subjects with HNSCC treated with 
pembrolizumab in KN012. 
KN001 was an open-label, Phase 1, first-in-human study conducted to evaluate clinical activity of 
pembrolizumab as a single agent in two cancers, melanoma and NSCLC. The ORR demonstrated the 
antitumor activity of pembrolizumab in subjects with melanoma (ipilumumab-naïve and previously 
treated with ipilumumab). 
KN002 was a randomized Phase 2 study comparing two doses of pembrolizumab to investigator’s 
choice chemotherapy in subjects with unresectable or metastatic (advanced) melanoma, who had 
progressed after prior treatment with IPI and BRAF (and/or MEK) inhibitor in subjects with BRAF-mutant 
melanoma. The study demonstrated superior PFS for both pembrolizumab treatment arms compared 
to the chemotherapy control arm. Treatment with pembrolizumab led to an ORR that was >4-fold higher 
than the response rate for the chemotherapy control arm. This difference was highly statistically 
significant. 
KN006 was a randomized Phase 3 pivotal study, designed to test whether pembrolizumab was superior 
to IPI in the co-primary efficacy endpoints of PFS and OS in IPI-naïve subjects with unresectable or 
metastatic melanoma. This study demonstrated statisticaly significant improvements in OS and PFS for 
subjects randomized to pembrolizumab compared to subjects randomized to IPI. In the 10 mg/kg 
treatment groups (Q2W and Q3W), 185 subjects experienced objective responses that ranged from 1.4 
months to 8.2 months in duration. 
KN010 was a randomized, adaptively designed Phase 2/3 trial of pembrolizumab at 2 dose levels vs 
docetaxel in subjects with NSCLC with PD-L1 positive tumors, who have experienced disease 
progression after platinum-containing systemic therapy. 
KN012 was a Phase 1b study of pembrolizumab in subjects with advanced solid tumors, including 
subjects with HPV-negative and HPV-positive head and neck cancer. The primary population for 
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The ORRs for pembrolizumab treatment in KN001, KN002, KN006, KN010, and KN012 compared 
favorably to historical response rates for available treatments for melanoma, NSCLC, and HNSCC, 
respectively, particularly in subjects who have progressed after multiple prior therapies. 
1.2.1.3 
Safety Profile 
Pembrolizumab is safe and well tolerated, as evidenced by a low rate of toxicity Grade 3 to 5 drug-
related AEs (13.8%), discontinuations due to AEs (11.9%), and deaths due to drug-related AEs (3.9%). 
Furthermore, the frequency of immune-mediated adverse reactions (AEOSIs) is low, and these events 
are readily managed in the clinical setting. 
The safety and efficacy data generated to date provide a favorable benefit-risk assessment for the use 
of pembrolizumab as a treatment for subjects with advanced/metastatic melanoma, NSCLC, and 
HNSCC. 
There are no specific safety concerns based on the results of nonclinical studies. Pembrolizumab has 
the same mechanism of action as other anti-PD-1 monoclonal antibodies. Preclinical studies have 
suggested similar potency, and PK modeling has suggested similar human PK in the class. Accordingly, 
the AEs observed with other anti-PD-1 antibodies may serve as an indicator for the AEs to expect in 
cancer subjects. 
Pembrolizumab is generally well-tolerated and demonstrates a favorable safety profile in comparison 
to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this mechanism of 
action, immune-mediated AEs are of primary concern. The important identified risks for pembrolizumab 
are of an immune-mediated nature, and include the following: pneumonitis; colitis; hepatitis; nephritis; 
endocrinopathies that include hypophysitis (including hypopituitarism and secondary adrenal 
insufficiency), thyroid disorder (hypothyroidism, hyperthyroidism) and Type 1 diabetes mellitus; uveitis; 
myositis; Guillain-Barré syndrome; pancreatitis; and severe skin reactions. Information on the nature 
and frequency of these identified risks is included in the Reference Safety Information of Version 13 of 
the Investigator’s Brochure. The majority of immune-mediated adverse events were mild to moderate 
in severity, manageable with appropriate care, and rarely required discontinuation of therapy. 
In addition, two important potential risks have been identified, although the data available thus far for 
these events does not provide sufficient evidence of a causal relationship to pembrolizumab. The two 
important potential risks are: a) myasthenic syndrome, and b) an increased risk of severe complications 
(such as early severe graft versus host disease and venoocclusive disease) of allogenic transplant in 
patients with hematologic malignancies who have previously been treated with PD-1 inhibitors. The 
Sponsor continues to monitor and collect data on these potential risks in order to further characterize 
their potential relationship to pembrolizumab. 
Further details regarding reporting and management of immune-related AEs (irAEs) in general are 
described below. 
In addition to the immune-related risks noted above, infusion-related reactions are also an important 
identified risk for pembrolizumab; however, they are not considered immune-mediated. Information 
regarding the nature and frequency of infusion-related reactions is included in the Reference Safety 
Information in Version 13 of the Investigator’s Brochure (dated 17-Feb-2017). 
Immune-Related Adverse Events 
Based on the mechanism of action of pembrolizumab and similar immunomodulatory agents, the 
Sponsor is interested in all potential irAEs, and encourages appropriate investigation of signs and 
symptoms suggestive of these.  


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Consultation with the appropriate medical specialist should be considered when investigating a possible 
irAE. These events can occur after the first dose to several months after the last dose of treatment. Mild 
irAEs are usually treated symptomatically and infrequently require dosing delays or discontinuation. 
Higher grade and persistent lower grade irAEs typically necessitate withholding or discontinuing 
treatment and administration of systemic steroids or other immunosuppressive agents (such as tumor 
necrosis factor blockers), when systemic steroids are not effective. Early recognition of irAEs and 
initiation of treatment are critical to reduce the risk of complications, since the majority of irAEs are 
reversible with the use of steroids and other immune suppressants. 
Table 1.2.1.3.1 All AEOSI Adverse Reactions Considered Expected for Pembrolizumab  
(Presented by Decreasing Frequency of AEOSI Category) 


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cont. Table 1.2.1.3.1 All AEOSI Adverse Reactions Considered Expected for Pembrolizumab 
(Presented by Decreasing Frequency of AEOSI Category)  
 
Nephritis: Five additional cases of the AEOSI nephritis were observed in the Reference Safety Dataset; 
however, they are not contained in the preceeding table because the reported AE coding at the time 
did not include an AEOSI nephritis term. The coding for each of these 5 cases has since been updated 
after the data-lock of the Reference Safety Dataset as follows, and each of the terms below is 
considered an AEOSI adverse reaction expected for pembrolizumab: 
 
Tubulointerstitial nephritis: n=2 (in addition to 4 cases already included in above table), for an 
overall frequency of n=6 (0.2%) 
 
Nephritis: n=2 (0.1%) 
 
Autoimmune nephritis: n=1 (0%) 
Therefore, based on the addition of the above 5 cases, the overall frequency for the AEOSI nephritis in 
the Reference Safety Dataset should be n=9 (0.3%) 
Colitis: One event in the Reference Safety Dataset was initially counted as an AEOSI of colitis. 
However, it was later determined that the subject did not have colitis, and had been included in the 
Reference Safety Dataset summary of colitis due to data entry errors. Therefore, the overall frequency 
of the AEOSI colitis should be n=48 (1.7%), and the frequency for the individual event of colitits should 
be n=45 (1.6%) 


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Infusion-Related Reactions: One subject had an event of anaphylactoid reaction that was not counted 
as an infustion-related reaction since this term was not part of the terms list for the AEOSI infusion-
related reactions at the time of reporting. Therefore, the incidence of AEOSI infusion-related reactions 
in the Referense Safety Dataset should be n=71 (2.5%). The term “anaphylactoid reaction” (n=1 [0%]) 
is considered an AEOSI expected for pembrolizumab. 
Table 1.2.1.3.2 All Additional Adverse Reactions Considered Expected for Pembrolizumab 
1.2.1.4 
Dose Selection 
PN001 is being conducted to evaluate the safety and clinical activity of single agent pembrolizumab.  
The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were 
well tolerated and no dose-limiting toxicities were observed.  This first in human study of pembrolizumab 
showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this 
protocol to test for initial tumor activity.  Recent data from other clinical studies within the pembrolizumab 
program has shown that a lower dose of pembrolizumab and a less frequent schedule may be sufficient 
for target engagement and clinical activity. 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release 


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assay) suggested that peripheral target engagement is durable (>21 days).  This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of 
pembrolizumab 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.  
Pembrolizumab has been found to have a wide therapeutic range based on the melanoma indication.  
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no significant 
impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between different 
indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumors 
is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg 
Q3W in melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both 
efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor 
burden or indication on distribution behavior of pembrolizumab (as assessed by the population PK 
model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 
200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with 
the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range 
established in melanoma as associated with maximal efficacy response and 3) will maintain individual 
patients exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. 
1.2.2 Oxaliplatin 
Oxaliplatin (Eloxatin®) is a platinum-based anti-cancer agent.  It is FDA-approved when used used in 
combination with infusional 5-fluorouracil /leucovorin for the following indications: 1) for adjuvant 
treatment of stage III colon cancer in patients who have undergone complete resection of the primary 
tumor and 2) treatment of advanced colorectal cancer.  
Mechanism of Action 
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via 
displacement of the labile oxalate ligand. Several transient reactive species are formed, including 
monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter-and 
intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two 
adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening 
nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle 
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In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 
5-fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either 
compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)]. 
Adverse Events 
Most common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, 
thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, 
emesis, fatigue and stomatitis. 
 
The following are serious adverse reactions as discussed in package insert dated October 201514: 
 
 
Anaphylaxis and Allergic Reactions: Grade 3/4 hypersensitivity, including anaphylactic/ 
anaphylactoid reactions, to oxaliplatin has been observed in 2-3% of colon cancer patients. These 
allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, 
and were similar in nature and severity to those reported with other platinum-containing compounds, 
such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The 
symptoms associated with hypersensitivity reactions reported in the previously untreated patients 
were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness 
of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These 
reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and 
require discontinuation of therapy. Rechallenge is contraindicated in these patients. Drug-related 
deaths associated with platinum compounds from anaphylaxis have been reported. 
 
 
Neuropathy:  Oxaliplatin is associated with two types of neuropathy, acute and persistent.  
An acute syndrome of pharyngolaryngeal dysesthesia seen in 1-2% (grade 3/4) of patients 
previously untreated for advanced colorectal cancer, and the previously treated patients, is 
characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or 
bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the 
infusion of oxaliplatin because cold temperature can exacerbate acute neurological symptoms. An 
acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within 
hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with 
further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature 
or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in 
the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye 
pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of 
sensory neuropathy was observed in about 56% of study patients who received oxaliplatin with 5-
fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 
30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory 
neuropathy was 9 in the previously treated patients the median number of cycles administered on 
the oxaliplatin with 5-fluorouracil/leucovorin combination arm was 6.  
An acute syndrome of pharyngolaryngeal dysesthesia seen in 1-2% (grade 3/4) of patients 
previously untreated for advanced colorectal cancer, and the previously treated patients, is 
characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or 
bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the 
infusion of oxaliplatin because cold temperature can exacerbate acute neurological symptoms. 
A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by 
paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can 
interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired 


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proprioception). These forms of neuropathy occurred in 48% of the study patients receiving 
oxaliplatin with 5-fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute 
neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy 
progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon 
discontinuation of oxaliplatin. 
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior 
Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and 
postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental 
functioning, seizures, abnormal vision from blurriness to blindness, associated or not with 
hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging. 
 
 
Severe Neutropenia: Grade 3 or 4 neutropenia occurred in 41-44% of patients with colorectal 
cancer treated with oxaliplatin in combination with 5-flurouracil (5-FU) and leucovorin compared to 
5% with 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been 
reported in patients treated with oxaliplatin, including fatal outcomes. 
 
 
Pulmonary Toxicity: Oxaliplatin has been associated with pulmonary fibrosis (<1% of study 
patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) 
and <1% (grade 3) with no grade 4 events in the oxaliplatin plus infusional 5-fluorouracil/ leucovorin 
arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-
fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died 
from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, 
dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin plus 5-
fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan 
plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated 
colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, 
dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be discontinued until 
further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. 
 
 
Hepatoxicity:  Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases 
(57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the 
oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin was similar 
on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia 
or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular 
disorders should be considered, and if appropriate, should be investigated in case of abnormal liver 
function test results or portal hypertension, which cannot be explained by liver metastases. 
 
 
Cardiovascular Toxicity: QT prolongation and ventricular arrhythmias including fatal Torsade de 
Pointes have been reported in postmarketing experiences following oxaliplatin administration. ECG 
monitoring is recommended if therapy is initiated in patients with congestive heart failure, 
bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, 
and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating oxaliplatin 
and monitor these electrolytes periodically during therapy. Avoid oxaliplatin in patients with 
congenital long QT syndrome. 
 
 
Rhabdomyolysis:  Rhabdomyolysis, including fatal cases, has been reported in patients treated 
with oxaliplatin. Discontinue oxaliplatin if any signs or symptoms of rhabdomyolysis occur. 
Refer to current package insert for full prescription drug information for oxaliplatin. 


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1.2.3 Capecitabine 
Capecitabine (Xeloda®) is a nucleoside metabolic inhibitor with antineoplastic activity.  It is FDA-
approved for the following indications: 1) adjuvant colon cancer (patients with Dukes’ C colon cancer); 
2) metastatic colorectal cancer (first-line as monotherapy when treatment with fluoropyrimidine therapy 
alone is preferred); and 3) metastatic breast cancer (in combination with docetaxel after failure of prior 
anthracycline-containing therapy or as monotherapy in patients resistant to both paclitaxel and an 
anthracycline-containing regimen). 
Mechanism of Action 
Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 
5-FU to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). 
These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, 
N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary 
complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the 
necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a 
deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can 
mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This 
metabolic error can interfere with RNA processing and protein synthesis. 
Adverse Events 
Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, 
abdominal pain, fatigue/weakness, and hyperbilirubinemia. 
The following are Warnings and Precautions as discussed in package insert dated December 201615: 
 
Coagulopathy: Patients receiving concomitant capecitabine and oral coumarin-derivative 
anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) 
monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly. 
 
 
Diarrhea: Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhea 
should be carefully either metastatic breast or colorectal cancer who received capecitabine 
monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 
1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute 
of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, 
grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 
4 diarrhea as an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral 
support.  
Necrotizing enterocolitis (typhlitis) has been reported. 
 
Cardiotoxicity: The cardiotoxicity observed with capecitabine includes myocardial infarction/ 
ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic 
changes, and cardiomyopathy. These adverse reactions may be more common in patients with a 
prior history of coronary artery disease. 
 
 
Dihydropyrimidine Dehydrogenase Deficiency (DPD): Based on postmarketing reports, patients 
with certain homozygous or certain compound heterozygous mutations in the DPD gene that result 
in complete or near complete absence of DPD activity are at increased risk for acute early-onset of 
toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine (e.g., 
mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have 
increased risk of severe, life-threatening, or fatal adverse reactions caused by capecitabine. 


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 
Dehydration and Renal Failure: Dehydration has been observed and may cause acute renal 
failure which can be fatal. Patients with pre-existing compromised renal function or who are 
receiving concomitant capecitabine with known nephrotoxic agents are at higher risk. Patients with 
anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated.  
 
 
Embryo-Fetal Toxicity: Based on findings from animal reproduction studies and its mechanism of 
action, capecitabine may cause fetal harm when given to a pregnant woman. Limited available data 
are not sufficient to inform use of capecitabine in pregnant women. In animal reproduction studies, 
administration of capecitabine to pregnant animals during the period of organogenesis caused 
embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the 
exposure (AUC) in patients receiving the recommended dose respectively. Apprise pregnant 
women of the potential risk to a fetus. Advise females of reproductive potential to use effective 
contraception during treatment and for 6 months following the last dose of capecitabine. 
 
 
Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, some with fatal 
outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in 
patients treated with capecitabine. Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or 
chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days 
(range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine 
monotherapy in the metastatic setting.  
 
 
Hyperbilirubinemia: In 875 patients with either metastatic breast or colorectal cancer who received 
at least one dose of capecitabine 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by 
a 1-week rest period, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) of 
patients and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 
patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at 
baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 
patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations 
(grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had 
postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of 
these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% 
(n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and 
postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% 
(n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases. 
In the 596 patients treated with capecitabine as first-line therapy for metastatic colorectal cancer, 
the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety 
database of capecitabine monotherapy. The median time to onset for grade 3 or 4 
hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin 
increased from 8 µm/L at baseline to 13 µm/L during treatment with capecitabine. Of the 136 
colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 
hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline. 
In 251 patients with metastatic breast cancer who received a combination of capecitabine and 
docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 x 
ULN) hyperbilirubinemia occurred in 2% (n=5). 
 
Hematologic:  In 875 patients with either metastatic breast or colorectal cancer who received a 
dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-week 
rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or 


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decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received 
a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had 
grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia. 
 
 
Geriatric Patients: Patients ≥80 years old may experience a greater incidence of grade 3 or 4 
adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received 
capecitabine monotherapy, 62% of the 21 patients ≥80 years of age treated with capecitabine 
experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 
(14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 
patients 70 years of age and greater (no patients were >80 years of age) treated with capecitabine 
in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and 
stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome. 
Among the 67 patients ≥60 years of age receiving capecitabine in combination with docetaxel, the 
incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse 
reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse 
reactions and treatment discontinuations within the first two treatment cycles was higher than in the 
<60 years of age patient group. 
In 995 patients receiving capecitabine as adjuvant therapy for Dukes’ C colon cancer after resection 
of the primary tumor, 41% of the 398 patients ≥65 years of age treated with capecitabine 
experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), 
diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/ granulocytopenia in 11 (2.8%), vomiting 
in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; 
capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection 
of the primary tumor, the hazard ratios for disease-free survival and overall survival for capecitabine 
compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively. 
 
Hepatic Insufficiency: Patients with mild to moderate hepatic dysfunction due to liver metastases 
should be carefully monitored when capecitabine is administered. The effect of severe hepatic 
dysfunction on the disposition of capecitabine is not known. 
Refer to current package insert for full prescription drug information for capecitabine. 
1.3 
Study Rationale 
This is a single arm, phase II study to assess the safety, tolerability, and efficacy of the RPTD of the 
combination of pembrolizumab, oxaliplatin and capecitabine in patients with previously untreated 
metastatic esophagogastric adenocarcinoma.  The study will be conducted in two stages: 1) safety 
validation and 2) dose expansion.  In the dose expansion cohort, the first cycle will be modified to allow 
one week of pembrolizumab monotherapy before starting XELOX chemotherapy, which will allow 
analysis of biomarkers related to pembrolizumab. 
Gastric cancer is likely a PD-1 sensitive tumor type. The KEYNOTE-012 study was a Phase 1b study 
evaluating the use of pembrolizumab in gastric cancer patients. This study, conducted in the United 
States, Israel, Japan, South Korea, and Taiwan, screened 162 patients to identify 65 (40%) that were 
PD-L1 positive.  Thirty-nine of these patients (19 from Asia Pacific and 20 from rest of the world) were 
enrolled and treated with pembrolizumab 10mg/kg every 2 weeks.  The therapy was generally well 
tolerated with the most common adverse events being hypothyroidism and fatigue; few Grade ≥ 3 
events were noted.  There were 8 (22%, 95% CI 10-39) centrally confirmed partial responses, 13 (33%, 
95% CI 19-50) investigator assessed partial responses, and 17 patients (53%) with at least one post-
baseline tumor assessment that showed disease response. The median duration of response 40 weeks, 


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median overall survival was 11.4 months (95% CI 5.7 – not reached), and proportion of patients alive 
at 6 months was 42% (95% CI 25 – 59)16. Pembrolizumab is now in phase III studies as monotherapy 
in 2nd/3rd line gastric cancer.   
The fluoropyrimidine/platinum combination is a common first line therapy for metastatic gastric cancer 
and it considered “preferred” by the NCCN Gastric Cancer Guideline committee17. This combination 
can either be fluorouracil plus oxaliplatin or capectabine plus oxaliplatin18-20. Given the toxicity 
associated with cisplatin and the non-inferiority data from REAL221, many clinicians prefer to use the 
less toxic and more convenient capecitabine/oxaliplatin combination. There are several studies 
evaluating the capecitabine/oxaliplatin doublet in the treatment of metastatic gastric cancer as well as 
others that have evaluated the doublet as a backbone for the addition of newer agents – as in this 
study22-26.  In addition, it has recently been appreciated that many chemotherapeutic agents augment 
anti-tumor responses. Oxaliplatin in particular has been reported by many labs to induce so called 
‘immunogenic cell death27-28. Thus, the combination of pembrolizumab and oxaliplatin can be 
considered a novel strategy for targeting the immune system for the treatment of advanced gastric 
cancer.  In addition, the effects of pembrolizumab in advanced gastric cancer have not yet been well 
defined.  The overall goals of this study are to both determine the activity of pembrolizumab + XELOX 
and to explore the immunological mechanisms of sensitivity and resistance to this therapy in patients 
with advanced gastric cancer with Duke collaborators who have experience in the analysis of immune 
markers, both in tumor tissue and in peripheral blood. 
2.0 
OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this trial is: 
1. To describe the progression free survival (PFS) associated with the combination of 
pembrolizumab, oxaliplatin and capecitabine (pembro+XELOX) in all patients with previously 
untreated metastatic esophagogastric adenocarcinoma. 
2.2 
Secondary Objectives 
The secondary objectives of this trial are: 
1. To describe the safety and tolerability of the combination of pembro+XELOX in patients with 
previously untreated metastatic esophagogastric adenocarcinoma. 
2. To describe the response rate (RR) and overall survival (OS) of the combination of 
pembro+XELOX in patients with previously untreated metastatic esophagogastric 
adenocarcinoma. 
2.3 
Exploratory Objectives 
The exploratory objectives of this trial are: 
1. To explore changes in CD8 and PDL1 expression in tumor tissue related to pembrolizumab 
treatment.  
2. To explore other changes in tissue and blood based biomarkers and their correlation with 
clinical outcomes. 
3. To explore changes in immune cells and biomarkers in those who completed treatment and 
remain in complete response. 


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3.0 
STUDY DESIGN 
3.1 
Study Description 
This is a single arm, phase II study to assess the safety, tolerability, and efficacy of the recommended 
phase II dose (RPTD) of the combination of pembrolizumab, oxaliplatin and capecitabine in patients 
with previously untreated metastatic esophagogastric adenocarcinoma.  The study will be conducted in 
two stages: 1) safety validation and 2) dose expansion.  Approximately 50 subjects may be accrued to 
ensure the trial obtains 5 evaluable subjects in the safety validation cohort and 30 evaluable subjects 
in the dose expansion cohort.  Patients will be enrolled at the Duke Cancer Institute and select external 
collaborating institutions (dose expansion cohort only).   
 
Enrolled subjects are defined as subjects who give informed consent. 
 
Screen failures are defined as subjects who give informed consent and do not meet eligibility 
criteria.  
 
Accrued subjects are defined as subjects who give informed consent and meet eligibility criteria.  
o Withdrawal:  Subject accrued but later withdrawn from the study, either before or after 
receiving a study drug.   
o Evaluable:  In the Safety Validation Cohort, subjects who are accrued, received study 
treatment, and completed the first cycle of safety assessments or have dose limiting 
toxicity (DLT) which is study treatment related that precludes completing the full cycle of 
assessments will be considered evaluable for DLT. All subjects (in Safety Validation and 
Dose Expansion) who are accrued and receive any study treatment will be considered 
evaluable for toxicity. All subjects in Safety Validation and Dose Expansion who are 
accrued and receive any study treatment will be considered evaluable for efficacy. 
o Non-evaluable:  In the Safety Validation Cohort, subjects who accrued but did not 
complete the first cycle of safety assessments due to reasons other than study treatment-
related toxicity (e.g. disease progression or inter-current illness) are considered non-
evaluable for DLT.  
Table 3.1 Cohorts 
Cohort 
No. Evaluable 
Subjects 
Oxaliplatin 
mg/m2 
IV, Day 1 
every 21 days* 
Capecitabine 
mg/m2 
PO, BID Days 1-14 
every 21 days* 
Pembrolizumab 
mg 
IV, Day 1 
every 21 days* 
Safety Validation 
 5 
130 
850 or 1000** 
200 
Dose Expansion 
 30 
130 
850 or 1000** 
200 
*For dose expansion cohort, Cycle 1, biomarker cycle, is 28 days in length. Cycles 2 and beyond 
are 21 days.  
**The dose of capecitabine is per treating physician discretion. 850mg/m2 and 1000mg/m2 are 
preferred doses for the regimen in US patients based upon safety.  While safety and activity in 
gastric cancer for capecitabine, particularly with oxaliplatin, in US vs non-US patients have not 
been systematically reviewed, most US doctors and many phase III protocols allow flexibility in 
dosing of capecitabine for this reason29-31. 
 


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3.2 
Safety Validation 
The first portion of the study will preliminarily establish the tolerability of the combination of 
pembrolizumab, oxaliplatin and capecitabine at the RPTD in patients with metastatic esophagogastric 
adenocarcinoma. Subjects on this portion of the study will only be enrolled at the Duke Cancer Institute. 
A total of five (5) evaluable patients will be accrued and their safety data after completion of the first 
cycle of safety assessments will be reviewed before additional patients are enrolled.  Proceeding to 
dose expansion cohort will be dependent on DLT (refer to Section 3.2.1) within the safety validation 
cohort.   
The following enrollment method will be employed for the safety validation stage of the study: 
 
If no DLT occurs with the 5 evaluable subjects, enrollment may proceed to the dose expansion 
cohort.   
 
If 1 DLT occurs with the 5 evaluable subjects, enrollment may proceed to the dose expansion 
cohort.   
 
If ≥ 2 DLTs occurs with the 5 evaluable subjects, enrollment must not proceed to the dose 
expansion cohort and alternative dose levels for oxaliplatin and capecitabine may be 
considered. 
3.2.1 Dose Limiting Toxicity 
Using the NCI-CTCAE version 4.0, the following adverse events will be considered dose limiting toxicity 
(DLT) if occurring during the first cycle (21 days) of treatment and deemed to be related to study 
treatment:  
 
Grade 4 neutropenia, thrombocytopenia or anemia. 
 
Grade ≥ 3 neutropenia or thrombocytopenia lasting over 7 days.  
 
Grade 3 thrombocytopenia associated with bleeding. 
 
Neutropenic fever.  
 
Grade ≥ 3 nausea/vomiting or diarrhea lasting ≥ 3 days despite adequate supportive 
measures. 
 
Grade ≥ 3 ALT, AST, or bilirubin elevation > 7 days. 
 
Grade ≥ 3 non-hematologic toxicity excluding alopecia, anorexia, fatigue, hypertension, 
isolated lab abnormalities (not clinically significant) and/or allerigic or idiosyncratic reactions to 
any of the study drugs.  Anorexia, fatigue and hypertension will be considered as DLT only if 
they reach Grade 4 or are considered unmanageable.  
 
Treatment delay of ≥ 14 days for Cycle 2 due to unresolved treatment-related toxicity. 
Management and dose modifications associated with all adverse events are outlined in Section 7.0. 
3.3 
Dose Expansion Cohort 
Once 5 evaluable subjects have been treated in the safety validation cohort with no more than one 
occurrence of DLT as defined in Section 3.2.1, the second portion of the study (ie. phase II) will accrue 


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30 evaluable patients to assess the safety, tolerability, and efficacy of the RPTD of the combination of 
pembrolizumab, oxaliplatin and capecitabine in patients with previously untreated metastatic 
esophagogastric adenocarcinoma. Subjects on this portion of the study will be enrolled at the Duke 
Cancer Institute and select external collaborating institutions. 
In the dose expansion cohort, the first cycle will be modified to allow one week of pembrolizumab 
monotherapy before starting XELOX chemotherapy, which will allow analysis of biomarkers related to 
pembrolizumab; thus Cycle 1 for the dose expansion cohort will be 4 weeks.    
4.0 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
1. Histologically and/or cytologically documented and radiographically measurable (by RECIST 
1.1) adenocarcinoma of the esophagus or stomach (HER2 negative only) that is 
metastatic/recurrent and not amenable to potentially curative treatment (e.g., inoperable 
metastatic or locally recurrent disease).  HER2 positive patients would be considered eligible 
only if there is a contraindication to Herceptin. 
2. No prior chemotherapy for metastatic/recurrent disease.  Prior adjuvant or neo-adjuvant 
treatment with a fluoropyrimidine or fluoropyrimidine based regimen is allowed only if it is 
completed at least 6 months prior to the start of study drug, whether given alone or with 
radiation therapy.  Patients who have received prior neo-adjuvant therapy (chemotherapy 
and/or radiation therapy) which did not contain 5-FU or capecitabine and have been diagnosed 
with metastatic disease (with no previous treatment in the metastatic setting) are eligible.  No 
6-month window is required for these patients.  In the setting of metastatic disease requiring 
local palliation, only radiosensitizing doses of 5-FU or capecitabine monotherapy are 
permitted.  
3. Prior radiation therapy is permitted, provided it is completed at least 28 days prior to the start 
of study drug. 
4. Age ≥ 18 years with ability to understand and willingness to provide informed consent. 
5. ECOG performance status of 0 or 1.   
6. Adequate organ and marrow function as defined below by the following: 
a) Absolute neutrophil count (ANC) ≥ 1500 µl 
b) Platelets ≥ 100,000/µl 
c) Hemoglobin (Hgb) ≥ 9 g/dL 
d) Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
e) AST/ALT ≤ 2 x ULN without liver metastasis;  ≤ 5 x ULN with liver metastasis  
f) Creatinine clearance  ≥ 50 cc/min 
4.2  
Exclusion Criteria  
1. Prior therapy with an anti-PD-1, anti PD-L1, anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) agents. 
2. Chemotherapy, targeted small molecule therapy, experimental agents, prior therapy with anti-
tumor vaccines or other immune-stimulatory antitumor agents, or biological cancer therapy 
(including monoclonal antibodies) within 14 days prior to the start of study drug, or not 
recovered (≤ grade 1 or baseline) from adverse events due to a previously administered agent. 


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3. Known CNS metastases and/or carcinomatous meningitis. Patients with radiated or resected 
lesions are permitted, provided the lesions are fully treated and inactive, patients are 
asymptomatic, and no steroids for treatment of CNS lesion have been administered for at least 
30 days prior to the start of study drug. 
4. Documented history of clinically significant autoimmune disease (other than well-controlled 
hypothyroidism) or a syndrome that requires systemic steroids or immunosuppressive agents. 
Subjects with vitiligo, type I diabetes mellitus, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll. 
5. Receiving systemic steroid therapy or any form of immunosuppressive therapy within 1 week 
prior to the start of study drug. Note: Patients are permitted to receive up to 12 mg 
dexamethasone prior to administration of oxaliplatin and low dose steroids for up to 48 hours 
after dosing to prevent nausea and vomiting.  
6. Received a live vaccine within 4 weeks prior to the start of study drug.   
7. Has known history of, or any evidence of active, non-infectious pneumonitis. 
8. Known history of HIV seropositivity, hepatitis C virus, acute or chronic active hepatitis B 
infection, or other serious chronic infection requiring ongoing treatment. Patients receiving 
prophylactic antibiotics (e.g., for prevention of urinary tract infection or chronic obstructive 
pulmonary disease) are eligible. 
9. Pregnant or breastfeeding. 
10. Not willing to use an effective method of birth control (refer to Section 6.5.1 for acceptable 
methods of contraception).  
11. Concurrent severe and/or uncontrolled medical conditions, which may compromise 
participation in the study, including impaired heart function or clinically significant heart 
disease.  
12. Current use of medications specified by the protocol as prohibited for administration in 
combination with study drug.  This includes patients with a condition requiring systemic 
treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days prior to the start of study drug (see section 
6.5.2 for exception for prophylactic use with oxaliplatin dosing).  Inhaled or topical steroids and 
adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence 
of active autoimmune disease.  Corticosteroids administered as pre-medication for IV contrast 
allergy are also allowed. 
13. Recent or current active infectious disease requiring systemic antibiotics, antifungal, or 
antiviral treatment within 2 weeks prior to the start of study drug. Subjects being treated for 
Helicobactor pylori infection are an exception and are allowed to start protocol based therapy 
while still on antibiotics.    
14. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the 
start of study drug (56 days for hepatectomy, open thoracotomy, major neurosurgery) or 
anticipation of need for major surgical procedure during the course of the study (except for the 
planned metastatectomy). 
15. Serious, non-healing wound, ulcer, or bone fracture.  
16. History of myocardial infarction, NYHA class III or IV congestive heart failure, unstable angina, 
cardiac or other vascular stenting, angioplasty, or surgery within 6 months prior to the start of 
study drug. 


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17. History of other carcinomas within the last five years, except cured non-melanoma skin 
cancer, curatively treated in-situ cervical cancer, or localized prostate cancer with a current 
PSA of <1.0 mg/dL on 2 successive evaluations, at least 3 months apart, with the most recent 
evaluation no more than 4 weeks prior to the start of study drug.   
4.3 
Inclusion of Women and Minorities 
Men and women of all races and ethnic groups are eligible for this trial.  
5.0 
STUDY ASSESSMENTS 
Note:  After Cycle 1, if the subject is unable to have a study assessment taken within the defined time 
window due to an event outside of his or her control (e.g., clinic closure, personal emergency, inclement 
weather, vacation), the assessment should be performed as close as possible to the required schedule. 
Refer to Appendix D for Study Calendar.    
5.1 
Screening Period 
During the Screening Period, subjects are consented and screened for the study. Informed consent 
must be obtained before initiation of any screening procedure that is performed solely for the purpose 
of determining eligibility for this study.  Evaluations performed as part of routine care before informed 
consent can be considered as screening evaluations if done within the defined screening period, and if 
permitted by the local Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) policies. 
Study eligibility is based on meeting all of the inclusion criteria and none of the exclusion criteria (refer 
to Section 4.0) before the first dose of study drug on Cycle 1 Day 1.   
The following study procedures must be done within 28 days prior to Cycle 1 Day 1:   
 
Demographics 
 
Medical and cancer history 
 
Physical examination 
 
Height 
 
Vital signs and weight 
 
Concomitant medications 
 
ECOG performance status (perform or repeat within 7 days prior to dosing on Cycle 1 Day 1) 
 
Thyroid function tests 
 
Adverse event assessment (review of baseline symptoms) 
 
Tumor assessment (CT and/or MRI scans)  
 
Blood tumor marker, if clinically indicated (e.g., CEA or CA19-9) 
 
Archived tumor tissue (if available) 
 
PBMC (may be collected pre-dose on Cycle 1 Day 1) 
 
Plasma (may be collected pre-dose on Cycle 1 Day 1) 
 
Whole blood (may be collected pre-dose on Cycle 1 Day 1) 
 
The following study procedures must be done within 7 days prior to Cycle 1 Day 1: 
 
 
CBC with differential 
 
Chemistries including liver function tests (LFTs) 
 
Serum pregnancy test (only for women of childbearing potential) 


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 
Tumor biopsy (only applicable to patients in dose expansion that have lesions amenable to 
safe biopsy) 
Subject eligibility is determined using lab results obtained up to 7 days prior to Cycle 1 Day 1.  Any 
laboratory assessments repeated on Cycle 1 Day 1 must meet eligibility requirements.  The Screening 
Period ends upon receipt of the first dose of study drug or final determination that the subject is ineligible 
for the study. 
5.2 
Treatment Period 
During the Treatment Period, subjects will receive pembrolizumab and oxaliplatin on Day 1 and 
capecitabine on Days 1-14 of each 21-day cycle until either: 1) disease progression; 2) the occurrence 
of unacceptable treatment-related toxicity; or 3) other reason(s) for subject discontinuation as described 
in Section 5.7.  Toxicity-related dose modifications of pembrolizumab, capecitabine and oxaliplatin may 
occur during the Treatment Period.  Dose modification guidelines are described in Section 7.1.   
NOTE: For the dose expansion cohort only, the first cycle (i.e. biomarker cycle) will be modified to allow 
assessment of biomarkers related to pembrolizumab; the length will be 28 days.  Patients will receive 
pembrolizumab monotherapy on Cycle 1 Day 1. Treatment with oxaliplatin and capecitabine will begin 
on Cycle 1 Day 8; capecitabine will be dosed for 14 days (ie. Days 8-21), followed by one week off drug 
(ie. Days 22-28).  Cycle 2 will start on Day 29 of study (ie. 28 days after pembrolizumab monotherapy 
and 20 days after start of capecitabine and oxaliplatin). For cycles 2 and beyond, the cycle length is 21 
days. A treatment window of +/- 3 days is allowed for day 1 of cycle 2 and all subsequent cycles. 
All subjects will have study procedures weekly during the first cycle, then Day 1 of each cycle.  After 
the completion of the first cycle, laboratory assessments may be obtained up to 3 days prior to 
treatment. If necessary, the treatment visit may be within +/- 3 days of the scheduled day 1 for cycle 2 
and all subsequent cycles.  If clinically indicated, additional visits and/or safety assessments may be 
warranted. 
The following study procedures must be completed on Day 1 of each cycle:    
 
Physical examination 
 
Vital signs and weight 
 
Concomitant medications 
 
ECOG performance status 
 
Adverse event assessment  
 
CBC with differential 
 
Chemistries including LFTs 
The following study procedures must be completed on weekly in Cycle 1 only: 
 
Physical examination 
 
Vital signs and weight 
 
Concomitant medications 
 
ECOG performance status 
 
Adverse event assessment  
 
CBC with differential 
 
Chemistries including LFTs 
 


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For dose expansion cohort only, the following study procedures must be completed pre-dose on 
Cycle 1 Day 8: 
 
 
PBMC 
 
Plasma 
 
Tumor biopsy (Can be performed on Day 7 if needed. Only applicable to patients in dose 
expansion that have lesions amenable to safe biopsy) 
 
For dose expansion cohort only, the following study procedures must be completed pre-dose on 
Cycle 1 Day 29 (i.e. Cycle 2 Day 1): 
 
 
PBMC 
 
Plasma  
 
The following study procedures must be completed every 3 (± 1) cycles:   
 
Thyroid function tests  
 
Serum pregnancy test (only for women of childbearing potential) 
 
Tumor assessment (CT and/or MRI scans)  
 
Blood tumor marker, if clinically indicated (e.g., CEA or CA19-9) 
 
PBMC - first restaging only  
 
Plasma  
Restaging scans will be performed every 3 cycles (ie. every 9 weeks) and disease reponse will be 
assessed using guidelines described in Section 5.6.  
The Treatment Period ends when a subject receives his or her last dose of study treatment; the subject 
then enters the Follow-up Period. 
5.3 
Follow-up Period 
Subjects should return 30 (±7) days after their last dose of study drug for an off-treatment visit to 
complete the following study procedures: 
 
Physical examination 
 
Vital signs and weight 
 
Concomitant medications 
 
ECOG performance status 
 
Adverse event assessment  
 
CBC with differential 
 
Chemistries including LFTs 
 
Thyroid function tests  
 
Serum pregnancy test (only for women of childbearing potential) 
 
Plasma  
 
Archived tissue collected at end of study (if available) 
Additional follow-up may occur for subjects with adverse events (AEs) related to study drug that are 
ongoing at the time of this off-treatment visit unless AE is deemed unresolveable or subject has started 
a new anti-cancer treatment regimen. 


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For subjects that are discontinued from study treatment for reasons other than disease progression, 
subjects will have disease status (blood tumor marker(s) and restaging scans per standard of care 
schedule) followed until disease progression or start of new anti-cancer treatment regimen.  Disease 
status may be collected by personal interviews or review of medical records. Disease progression follow 
up will continue for as long as patient is in survival follow up, provided they have not progressed or 
started a new anti-cancer treatment.  For subjects that completed therapy and remain in complete 
response, PBMCs and plasma will be collected approximately every three months with standard of care 
visits, provided subjects consent to this additional follow-up.  
Subjects will be followed for survival up to 3 years after the last subject starts the study drug regimen 
or until the study is closed (whichever comes first).  Survival status may be collected by phone call or 
review of medical or public records approximately every 12 weeks. 
5.4 
Laboratory Assessments 
Local laboratories will perform all clinical laboratory tests using standard procedures, and results will be 
provided to the Investigator. Abnormalities in clinical laboratory tests that lead to a change in subject 
management (e.g., dose modification, requirement for additional medication, treatment or monitoring) 
are considered clinically significant for the purposes of this study, and will be recorded on the case 
report form (CRF).  If laboratory values constitute part of an event that meets criteria defining it as 
serious, the event (and associated laboratory values) must be reported as a serious adverse event 
(SAE). 
Refer to Appendix E for details of laboratory tests for this study.  In addition, blood tumor markers (if 
clinically indicated) such as CEA and/or CA19-9, will be obtained at baseline and at every restaging. 
5.5 
Adverse Event Assessment 
AE definition is described in Section 10.1.  AEs will be documented throughout the study.  AE 
seriousness, grade, and relationship to study drug will be assessed by the Investigator using NCI-
CTCAE version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf).   
SAE definitions and reporting requirements are described in Section 10.2. 
Select non-serious and serious adverse events also known as Events of Clinical Interest (ECI) must 
be recorded and reported as described in Section 10.3.   
5.6 
Tumor Assessments 
Tumor response will be assessed using RECIST version 1.1 and irRC.  Radiographic imaging will be 
performed with CT scan of chest/abdoment/pelvis with and without contrast and/or MRI scan of 
abdomen/pelvis every 3 cycles (i.e., every 9 weeks) after the start of study treatment.  The same method 
for tumor assessment should be employed at every assessment.  
5.6.1 RECIST version 1.1 
RECIST is a set of published rules that define when cancer patients improve ("respond"), stay the same 
("stabilize"), or worsen ("progression") during treatments. The original criteria were published in 
February 2000 by an international collaboration including the European Organization for Research and 
Treatment of Cancer (EORTC), National Cancer Institute (NCI) of the United States and the National 


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Cancer Institute of Canada Clinical Trials Group. RECIST 1.1, published in January 2009, is an update 
to the original criteria and will be used for this study.   
Refer to Appendix A for definition of target lesions, methods of measurement and all other related 
criteria for RECIST version 1.1. The following summarizes the definitions of the criteria used to 
determine objective tumor response for 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 diameters of target lesions, taking 
as reference the baseline sum diameters.   
 
Progressive Disease (PD): At least a 20% increase in the sum of 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 
progression).  
 
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. 
5.6.2  Immune-Related Response Criteria 
The responses that are seen with immunotherapeutic agents may extend beyond those of cytotoxic 
agents and could include responses after disease progression that is not captured by RECIST.  To 
account for this, for this study, immune-related response criteria (irRC) will be used to allow for more 
comprehensive evaluation of clinical activity. Conventional response criteria may not adequately assess 
the activity of immunotherapeutic agents because PD (progressive disease) by initial radiographic 
evaluation does not necessarily reflect therapeutic failure, thus stopping the study treatment with initial 
perceived PD may be premature.  
Refer to Appendix B for definitions and guidelines of the irRC.  The overall response according to the 
irRC is derived from time-point response assessments (based on tumor burden) as follows:  
 
irCR:  complete disappearance of all lesions (whether measurable or not, and no new lesions) 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented  
 
irPR:  decrease in tumor burden ≥50%relative to baseline confirmed by a consecutive assessment 
at least 4 weeks after first documentation  
 
irSD:  not meeting criteria for irCR or irPR, in absence of irPD  
 
irPD:  increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
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5.7 
Subject Discontinuation 
Subjects will receive study treatment until treatment discontinuation for one of the reasons listed below. 
However, subjects may discontinue study treatment or withdraw their consent to participate in the study 
at any time without prejudice.  All reasons for discontinuation or withdrawal from trial will be recorded. 
The maximum duration of treatment for pembrolizumab will be up to 35 cycles. The duration of treatment 
for XELOX will be until unacceptable drug-related toxicity or disease progression. If capecitabine is not 
tolerated, monotherapy with pembrolizumab may be continued. Patients who complete 35 cycles of 
therapy and have complete response or prolonged stable disease may also elect to end therpy with 
capecitabine after a discussion with their treating physician and with approval of the PI. Re-introduction 
of oxaliplatin is permitted provided that neuropathy has improved.Reasons for subject discontinuation 
by the Investigator may include, but are not limited to, the following:   
 
Death 
 
Confirmed radiographic disease progression (Note: With approval of the Lead PI, a subject may be 
granted an exception to continue on study treatment with confirmed radiographic progression if 
clinically stable or clinically improved.) 
 
Significant noncompliance by subject or Investigator 
 
Investigator or Lead PI determination that it is no longer safe and/or no longer in the subject’s best 
interest to continue participation 
 
Withdrawal of consent 
 
Lost to follow-up 
 
Necessity for treatment with other anticancer treatment prohibited by protocol 
 
Sexually active subjects who refuse to use medically accepted methods of contraception during the 
course of the study and for 120 days following the last dose of study drug 
 
Women who become pregnant or are breast feeding 
 
Request by regulatory agencies for termination of treatment of an individual subject or all subjects 
under the protocol 
 
The following Treatment-Related Discontinuation Criteria attributed to pembrolizumab: 
– 
Any Grade 2 uveitis, eye pain, or blurred vision that does not respond to topical therapy and 
does not improve to Grade 1 OR requires systemic treatment. 
 
Recurrent Grade 2 pneumonitis 
 
Any Grade 3 non-skin adverse event lasting > 7 days, with the following exceptions 
for treatment-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions: 
 
Grade 3 uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation 
 
Grade 3 laboratory abnormalities do not require treatment discontinuation except 
Grade 3 thrombocytopenia > 7 days OR associated with bleeding requires 
discontinuation 
– 
Any liver function test (LFT) abnormality that meets the following criteria: 


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 
AST or ALT > 8 x ULN 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
– 
Any Grade 4 adverse event or laboratory abnormality, except for the following events: 
 
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations, or radiographic signs of pancreatitis  
 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 3 days of their onset 
 
Grade 4 endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively, retreatment can be 
considered 
– 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
Dosing interruptions to allow for prolonged steroid tapers to manage treatment-
related adverse events are allowed  
 
Dosing interruptions > 6 weeks that occur for non-treatment-related reasons may be 
allowed 
– Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued 
pembrolizumab or lanreotide depot dosing 
6.0 
STUDY DRUGS  
6.1 
Treatment Compliance and Study Drug Accountability 
The Investigator will maintain accurate records of receipt of all study drugs, including dates of receipt. 
In addition, accurate records will be kept regarding when and how much study drug is dispensed and 
used by each subject in the study. Reasons for deviation from the expected dispensing regimen must 
also be recorded. At completion of the study, to satisfy regulatory requirements regarding drug 
accountability, all unused study drug will be reconciled and destroyed in accordance with applicable 
state and federal regulations. 
6.2 
Pembrolizumab 
Pembrolizumab will be provided for this study by Merck & Co., a sterile, non-pyrogenic lyophilized 
powder for intravenous infusion supplied in single-use Type I glass vial containing 50 mg of 
pembrolizumab. The product is preservative-free, white to off-white powder and free from visible foreign 
matter.  It is reconstituted with 2.3 mL sterile water for injection (WFI) to yield a 2.4 mL solution 
containing 25 mg/mL of pembrolizumab. The reconstituted vial contains an excess fill of 10 mg 
(equivalent to 0.4 mL of reconstituted solution) to ensure the recovery of label claim of 50 mg 
pembrolizumab per vial (equivalent to 2 mL of reconstituted solution). 


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6.2.1 Storage and Handling 
Pembrolizumab Powder for Solution for Infusion vials should be stored at refrigerated conditions (2-8 
°C). Prior to reconstitution, the vial of lyophilized powder can be out of refrigeration (temperatures at or 
below 25°C (77°F) for up to 24 hours. Following reconstitution with sterile water for injection, 
Pembrolizumab infusion solutions should be prepared in 0.9% Sodium Chloride Injection, USP (normal 
saline) or regional equivalent and the final concentration of pembrolizumab in the infusion solutions 
should be between 1 mg/mL and 10 mg/mL.  If normal saline is not available, 5% Dextrose Injection, 
USP or regional equivalent (5% dextrose) is permissible.  The preferred diluent is 0.9% Sodium Chloride 
and 5% dextrose is only permissible if normal saline is not available. 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 hours. 
This includes room temperature storage of reconstituted drug product solution in vials, room 
temperature storage of admixture solutions in the IV bags and the duration of infusion.  In addition, 
reconstituted vials and/or IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for 
up to 20 hours. If refrigerated, allow the vials and/or IV bags to come to room temperature prior to use.   
Refer to Pembrolizumab Pharmacy Manual for additional drug product stability and handling guidelines. 
6.2.2 Administration 
Pembrolizumab 200 mg will be administered in an outpatient setting as a 30-minute IV infusion on Days 
1 of each cycle. A treatment window of +/- 3 days of day 1 is allowed for cycle 2 and all subsequent 
cycles. Every effort should be made to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
It is preferred, but not mandatory, that pembrolizumab be administered after oxaliplatin infusion.  
Refer to Pembrolizumab Pharmacy Manual specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
6.3 
Oxaliplatin 
Oxaliplatin will be obtained from commercial sources; the cost of oxaliplatin and its infusion will be billed 
to the subject and/or subject’s insurance. 
 
Oxaliplatin for injection and oxaliplatin injection) is an antineoplastic agent with the molecular formula 
C8H14N2O4Pt and the chemical name of cis-[(1 R,2 R)-1,2 cyclohexanediamine-N,N’] [oxalato(2-)- 
O,O’] platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 
1,2-diaminocyclohexane(DACH) and with an oxalate ligand as a leaving group. The molecular weight 
is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and 
practically insoluble in ethanol and acetone. 
 
Powder for solution for infusion: Oxaliplatin is supplied in vials containing 50 mg or 100 mg of oxaliplatin 
as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is present as 
an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively.  
 
Concentrate for solution for infusion: Oxaliplatin is supplied in vials containing 50 mg, 100 mg or 200 
mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/ml. Water 
for Injection, USP is present as an inactive ingredient. 


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6.3.1   Storage and Handling 
Powder for Solution for Infusion 
Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride 
containing solutions. The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 
mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer 
the reconstituted solution without further dilution. The reconstituted solution must be further diluted in 
an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. After reconstitution in the original 
vial, the solution may be stored up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution 
with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C 
(68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. Oxalipatin is not light sensitive. 
 
Concentrate for Solution for Infusion 
Do not freeze and protect from light the concentrated solution. A final dilution must never be performed 
with a sodium chloride solution or other chloride-containing solutions. The solution must be further 
diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. After dilution with 250-500 
mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or 
up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not 
required. 
 
Incompatibilities 
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-
fluorouracil) and must not be mixed with these or administered simultaneously through the same 
infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration 
of any concomitant medication. 
 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration and discarded if present. 
 
Needles or intravenous administration sets containing aluminum parts that may come in contact with 
oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to 
cause degradation of platinum compounds. 
 
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of infusion solutions prepared from oxaliplation. The use of gloves is recommended. If a 
solution of oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. 
If oxaliplatin contacts the mucous membranes, flush thoroughly with water.  
6.3.2 Administration 
The dose of oxaliplatin will be 130 mg/m2 given on day 1 of a 3-week cycle, except in the “biomarker 
cycle” (i.e. first cycle for subjects in the dose expansion cohort).  During the biomarker cycle, oxaliplatin 
will be given on Day 8 (to allow for one week of pembrolizumab monotherapy for biomarkers). A 
treatment window of +/- 3 days of day 1 is allowed for cycle 2 and all subsequent cycles. 
 
It is preferable but not mandatory that oxaliplatin infusion should be administered before pembrolizumab 
on days when both drugs are given. 
 
Oxaliplatin must be infused either by peripheral vein or central venous line over 2 hours.  Infusion lines 
should be adequately flushed with 5% dextrose solution between the administrations of any other drugs.  
The administration of oxaliplatin does not require pre-hydration. Oxaliplatin should not be administered 
with saline or other chloride containing solutions.  Oxaliplatin is unstable in the presence of chloride. 


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6.4 
Capecitabine 
Capecitabine will be obtained from commercial sources; the cost of capecitabine will be billed to the 
subject and/or subject’s insurance.  
 
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered 
systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-fluorouracil. The 
chemical name for capecitabine is 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a 
molecular weight of 359.35. Capecitabine is a white to off-white crystalline powder with an aqueous 
solubility of 26 mg/mL at 20ºC. 
 
Capecitabine is supplied as biconvex, oblong film-coated tablets for oral administration. Each peach-
colored tablet contains 500 mg capecitabine. The inactive ingredients in capecitabine include: 
anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, 
magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl 
methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.  
6.4.1   Storage and Handling 
Capecitabine tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). 
The container should be kept tightly closed.  
 
Care should be exercised in the handling of capecitabine. Capecitabine tablets should not be cut or 
crushed. Procedures for the proper handling and disposal of anticancer drugs should be considered. 
6.4.2 Administration 
At the discretion of the treating physician, the patient may receive 850mg/m2 or 1000mg/m2 of 
capecitabine. Capecitabine will be administered at a dose of 850/1000 mg/m2 twice daily, for a total 
daily dose of 1700/2000 mg/m2 beginning the morning of Day 1 of each 3-week cycle and continuing 
through the evening of Day 14; except in the “biomarker cycle” (i.e. first cycle for subjects in the dose 
expansion cohort).  During the biomarker cycle, capecitabine will begin on Day 8 (to allow for one week 
of pembrolizumab monotherapy for biomarkers). A treatment window of +/- 3 days of day 1 is allowed 
for cycle 2 and all subsequent cycles.  
 
See current capecitabine package insert for dosing instructions in patients with moderate renal 
impairment.  
 
The dose of capecitabine will be calculated on the basis of milligrams of drug per square meter (mg/m2) 
of body surface area (BSA). The dose of capecitabine will be rounded to the nearest dose that can be 
obtained by using the 500 mg tablets. Since capecitabine tablets cannot be split, patients may take 
different numbers of pills in the morning and evening in order to achieve the appropriate dose. The 
following is an example of how dose rounding may be performed: 
Explanation: 
[{BSA} m2 x {dose level} mg/m2] x 2 = Daily Dose mg 
Daily Dose mg ÷ 500 mg tablet = number of tablets per day, rounded to whole tablets 
Divide number of whole tablets per day into 2 doses for morning (AM) and evening (PM) 
Calculation: 
[1.68m2 x 1000mg/m2] x 2 = 3360mg 
3360mg ÷ 500mg tablet = 6.72 tablets per day, rounded to 7 tablets per day 
Divide 7 tablets into 2 doses = three 500mg tablets in AM and four 500mg tablets in PM  
 
The dose will be recalculated per institutional standard (e.g., based on the new body surface area prior 
to the start of each cycle only if the weight changes by 10% from baseline). 


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Capecitabine will be taken orally. The total daily dose should be taken as two divided doses 
approximately 12 hours apart, within 30 minutes after the ingestion of food, ideally after breakfast and 
the evening meal. Tablets should be swallowed with approximately 200 ml of water (not fruit juices). 
Tablets are not scored and should not be split.  If needed, capecitabine may be dissolved for 
administration either orally or via G or J tube but patient must receive safety handling training from 
pharmacy personnel. 
6.5 
Concomitant Medications/Vaccinations 
Concomittant medications will be documented throughout the study.  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 Lead PI.   
6.5.1 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 local standards of medical care.  All concomitant 
medication received from the date of signed informed consent through 30 days after the last dose of 
study drug should be recorded on the CRF including all prescription, over-the-counter (OTC), herbal 
supplements, and IV medications.   
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.  
Otherwise, subjects must agree to use two birth control methods after informed consent is signed 
through 120 days after the last dose of study drug.  The two methods can either be two barrier methods 
or a barrier method plus a hormonal method to prevent pregnancy. The following are considered 
adequate barrier methods of contraception: diaphragm with spermicide (cannot be used in conjunction 
with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive 
sponge (nulliparous women only), and male condom or female condom (cannot be used together). 
Appropriate hormonal contraceptives will include oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection.  
6.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Period of this study: 
 
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 to target lesions. If subject needs palliative local radiation (e.g., for relief of 
dysphagia or of pain from bony metastases), protocol therapy may be delayed with the 


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approval of the lead PI. Radiation therapy must be completed for at least 14 days prior to 
resumption of protocol treatment.   
 
Live vaccines within 30 days prior to the first dose of study drug and while participating in the 
study.  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.  Prophylactic dosing of steroids prior to 
treatment and administration of low dose steroids for up to 48 hours post treatment is 
permitted.  Corticosteroids administered as pre-medication for IV contrast allergy are also 
allowed. 
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. 
There are no prohibited therapies during the Follow-up Period. 
7.0 
DOSE MODIFICATION AND TOXICITY MANAGEMENT 
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the last dose 
of study drug.  Subjects will be instructed to notify their treating physician of any and all AEs. Toxicity 
will be graded according to NCI-CTCAE version 4.0.   
All AEs should also be managed with supportive care at the earliest signs of toxicity considered related 
to study drug(s). 
7.1 
Dose Modifications  
Subjects experiencing one or more AEs due to the study drug(s) may require dose modification(s) as 
described in Section 7.1.1 and Section 7.1.2.  At the discretion of the Investigator, dose modifications 
are permitted outside of the those provided in the protocol if the Investigator feels it is in the interest of 
the subject’s safety (e.g., due to multiple toxicities, persistent toxicities, intercurrent illness, or short term 
compliance or monitoring issues, etc.). 
Subjects may need to be followed at least weekly when any study drug is held for toxicity until the 
toxicity returns to Grade ≤ 1 or is determined to be chronic or irreversible.   
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 4 weeks of the scheduled 
interruption, unless otherwise discussed with the Lead PI. The reason for interruption should be 
documented in the patient's study record. Dosing may be interrupted if there is a need for local palliative 
radiation therapy, with the approval of the lead PI. In this case, protocol-based therapy cannot be 
resumed until patients are at least 14 days out from the end of radiation. 
If pembrolizumab is permanently discontinued, the subject will be discontinued from study treatment. 
Maximum duration of treatment for pembrolizumab will be up to 35 cycles. If patients discontinue 
oxaliplatin due to intolerance, they can be maintained on capecitabine and pembrolizumab. If 
capecitabine is not tolerated, pembrolizumab monotherapy may be continued. Re-introduction of 
oxaliplatin is permitted provided neuropathy has improved. 


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All dose modifications and reasons for modification must be recorded in the CRF. 
7.1.1 Pembrolizumab Dose Modifications  
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 treatment-related toxicities as per Table 7.1.1. There are no dose 
reductions for pembrolizumab.   
Note:  Subject must be permanently discontinued for any severe or Grade 3 treatment-related toxicity 
that recurs or any life-threatening event unless otherwise specified in Table 7.1.1. 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to 
taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after 
AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab 
should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.  
Table 7.1.1 Pembrolizumab Dose Modifications  
Immune-
related AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
 
 
 
Monitor participants for 
signs and symptoms of 
pneumonitis 
 
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment 
 Add prophylactic 
antibiotics for 
opportunistic infections 
Grade 3 or 
4, or 
recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
 Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper 
 
 
 
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation 
Grade 4 
Permanently 
discontinue 


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Immune-
related AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
(ie, peritoneal signs and 
ileus). 
 
Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis.  
 Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycemi
a 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycem
ia 
associated 
with 
evidence of 
-cell failure 
Withhold 
 Initiate insulin 
replacement therapy for 
participants with T1DM  
 Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
 Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.   
 
 
 Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidis
m  
 
Grade 2 
Continue  
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate  
 
 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or 
permanently 
discontinue1 


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Immune-
related AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Hypothyroidis
m 
Grade 2 
Continue 
Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per standard 
of care 
 
Monitor for signs and 
symptoms of thyroid 
disorders.  
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
 
 
Monitor changes of 
renal function 
 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE 
administer corticosteroids 
 
 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold  
Based on type and severity 
of AE administer 
corticosteroids  
 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
1 Withhold or permanently discontinue pembrolizumab at the discretion of the investigator or treating physician. 
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM). 
7.1.2 XELOX Dose Modifications 
Toxicity 
Gradea 
Occurrence 
Oxaliplatin 
Capecitabine 
DIARRHEA 
Grade 1 
Any 
Maintain dose 
Maintain dose 


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Grade 2 
Any 
If tolerable: Maintain dose 
 
If intolerable: Hold until grade ≤1, 
then resume at 80% of current 
dose 
If tolerable: Maintain dose 
 
If intolerable: Hold until 
grade ≤1,then resume at 80% of 
current dose b 
Grade 3 
1st – 3rd 
Hold until grade ≤1, then resume at 
80% of current dose 
Hold until grade ≤1, then resume at 
80% of current dose 
4th and higher 
Hold until grade ≤1, –obtain 
permission of PI to resume at 
80% of current dose 
Hold until grade ≤1, obtain 
permission of PI to resume at 
80% of current dose– 
Grade 4 
1st 
Hold until grade ≤1, then resume at 
60% of current dose 
Hold until grade ≤1, then resume at 
60% of current dose 
2nd and higher 
Hold until grade ≤1, obtain 
permission of PI to resume at 60% 
of current dose b 
Hold until grade ≤1, obtain 
permission of PI to resume at 
60% of current dose b 
 
VOMITING 
Grade 1 
Any 
Maintain dose 
Maintain dose 
Grade 2 
Any 
Maintain dose 
Maintain dose 
Grade 3 
[occurring within 3 
days of Oxaliplatin 
dosing despite 
optimal anti-emetic 
prophylaxis] 
1st 
Hold until grade ≤1, then resume 
at 80% of current dose c 
Maintain dose 
2nd and higher 
Hold until grade ≤ 1, then 
resume at current dose. c 
Maintain dose 
Grade 4 
(TPN, intensive care 
or hemodynamic 
collapse) [occurring 
within 3 days of 
Oxaliplatin dosing 
despite optimal anti-
emetic prophylaxis] 
1st 
Hold  until grade ≤1 c, then 
resume at 60% of current dose 
Hold  until grade ≤1, then resume 
at 60% of current dose 
2nd and higher 
Discontinue 
Hold until grade ≤1, obtain 
permission of PI to resume  at 60% 
of current dose 
a. 
National Cancer Institute Common Terminology Criteria Version 3. 
b. 
Continue treatment if it is considered to be in the best interest of the patient 
c. 
NOTE: After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to 
grade ≤1, the treating physician may choose, to hold oxaliplatin and continue capecitabine and 
pembrolizumab at current dose as clinically indicated.  If the treating physician chooses to restart 
oxaliplatin later in the patient’s treatment course, the dose of oxaliplatin at which the patient restarts 
should be one dose level lower than last dose level on which patient was treated.  The specific treatment 
approach used and dose modifications that occur are required to be reported in the Case Report Forms. 
 
OTHER CLINICALLY SIGNIFICANT* NON-HEMATOLOGIC ADVERSE EVENTS 
ToxicityGradea 
Occurrence 
Oxaliplatin 
Capecitabine 
Grade 1 
Any 
Maintain dose 
Maintain dose 
Grade 2 
1st 
Hold  until grade ≤1, then 
resume at 80% of current 
dose c 
Hold until grade ≤1, then 
resume at 80% of current 
dose 


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OTHER CLINICALLY SIGNIFICANT* NON-HEMATOLOGIC ADVERSE EVENTS 
ToxicityGradea 
Occurrence 
Oxaliplatin 
Capecitabine 
2nd and higher 
Hold until grade ≤ 1, then 
resume at current dose. b,c 
Hold until grade ≤1, then 
resume at 80% of current 
dose 
Grade 3 
1st 
Hold  until grade ≤1, then 
resume at 80% of current 
dose c 
Hold until grade ≤1, then 
resume at 80% of current 
dose 
2nd and higher 
Hold until grade ≤ 1, then 
resume at current dose. b,c 
Hold until grade ≤1, then 
resume at 80% of current 
dose 
Grade 4 
1st 
Hold  until grade ≤1, then 
resume at 60% of current 
dose c 
Hold  until grade ≤1, then 
resume at 60% of current 
dose 
2nd and higher 
Hold until grade ≤1, 
obtainpermission of PI to 
resume  at 60% of current 
dose b 
Hold until grade ≤1, obtain 
permission of PI to resume  at 
60% of current dose b 
a. 
National Cancer Institute Common Terminology Criteria Version 3.0 
b. 
Continued treatment if it is considered to be in the best interest of the patient. 
c. 
NOTE: After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to grade 
≤1, the treating physician may choose, instead of lowering the dose of capecitabine, to hold oxaliplatin and 
continue capecitabine and pembrolizumab at current dose as clinically indicated.  If toxicity recurs, follow 
original dose modification instructions for capecitabine.  If the treating physician chooses to restart oxaliplatin 
later in the patient’s treatment course, the dose of oxaliplatin at which the patient restarts should be one dose 
level lower than last dose level on which patient was treated.  The specific treatment approach used and dose 
modifications that occur are required to be reported in the Case Report Forms. 
 
*  Dose adjustments only for clinically significant toxicities (e.g. asymptomatic lab abnormalities do not necessarily 
require dose modifications) If non-hematologic toxicities can be attributed solely to either oxaliplatin, capecitabine, or 
pembrolizumab then no dose adjustments of the other agents are needed. 
 


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HEMATOLOGIC ADVERSE EVENTS 
ToxicityGradea 
Occurrence 
Oxaliplatin 
Capecitabine 
NEUTROPENIA 
Grade 1 
Any 
Maintain dose 
Maintain dose 
Grade 2 
Any 
Maintain dose 
Maintain dose 
Grade 3(≥0.5 -
<1x109/L) 
1st 
Hold until grade 1, then 
resume at current dose 
Maintain dose 
2nd and higher 
Hold until grade 1, then 
resume at 80% of current 
dose d 
Maintain dose 
Grade 4 (< 0.5 
x109/L) 
1st 
Hold until grade  1, then 
resume at 80% of current 
dose.b,c,d 
Hold until grade ≤1, then 
resume at 80% of the current 
dose b,c 
2nd and higher 
Hold until grade ≤1, obtain 
permission of PI to resume  
at 60% of current dose d 
Hold until grade ≤1, obtain 
permission of PI to resume  at 
60% of current dose 
FEBRILE NEUTROPENIA 
Grade 3 
(neutropenia and 
fever  38.5C) 
1st – 2nd 
Hold until resolution of fever 
and neutropenia to grade ≤ 
1,  then resume at 60% of 
current dose d 
Hold until resolution of fever 
and neutropenia to grade ≤1, 
then resume at 60% of current 
dose b,c,d 
3rd 
Discontinue Protocol 
Therapy 
Discontinue Protocol Therapy 
Grade 4 
(neutropenia and 
fever > 38.5 C) 
Any 
Discontinue Protocol 
Therapy 
Discontinue Protocol Therapy 
THROMBOCYTOPENIA 
Grade 1 (< LLN - 
<75.0 x 109 /L) 
Any 
Maintain dose 
Maintain dose 
Grade 2(50.0 - < 
75.0 x 109 /L) 
1st 
Hold until grade ≤1, then 
resume at 80% of current 
dose d 
Maintain dose 
2nd and higher 
If stable grade 2, maintain 
current dose 
Maintain dose 
Grade 3(25.0 - < 
50.0 x 109 /L) 
1st 
Hold until grade ≤1, then 
resume at 80% current dose 
d 
Hold until grade ≤1, then 
resume at 80% of the current 
dose 
2nd and higher 
Hold until grade ≤1, then 
resume at 80% current 
dose d 
Hold until grade ≤1, then 
resume at 80% of the current 
dose b 
Grade 4(< 25.0 x 
109 /L) 
1st 
Hold until grade ≤1, then 
resume at 60% of the 
current dose b,d 
Hold until grade ≤1, then 
resume at 60% of the current 
dose b 
2nd 
Discontinue Protocol 
Therapy 
Discontinue Protocol Therapy 
 


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HEMOGLOBIN 
Grade 1 
< LLN - 10.0 g/dL < 
LLN - 100 g/L  < 
LLN - 6.2mmol/L 
Any 
Maintain dose 
Maintain doseb 
Grade 2 
8.0 - < 10.0 g/dL 
80 - < 100 g/L 
4.9 - < 6.2 mmol/L 
Any 
Maintain dose 
Maintain dose 
Grade 3 
6.5 - < 8.0 g/dL 
65 - < 80 g/L 
4.0 - < 4.9 mmol/L 
Any 
Maintain dose 
Maintain dose 
Grade 4 
< 6.5 g/dL 
< 65 g/L 
< 4.0 mmol/L 
Any 
Hold until < grade 2; then 
resume at current dose, may 
transfuse b 
Maintain dose b 
OTHER HEMATOLOGIC TOXICITY 
Grades 1 - 4 
Any 
Maintain dose 
Maintain dose 
a. 
National Cancer Institute Common Terminology Criteria Version 3.0 
b. 
Continued treatment only if it is considered to be in the best interest of the patient 
c. 
Consider growth factor support if continuing treatment is felt to be in the patient’s best interest. 
d. 
NOTE: After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to grade ≤1, 
the treating physician may choose, to hold oxaliplatin and continue capecitabine and pembrolizumab at current 
dose as clinically indicated.  If the treating physician chooses to restart oxaliplatin later in the patient’s treatment 
course, the dose of oxaliplatin at which the patient restarts should be one dose level lower than last dose level on 
which patient was treated.  The specific treatment approach used and dose modifications that occur are required to 
be reported in the Case Report Forms. 
7.1.2.1 Special Guidelines Related to Capecitabine Toxicity 
 
7.1.2.1.1 Diarrhea 
Capecitabine can cause diarrhea, and should be stopped at diarrhea grade  2, and treated 
symptomatically (recommend IV hydration and use of loperamide for diarrhea, observing loperamide 
dosage recommendation and treatment start, see below).  If control takes longer than 2 days, medical 
evaluation including relevant diagnostic procedures, alternative treatment and possible investigation 
of Dihydropyrimidine Dehydrogenase Deficiency (DPD) deficiency should be considered.  
Capecitabine cannot be re-started until diarrhea has resolved to baseline or grade < 2. 
 
The recommended dosage regimen for loperamide: 4 mg at the first onset of late diarrhea and then 2 
mg every 2 hours until the patient is diarrhea-free for at least 12 hours.  During the night, the patient 
may take 4 mg of loperamide every 4 hours.  Note: This dosage regimen exceeds the usual dosage 
recommendations for loperamide.  Premedication with loperamide is not recommended.  
 
The use of drugs with laxative properties should be avoided because of the potential for exacerbation 
of diarrhea. Patients should be advised to contact their physician to discuss any laxative use. 
 
Patients with ≥ grade 3 diarrhea should also be evaluated for c-difficile.  
 
Patients with neutropenia and diarrhea should be considered for empiric use of prophylactic 
antibiotics, such as oral quinolones. 
 


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7.1.2.1.2  
Hand-Foot Syndrome 
 
Toxicity 
Gradea 
Occurrence 
Oxaliplatin 
Capecitabine 
1 
Any 
Maintain dose 
Maintain dose 
2 
1st – 3rd 
Maintain dose 
Hold until grade ≤1, then 
resume 80% of current 
dose 
4th and higher 
Discontinue Protocol 
Therapy 
Discontinue Protocol 
Therapy 
3 
1st – 2nd 
Maintain dose 
Hold until grade ≤1, then 
resume at 80% of current 
dose 
3rd and higher 
Discontinue Protocol 
Therapy 
Discontinue Protocol 
Therapy 
a. 
National Cancer Institute Common Terminology Criteria Version 3.0 
b. 
Continued treatment only if it is considered to be in the best interest of the patient 
c. 
NOTE: After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to grade ≤1, 
the treating physician may choose, to hold oxaliplatin and continue capecitabine and pembrolizumab at current 
dose as clinically indicated.  If the treating physician chooses to restart oxaliplatin later in the patient’s treatment 
course, the dose of oxaliplatin at which the patient restarts should be one dose level lower than last dose level on 
which patient was treated.  The specific treatment approach used and dose modifications that occur are required to 
be reported in the Case Report Forms. 
*Applies only for grading hand–foot syndrome and should not be used to describe any other skin event and/or other 
cutaneous area. 
In the case of a discrepancy between the clinical domain and the functional domain, the assigned 
grade should correspond to the domain with the higher grade.  
 
Grade 2-3 Hand-Foot Skin Reaction 
Treat symptomatically (recommended use of emollients) and according to above table.  The use of 
vitamin B6 (Pyridoxine) has been reported to be of possible benefit for symptomatic or secondary 
prophylactic treatment, but due to a possible interaction with cisplatin (and thus possibly oxaliplatin) 
the use of B6 is not permitted in this trial.  
 
7.1.2.1.3 
 
Stomatitis/Oral Mucositis/Mouth Ulcers 
Stomatitis/oral mucositis/mouth ulcers due to capecitabine should be treated using local supportive 
care.  Please follow the paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers: 
 
For mild toxicity (grade 1), use conservative measures such as  
non-alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. 
 
 
For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 
anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or 
phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog 
in Orabase®).  For patients with grade 2 and above stomatitis, capecitabine may be held or 
dose reduced according to dose reduction table for non-hematologic toxicities (Section 3.3.4). 
 


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 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents.  The ingredient list of used toothpastes 
and mouthwashes should be checked for these agents. 
 
 
Antifungal agents must be avoided unless a fungal infection is diagnosed.  Topical antifungal 
agents are preferred if an infection is diagnosed. Similarly, antiviral agents such as acyclovir 
should be avoided unless a viral infection is diagnosed.  
  
Note: Stomatitis/oral mucositis should be appropriately graded using the functional grading given 
on the NCI-CTC for Adverse Events, version 3.0.  
 
7.2.1.2 Special Guidelines Related to Oxaliplatin Toxicity 
 
7.2.1.2.1 Dose Modifications for Neurological Toxicity Related to Oxaliplatin 
Toxicity Grade 
Duration of Toxicity 
Persistent 
Between Cyclesa 
1-7 Days 
> 7 Days 
Grade 1 
Paresthesias/dysesthesiasb that do not interfere 
with function 
Maintain dose 
Maintain dose 
Maintain dose 
Grade 2 Tolerable 
Paresthesias/dysesthesiasb interfering with 
function, but not activities of daily living (ADL) 
Maintain dose 
Maintain dose 
Continue to dose 
but reduce to 80% 
of current dose c 
Grade 2 Intolerable 
Paresthesias/dysesthesiasb interfering with 
function, but not activities of daily living (ADL) 
Hold until grade ≤1; 
then resume at 80% 
of current dose d 
Hold until grade ≤1; 
then resume at 80% 
of current dose d 
Hold until grade ≤1; 
then resume at 80% 
of current dose d 
Grade 3 
Paresthesias/dysesthesiasb with pain or with 
functional impairment that also interfere with 
ADL 
Hold until grade ≤1; 
then resume at 80% 
of current dose  d 
Hold until grade ≤1; 
then resume at 80% 
of current dose d 
Hold until grade ≤1; 
then resume at 80% 
of current dose d 
Grade 4 
Persistent paresthesias/dysesthesiasb that are 
disabling or life-threatening 
Hold until grade ≤1; 
then resume at 60% 
of current dose d 
Hold until grade ≤1; 
then resume at 60% 
of current dose  d 
Hold until grade ≤1; 
then resume at 60% 
of current dose d 
ACUTE 
(during or after the 2 hour infusion) 
laryngopharyngeal dysesthesiasb 
1st occurrence: 
Increase duration of 
next infusion to 4 
hoursd 
2nd and higher 
occurrence: 
Increase infusion to 
6 hours 
N/A 
N/A 
a. 
Not resolved by the beginning of the next cycle. 
b. 
May be cold-induced. 
c. 
If grade 2 tolerable neurologic toxicity persists longer than 6 weeks, despite oxaliplatin dose adjustments, oxaliplatin 
should be held and therapy with capecitabine and pembrolizumab can be continued.  If neurologic toxicity 
subsequently resolves to < Grade 1, oxaliplatin therapy may resume at 80% of current dose. 
d. 
NOTE: After Cycle 1, the treating physician may choose to hold oxaliplatin and continue capecitabine and 
pembrolizumab at current dose as clinically indicated.  If toxicity resolves to grade 1 or less the treating physician may 
chooses to restart oxaliplatin later in the patient’s treatment course, the dose of oxaliplatin at which the patient restarts 
should be one dose level lower than last dose level on which patient was treated.  The specific treatment approach 
used and dose modifications that occur are required to be reported in the Case Report Forms. 
 
If grade 2 intolerable, grade 3 or grade 4 neurological toxicity (see Table 3E) is evident at the time of 
the next planned administration of oxaliplatin, then oxaliplatin administration will be held until the next 
treatment cycle.  Capecitabine and pembrolizumab will be administered if otherwise appropriate. 


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Missed doses will not be made up.  If toxicity resolves to grade 1 or less at next treatment cycle, 
resume oxaliplatin per instructions provided in Table 3E.  If neurological toxicity is still present and has 
not resolved to grade 1 or less at the next treatment cycle, oxaliplatin will continue to be held.  
Patients may continue to receive capecitabine and pembrolizumab on study if otherwise appropriate.   
 
Oxaliplatin may be repeatedly temporarily discontinued and then re-initiated in this fashion unless the 
patient has disease progression, whereby the patient will be removed from the study.  However, if the 
patient is not receiving oxaliplatin at the time of progression, if it is appropriate and safe as determined 
by the treating physician that oxaliplatin can be restarted, oxaliplatin may be restarted and the patient 
may continue on treatment.  If the patient has disease progression on oxaliplatin or it is not safe or 
appropriate to restart oxaliplatin, the patient will be removed from the study.   
 
Dose escalations of oxaliplatin are not permitted at any time. 
 
Laryngopharyngeal Dysesthesia 
An unusual laryngopharyngeal dysesthesia (LPD), a loss of sensation of breathing without any 
objective evidence of respiratory distress (laryngospasm, bronchospasm or hypoxia) has also been 
observed.  This neurotoxicity may be induced or exacerbated upon exposure to cold and should be 
distinguished from a hypersensitivity reaction.  If a patient develops LPD, the patient’s oxygen 
saturation should be evaluated via a pulse oximeter and, if normal, reassurance, a benzodiazepine or 
other anxiolytic agent should be considered and the patient should be observed in the clinic until the 
episode has resolved.  The oxaliplatin infusion may then be continued at a reduced rate, 33% of the 
original rate.  Because this syndrome may be associated with the rapidity of oxaliplatin infusion, 
subsequent doses of oxaliplatin should be administered as 4-6-hour infusions.  To minimize the risk of 
LPD, patients will be instructed to avoid ice and cold drinks the day of treatment.   
 
Hypersensitivity Reactions 
Oxaliplatin, as is the case with all platinum-containing compounds, is associated with a measurable 
(approximately 11%) incidence of hypersensitivity reactions, usually after multiple doses of treatment. 
This may present as bronchospasm, hypotension, and even hemolytic anemia.  Pre-treatment with 
glucocorticoids and anti-histamines may be useful for some patients, but may not always prevent the 
development of anaphylactoid reactions, especially in patients with a prior history of hypersensitivity to 
this agent.  For patients who have experienced a Grade 1 or 2 acute hypersensitivity reaction that is 
assessed as related to oxaliplatin administration, the following premedication is recommended prior to 
each subsequent dose of oxaliplatin:   
 
Dexamethasone 20 mg PO or IV, 12 and 6 hours prior to the oxaliplatin dose; 
OR 
Dexamethasone 20 mg PO or IV, as well as diphenhydramine 50 mg IV, and one of the following: 
cimetidine 300 mg IV, ranitidine 50 mg IV, or famotidine 20 mg IV 30-60 minutes prior to oxaliplatin 
administration. 
If these prophylactic measures fail to prevent oxaliplatin-related hypersensitivity, therapy with 
oxaliplatin should be discontinued. 
Patients who have grade 3 or 4 acute hypersensitivity reactions should discontinue oxaliplatin 
therapy.  
Pulmonary Fibrosis 
In the case of unexplained respiratory symptoms such as nonproductive cough, dyspnea or 
radiological pulmonary infiltrates, oxaliplatin should be discontinued until further investigation excludes 


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interstitial pulmonary fibrosis.  If interstitial pulmonary fibrosis is confirmed, oxaliplatin therapy should 
be terminated. 
7.2  
Toxicity Management 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
Investigator. It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 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.  
7.2.1  Pneumonitis 
 
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. 
 
For recurrent Grade 2 events, discontinue treatment with pembrolizumab. 
 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional anti-
inflammatory measures, as needed. 
 
For first occurrence of Grade 3-4 events, discontinue treatment with pembrolizumab. 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid administration. 
7.2.2  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).   
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. 
 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral corticosteroids.  
 
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids followed by 
high dose oral steroids.   
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 


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7.2.3  Diabetes Mellitus 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or Grade 3-4 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
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.  
7.2.4  Hypophysitis 
 
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. 
 
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. 
7.2.5  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. 
 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, 
is indicated per standard of care. 
 
Grade 3-4 hyperthyroidism  
o 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. 
7.2.6  Hepatic 
 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline values 
(consider weekly). 
 
Treat with IV or oral corticosteroids 
 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  


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 
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over 
no less than 4 weeks. 
7.2.7  Renal Failure or Nephritis 
 
For Grade 2 events, treat with corticosteroids. 
 
For Grade 3-4 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.  
7.2.8  Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Appropriate resuscitation equipment should be 
available in the room and a physician readily available during the period of drug administration. 
Table 7.2.8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
Table 7.2.8 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 


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NCI-CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
 
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 1hr 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 1.5hr 
(± 30 minutes) prior to infusion of 
pembrolizumab 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 


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8.0 
CORRELATIVES 
Tissue and blood based biomarker studies will be performed to better understand the role of factors 
that may be associated with efficacy or toxicity from study treatment and/or cancer biology. Additional 
markers related to efficacy, toxicity, and/or cancer biology may be analyzed.  Anticipated analyses are 
listed below and focus on factors associated with angiogenesis, inflammation, immunity, and tumor 
growth. However, final analyte lists and technology platforms will be based upon best science and 
available funding at the time of analysis. External vendors and collaborators may conduct or participate 
in these analyses, provided sampels are de-identified.  All collaborations will be subject to Duke policies 
on sample and data sharing.    
8.1 
Tumor Tissue Biomarkers 
Archived formalin fixed paraffin embedded (FFPE) tumor tissue will be collected for all subjects (if 
available). Refer to Study Manual for collection, processing, and submission details. 
 
For patients accrued to the dose expansion cohort, pre-treatment and on-treatment tumor biopsies will 
be performed only on patients who have a tumor lesion that is amenable to safe biopsy.  In the biomarker 
cycle, patients will undergo tumor biopsy up to 1 week before starting treatment (i.e., pre-treatment) 
and will undergo a second tumor biopsy on Day 7 or 8 prior to start of oxaliplatin and capecitabine (i.e., 
on-treatment). The preferred type of biopsy is a core biopsy: five 18-gauge core needle biopsies 
(diameter about 2 mm) with a throw length of approximately 2 cm will provide adequate tissue for study. 
Refer to Study Manual for collection, processing, and submission details. Note: Those patients accrued 
to the dose expansion cohort who do not have a tumor lesion that is amenable to safe biopsy will only 
have blood-based biomarker collections in the biomarker cycle (ie. Cycle 1).   
 
We will interrogate these tissue specimens using whole exomic sequencing studies, spacial 
transcriptomic analysis, and proximity ligation assays to spatially resolve the impact of pembrolizumab 
on tumor T cell/PMN-MDSC infiltration and NLRP3 inflammasome activation. These data will be 
correlated with mutations associated with this resistance pathway as well as with clinical response. This 
work will leverage a rare tissue bank of pre- and post-pembro tumor specimens to reveal a series of 
novel pharmacologic targets and potential biomarkers capable of overcoming immunotherapy 
resistance and improving the management of patients with gastrointestinal maligancies.  
 
Archived FFPE tumor tissue and pre-treatment/on-treatment tumor biopsy samples will be tested by 
IHC for CD8 and PDL1 staining, the primary biomarker endpoints for this study. Expression of additional 
proteins that may be associated with sensitivity or resistance to pembrolizumab or XELOX and 
pembrolizumab, including but, not limited to, TGF1, STAT3, and various immune cell populations, 
including CD3, CD4, CD8, Treg, (FoxP3), Th17 T-cells and monocyte/macrophage and neutrophil 
populations.  RNA Seq or PCR may also be performed for analyses of factors that may be associated 
with sensitivity or resistance to these agents including but not limited to CD3, CD4, CD8, EOMES, IFNγ, 
FOXP-3, Granzyme-A, Granzyme-B, Perforin, IL1β, IL6, IL7, IL10, IL11, IL12, IL17A, IL17E, IL22, and 
IL23. Micro-satellite instability (MSI) by IHC and/or polymerase chain reaction (PCR) may also be 
assessed. 
 
Genetic alterations, including both gene mutation and copy number alteration, may be characterized 
using a customized Next Gen Sequencing platform.  Samples evaluated will be archived FFPE tumor 
samples.  Further refinement of these approaches can be made depending on interest.   
8.2 
Circulating Immune Cells (PBMC) 
Peripheral blood will be collected for peripheral blood mononuclear cells (PBMCs) from each subject at 
the following timepoints: baseline, end of monotherapy lead-in on Day 8 (biomarker cycle of dose 


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expansion cohort only), end of first cycle of combination therapy on Day 29 (biomarker cycle of dose 
expansion cohort only), first restaging only, disease progression or treatment discontinuation, and for 
complete responders on long term follow-up.  Refer to Study Manual for collection and submission 
details. 
 
PBMCs will be processed and stored by the Duke Immune Profiling Core facility under the direction of 
Dr. Kent Weinhold. Polychromatic flow cytometry (PFC) panels will be used to compare treatment 
related changes in both tumor and peripheral immune cell compartments. Up to 50 markers may be 
analyzed using 3 PFC panels: 1) a 12-color ‘Exhaustion Panel’, 2) a 12-color ‘Tumor Reactive T Cell 
Panel’, and 3) a 14-color regulatory T cell (Treg) and myeloid-derived suppressor cells (MDSC) panel. 
This analysis will be overseen by Dr. Weinhold. 
8.3 
Protein Multiplex Arrays (Plasma) 
Peripheral blood will be collected for plasma from each subject at the following timepoints: baseline, 
end of monotherapy lead-in on Day 8 (biomarker cycle of dose expansion cohort only), end of first cycle 
of combination therapy on Day 29 (biomarker cycle of dose expansion cohort only), every restaging, 
disease progression or treatment discontinuation, off treatment follow-up, and for complete responders 
on long term follow-up. Refer to Study Manual for collection, processing, and submission details. 
 
Plasma will be stored by the Duke Phase I Biomarker Laboratory under the direction of Dr. Andrew 
Nixon.  Markers of inflammation will be analyzed in the Duke Phase I Biomarker lab. Analyses will be 
performed on pre-treatment and on-treatment samples. Analyte levels, and changes in analyte levels, 
will be correlated with clinical outcome (PFS, OS).  Plasma and serum samples will be evaluated by 
ELISA for protein markers that may be associated with sensitivity or resistance to pembrolizumab. 
These may include CRP and other markers of inflammation, including but not limited to IFNγ, IL1β, IL4, 
IL6, IL7, IL10, IL12, IL17A, IL17E, and IL23.  
8.4 
Pharmacogenomics (Whole Blood)  
Subjects will have whole blood collected at baseline. Refer to Study Manual for collection, processing, 
and submission details. 
 
Whole blood will be stored for possible future analysis of HLA type and other candidate markers of 
efficacy and toxicity by the Duke Phase I Biomarker Laboratory under the direction of Dr. Andrew Nixon 
with the consent of the patient.   
8.5 
Future Use of Patient Samples 
Any remaining biological materials at the end of the study will be deidentified and deidentified samples 
may be retained for possible use in biomarker research with the consent of the patient. 
 
8.6  
Correlative Collaborations 
 
8.6.1. Duke-Personalis Collaboration 
In order to identify potential mechanisms of sensitivity and resistance to pembrolizumab in gastric 
cancer and to better characterize the changes of key tumor and immune factors in response to 
pembrolizumab therapy, we plan to collaborate with Personalis, Inc. for both tissue- and blood-
based biomarker analyses using their comprehensive, state-of-the-art technology platforms 
(https://www.personalis.com/). 
 
8.6.1.1   The following samples for the specified assays and analytic pipelines will be shared with 
Personalis.  


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Sample Type 
Sample Format/Quantity 
Assay Type 
FFPE tumor tissue 
50 samples 
4 x 5um unstained slides or 2 x 10um 
curls, 25mm2 surface area per sample 
ImmunoID NeXT  
PBMC  
36 samples 
2-4 million frozen PBMC per sample 
ImmunoID NeXT  
Plasma 
150 samples 
Up to 8 ml per sample 
NeXT Liquid Biopsy 
8.6.1.2    The following clinical data will be shared with Personalis in order to utilize pre-existing 
biomarker analytic pipelines. Duke statisticians will work with both teams in a collaborative 
fashion to analyze and interpret the data from each project. 
 
Deidentified patient metadata. 
o 
Patient age, gender, race/ethnicity, prior therapies, treatment duration, 
treatment dosage, smoking status, tumor size, tumor site 
 
RECIST and iRECIST response data for each patient case per timepoint 
 
Deidentified patient outcomes data.   
o 
OS, PFS and response to therapy 
 
No personal health information will be shared with Personalis.  
 
 
8.6.2 Duke – Olink Collaboration 
In order to identify potential mechanisms of sensitivity and resistance to pembrolizumab in gastric 
cancer and to better characterize the changes of key tumor and immune factors in response to 
pembrolizumab therapy, we plan to collaborate with Olink for both tissue- and blood-based 
biomarker analyses using their comprehensive, state-of-the-art technology platforms 
(https://www.olink.com/) 
 
8.6.2.1   The following samples for the specified assays and analytic pipelines will be shared with 
Olink.  
Sample Type 
Sample Format/Quantity 
Assay Type 
Fresh frozen tumor tissue 
25 samples 
Tissue lysate, 20 ug per sample 
Olink Explore 1536 
PBMC 
150 samples 
Cell lysate, 1000 PBMCs per sample 
Olink Explore 1536  
Plasma 
150 samples 
100 µl per sample 
Olink Explore 1536 
 
8.6.2.2    The following clinical data will be shared with Olink in order to utilize pre-existing biomarker 
analytic pipelines. Duke statisticians will work with both teams in a collaborative fashion to 
analyze and interpret the data from each project. 
 
Deidentified patient metadata. 
o 
Patient age, gender, race/ethnicity, prior therapies, treatment duration, 
treatment dosage, smoking status, tumor size, tumor site 
 
RECIST and iRECIST response data for each patient case per timepoint 
 
Deidentified patient outcomes data.   
o 
OS, PFS and response to therapy 
 
No personal health information will be shared with Olink. 
 
 


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9.0 
STATISTICAL ANALYSIS 
9.1 
General Analysis Considerations 
Thirty-five (35) evaluable patients will be enrolled and treated.   
9.1.1  Primary Endpoint 
The primary endpoint will be progression-free survival (PFS) measured from study entry until 
documented progression or death from any cause. Patients who have not experienced progression will 
be censored at the date of the last radiographic assessment. Based on the results of the AVAGAST 
and ToGA trials a median PFS of approximately 5.5 months is expected for patients treated with 
oxaliplatin and capecitabine alone.  Also, observed PFS hazard ratios of 0.80 and 0.71 were reported 
for AVAGAST and ToGA, respectively. With 35 patients enrolled, the difference between a historical 
median PFS of 5.5 months and experimental median of 7.3 months, a hazard ratio of 0.75, can be 
detected with 80% power (1-sided test of single exponential mean, α=0.2). 
PFS and median PFS will be estimated using the Kaplan-Meier method. The 95% confidence interval 
estimate for median PFS will be computed using the variance estimate proposed by Brookmeyer and 
Crowley. Under the alternative hypothesis, 32 PFS events are expected at the end of the follow-up 
period. 
The primary analysis of PFS will be intention-to-treat in that all patients who have undergone at least 
one scheduled restaging on-treatment, or who have had unequivocal progression prior to the first 
scheduled restaging will be followed for progression. These patients will be followed for PFS, even if 
they are removed from treatment due to unacceptable toxicity or because they withdrew consent. As a 
secondary analysis, these patients will be censored at the time they were removed from treatment. 
The magnitude of reduction in tumor burden will be summarized descriptively (such as a waterfall plot) 
based on change in the sum of the longest diameters of target lesions relative to baseline. 
9.1.2  Secondary Endpoints 
Secondary endpoints include the safety and tolerability of the XELOX/pembro regimen and response 
rate (RR). Adverse events will be described and presented by Type and Grade according to NCI-CTCAE 
version 4.03 criteria and descriptively compared with historical controls. 
Radiographic imaging will be repeated every three cycles (approximately every 9 weeks) as described 
in Section 5.0. Tumor response defined as complete response (CR) or partial response (PR) will be 
assessed using RECIST 1.1 (see Section 5.6). 
RR will be estimated by the 90% confidence interval for the binomial proportion. With 35 patients studied 
(5 in the safety validation and 30 in the expanded cohort), RR can be estimated to within at most +/- 
0.14 with 90% confidence. 
The magnitude of reduction in tumor burden will be summarized descriptively (such as with a waterfall 
plot) based on change in the sum of the longest diameters of target lesions relative to baseline. 
Overall survival (OS) will be described. 


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9.1.3  Exploratory Endpoints 
CD8 and PDL1 staining measured by IHC are the primary biomarker endpoints for this study. 
Descriptive statistics will be provided for each of these endpoints at each time point (pre-, P, and on-
treatment, OT) and for the change P vs OT.  
For continuous CD8 and PDL1 expression measures (e.g., percentages), the paired t-test will be used 
to compare change in P vs OT. We expect approximately 25 patients to have paired measurements. 
With 25 patients studied a difference of 0.53 standard deviation (SD) can be detected with 90% power 
(1-sided α=0.1). With this sample size differences of 13%, 27%, and 40% can be detected with 80% 
power assuming SDs of 0.25, 0.5, and 0.75, respectively.  
For dichotomous paired proportions (e.g., <2+ versus >2+ by IHC) McNemar’s test will be used to test 
the null hypothesis that the difference in P and OT proportions is 0 versus the alternative that it is > 0 
or < 0.  With 25 paired patient samples studied 79% power is achieved to detect the difference illustrated 
in Table 1a below and 86% power is achieved to detect the difference illustrated in Table 1b (2-sided 
α=0.1). 
Table 1a: Alternative hypothesis resulting in 79% power using McNemar’s test (2-sided α=0.1). 
   
 
Post Treatment 
 
Total 
Pre Treatment 
<2+ 
>2+ 
 
<2+ 
0.15 
0.45 
0.60 
>2+ 
0.10 
0.30 
0.40 
Total 
0.25 
0.75 
1.00 
 
Table 1b. Alternative hypothesis resulting in 86% power using McNemar’s test (2-sided α=0.1). 
   
 
Post Treatment 
 
Total 
Pre Treatment 
<2+ 
>2+ 
 
<2+ 
0.10 
0.50 
0.60 
>2+ 
0.10 
0.30 
0.40 
Total 
0.20 
0.80 
1.00 
Similar analyses will be conducted for other biomarkers as described in Section 8.0. No adjustments 
will be made for multiple comparisons. Data transformations or non-parametric methods will be used 
as appropriate. 
Associations between changes in immune infiltrates and outcomes (PFS, RR, OS) will be explored 
using Cox regression (PFS), 2-sample t-tests or non-parametric Wilcoxon rank-sum tests, or the Chi-
square test (6-month PFS, RR) based on the distribution and structure of the data (i.e., either parametric 
or non-parametric methods will be used as appropriate). 
10.0 SAFETY 
Refer to Study Manual for required reporting forms. 
 
10.1 Adverse Events 
An adverse event (AE) 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 


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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 supporting company product(s), is also an AE. 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered AEs.  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. 
Supporting company 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 the 
supporting company for human use. 
AEs may occur during the course of the use of supporting company product(s) in clinical trials or within 
the follow-up period specified by the protocol, or 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 AE unless it is considered to be drug related 
by the Investigator. 
AEs will be documented from the date of first dose of study drug through 30 days after the last dose of 
study drug.  All Grade 2-5 AEs as well as special reporting circumstances, such as exposure via a 
parent during pregnancy or breast-feeding, overdose, medication error, misuse, abuse, off-label use or 
occupational exposure must be recorded on the CRF. 
10.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is immediately life-threatening (ie, in the opinion of the Investigator, the AE places the subject at 
immediate risk of death; it does not include a reaction that, had it occurred in a more severe form, 
might have caused death). 
3. Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
4. Results in persistent or significant disability or incapacity. (Note: The term “disability” refers to 
events that result in a substantial disruption of a subject’s ability to conduct normal life function.) 
5. Is a congenital anomaly or birth defect. 
6. Is an important medical event (Note: The term “important medical event” refers to an event that, 
based upon appropriate medical judgment, may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the subject or require intervention to prevent one of 
the other serious outcomes listed under the definition of SAE. Examples of important medical 
events include intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias, or convulsions that do not result in hospitalization; or development of product 
dependency or product abuse.) 
SAEs and/or follow up to SAEs including death due to any cause other than progression of the cancer 
under study, that occurs from the date of the first dose of study drug through 30 days following the last 


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dose of study drug, whether or not related to study drug(s), must be recorded on the CRF and must be 
reported within 2 business days supporting companies. External sites should report SAEs to the Duke 
study team within 24 hours. Reporting instructions for external sites can be found in the REDCap study 
eManual.  
All SAEs must be followed until resolution, return to baseline condition, or stabilization.  Any SAEs that 
are ongoing at the time the clinical database is closed will be reported to supporting companies as 
unresolved. 
The initial report for each SAE or death should include at minimum the following information: 
 
protocol number and title 
 
patient initials, study identification number, sex, age 
 
date the event occurred 
 
description of the event 
 
seriousness criteria 
 
event causality or causal relationship 
 
study drug name(s) 
 
dose level and cycle number at the time the event occurred 
 
description of the patient’s condition 
 
study status of patient at time of report 
 
responsible investigator name and contact details 
The Investigator should report a diagnosis or a syndrome rather than individual signs or symptoms. The 
Investigator should also try to separate a primary AE considered as the foremost untoward medical 
occurrence from secondary AEs which occurred as complications. Whenever possible, the Investigator 
should also provide the batch or lot number of the study drug(s). 
SAE Reporting Procedure: 
Immediately upon awareness of a SAE, the Investigator (or designee) completes the DCI SAE Report 
Form  and will submit the form within 2 business days of knowledge of the event to the funding company. 
External sites should submit the form within 24 hours to the Duke study team via the REDCap SAE 
reporting tool. In accordance with applicable regulations, Investigators must report SAEs to their local 
IRB according to their institutional guidelines.  
 
Note:  It is imperative that initial SAE reports are submitted as soon as possible (within 2 business days 
of knowledge of the event) with available information to the supporting company.  Missing and/or 
clarified event information may be provided in a follow-up report.   
Follow-up information including severity, action taken, concomitant medications, and outcome should 
be communicated to the funding company as soon as possible using the same forms mentioned above. 
: 
The Lead PI will review the report form with accompanying source document, sign page 5, and then the 
PI or designee will promptly submit it to the supporting company.   
If the event meets the Duke University Health System (DUHS) IRB reporting requirements, the Duke GI 
Oncology regulatory coordinator will submit information about the SAE including the Lead PI’s 


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assessment as a safety event to the DUHS IRB within 5 business days. Any study-related death must 
be reported to the IRB within 24 hours of discovery.   
Within two business days of receipt, the Duke study team will also submit the SAE report form and other 
relevant safety information to the following supporting companies: 
Merck Global Safety 
ATTN: Worldwide Product Safety 
Fax: 215-993-1220 
Expedited Reporting Procedure for Duke Cancer Institute (Coordinating Center): 
Duke Cancer Institute as the coordinating center for this study is responsible for reporting SAEs to the 
FDA in accordance with 21CFR 312.32.  Any SAE that is possibly related and unexpected must be 
submitted to the FDA attached to the IND.  If the SAE meets criteria for reporting to the FDA, the Duke 
study team will complete the Form FDA 3500A (MedWatch) and send to the Lead PI and the supporting 
companies that are noted above.  This submission of the Form FDA 3500A to the FDA attached to the 
IND will be completed by the Duke GI Oncology Clinical Trials Regulatory Coordinator. 
 
All unexpected, drug related SAEs that are fatal or life-threatening will be reported to the FDA by 
phone or fax within 7 calendar days of initial receipt of the information and will provide a complete 
report within 8 days of the initial report submission (by calendar day 15).  
 
All unexpected, treatment-related SAEs that are not fatal or life-threatening will be reported in a 
written report to the FDA within 15 days of initial receipt of the information. 
The Duke study team will forward all expedited reports to all participating investigators in the form of 
an Investigator Alert. The Investigator Alert template is available on the DCI intranet titled “Safety 
Reporting for Multi-site IITs Notification Email”. 
10.3 Events of Clinical Interest 
Select (non-serious and serious) adverse events called Events of Clinical Interest (ECI) that occur from 
the date of the first dose of study drug through 30 days following the last dose of study drug, must be 
recorded on the CRF and must be reported within 2 working days to Merck Global Safety. 
An ECI for this study is any hepatic toxicity that is ≥ Grade 2 or any grade resulting in dose modification 
or use of systemic steroids to the adverse event.  Such adverse events include but are not limited to; 
hepatitis, autoimmune hepatitis, and transaminase elevations (ALT and/or AST).   
Any overdose of pembrolizumab (1,000 mg or greater) is also considered an ECI for this study and 
should be reported as such, regardless of the outcome. 
ECI Reporting Procedure: 
Immediately upon awareness of an ECI, the Investigator (or designee) completes the DCI SAE Report 
Form and will submit the form within 2 business days of knowledge of the event to the funding company. 
External sites should submit the form within 24 hours to the Duke study team via the REDCap SAE 
reporting tool. 
Note:  It is imperative that initial ECI reports are submitted as soon as possible (within 2 business days 
of knowledge of the event) with available information to the supporting company.  Missing and/or 
clarified event information may be provided in a follow-up report.   


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Follow-up information including severity, action taken, concomitant medications, and outcome should 
be communicated to the funding company as soon as possible using the same form mentioned above. 
The Lead PI will review the report form with accompanying source document, sign page 5, and the PI 
or designee will then promptly submit it to the funding company.   
Within two business days of receipt, the study team will also submit the SAE report form and other 
relevant safety information to the following supporting company: 
Merck Global Safety 
ATTN: Worldwide Product Safety 
Fax: 215-993-1220 
10.4 Other Safety Considerations 
The Investigator must also report in the same timelines as SAEs any incidence of medication error, 
occupational exposure, abuse or misuse that is associated with or result in an adverse event.  All related 
fatal outcomes must also be reported in the same timeline as a SAE.   
Refer to SAE reporting procedures in Section 10.2. 
10.4.1 Pregnancy and Lactation 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
Investigator or designee to report any pregnancy or lactation in a subject (spontaneously reported to 
them), including the pregnancy of a male subject's female partner that occurs during the trial or within 
120 days of following cessation of treatment.  All subjects and female partners of male subjects who 
become pregnant 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 reported in the same procedure as an SAE.  Refer to SAE reporting 
procedures in Section 10.2. 
10.4.2 Medication Overdose and Error 
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) and is an event of clinical interest (see Section 10.3 for reporting 
instructions).  No specific information is available on the treatment of overdose of pembrolizumab. 
Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the 
subject should be observed closely for signs of toxicity. Monitoring should be based upon good medical 
judgment, taking into account the level of overdose, evolving toxicities, and other relevant medical and 
social factors specific to the patient. Appropriate supportive treatment should be provided if clinically 
indicated.  
If an adverse event(s) is associated with (“results from”) the overdose of study drug(s), the adverse 
event(s) is reported as a SAE, even if no other seriousness criteria are met. Refer to SAE reporting 
procedures in Section 10.2. 


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If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as an ECI, using the 
terminology “accidental or intentional overdose without adverse effect.”  Refer to ECI reporting 
procedures in Section 10.3. 
11.0 ADMINISTRATIVE RESPONSIBILITIES 
11.1 Institutional Review Board/Independent Ethics Committee  
Before study initiation, the Investigator must have written and dated approval/favorable opinion from the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the protocol, consent form, 
subject recruitment materials/process (e.g., advertisements), and any other written information to be 
provided to subjects.  
The Investigator should provide the IRB/IEC with reports, updates, and other information (e.g., Safety 
Updates, Amendment IRB/IECs, and Administrative Letters) according to regulatory requirements and 
institution procedures. 
Copies of all IRB/IEC approvals, as well as annual re-approvals and approved/stamped informed 
consent forms must be submitted to Duke GI Oncology Clinical Trials Office. 
11.2 Protocol and Protocol Revisions 
All revisions to the protocol will be provided to the supporting companies by the Lead PI or designee(s) 
at the Duke GI Oncology Clinical Trials Office.  The Lead PI must have written and dated 
approval/favorable opinion from the Duke University Health System (DUHS) IRB of revised protocol 
prior to distribution to Investigators at external participating sites.   
Investigators must obtain written and dated and approval/favorable opinion from the IRB/IEC before 
conducting any updated protocol version.  Study must be conducted as described in the approved 
protocol.  The Investigator must not implement changes of the approved protocol without prior written 
agreement by the Lead PI and prior review and documented approval/favorable agreement by the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects, or when the changes involve only logistical or administrative aspects of the study (e.g., 
changes in research personnel or change in phone numbers). 
Documentation of approval(s) from the IRB/IEC must be sent to Duke GI Oncology Clinical Trials Office.  
11.3  Protocol Deviations and Violations  
A protocol deviation is non-adherence to protocol specific study procedures or schedules that does not 
involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or Good Clinical Practice 
(GCP) guidelines.  
A protocol violation is any significant divergence from the protocol such as non-adherence on the part 
of the subject, the Investigator, or the sponsor to protocol specific inclusion/exclusion criteria, primary 
objective evaluation criteria, and/or GCP guidelines.  
As a matter of policy, the Lead PI (ie. sponsor) will not grant exceptions to protocol specific entry criteria 
to allow subjects to enter a study.  If it is found that a subject who did not meet protocol eligibility criteria 
was entered in a study (a protocol violation), the Lead PI and/or designee(s) at the Duke GI Oncology 
Clinical Trials Office must be informed immediately.  Such subjects will be discontinued from the study, 


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except in an exceptional instance following review and written approval by the Lead PI and the 
responsible IRB/IEC. 
Protocol deviations and violations must be documented and reported to the Lead PI and/or designee(s) 
at the Duke GI Oncology Clinical Trials Office.   
In accordance with applicable regulations, Investigators must report protocol deviations and violations 
to their local IRB/IEC according to their institutional guidelines.  
11.4 Informed Consent 
The Investigator must ensure that subjects or their legally acceptable representatives are clearly and 
fully informed about the purpose, potential risks and other critical issues regarding clinical trials in which 
they volunteer to participate.  Preparation of the consent form is the responsibility of the Investigator 
and must include all elements required by CFR 21 Part 50.25 and their IRB.  A copy of the proposed 
informed consent document must be submitted to the Lead PI or designee(s) at the Duke GI Oncology 
Clinical Trials Office for review and comment prior to submission to the local IRB/IEC. 
Informed consent must be obtained prior to performing any study-related procedures that are not part 
of normal subject care, including screening and changes in medications. A copy of the signed informed 
consent form must be given to the study subject.  
11.5 Source and Study Documentation 
Source documents include all original recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical study.  
Accordingly, source documents include, but are not limited to, laboratory reports (including normal and 
abnormal results), radiology reports, subject diaries, biopsy reports, ultrasound photographs, subject 
progress notes, hospital charts or pharmacy records and any other similar reports or records of any 
procedure performed in accordance with the protocol. 
Whenever possible, the original recording of an observation should be retained as the source document; 
however, a photocopy is acceptable provided that it is a clear, legible, and exact duplication of the 
original certified document.   
When clinical observations are entered directly into an electronic medical record system (i.e. in lieu of 
original hardcopy records), the electronic record can serve as the source document if the system has 
must be validated to meet the FDA requirements for electronic records and signatures (i.e. meets 21 
CFR Part 11 compliant).   
Regulations require that Investigators maintain information in the study subject’s medical records which 
corroborate data recorded on the CRF.  In order to comply with these regulatory requirements, the 
following information will be maintained and made available as required by the Lead PI or designee(s), 
monitors, and/or regulatory inspectors: 
 
Medical history/physical condition of the study subject prior to involvement in the study sufficient 
to verify protocol entry criteria. 
 
Dated note that informed consent was obtained for the subject’s participation in the study. 
 
Dated and signed notes for each subject visit including results of examinations. 
 
Notations on abnormal lab results and their resolution. 
 
Dated reports of special assessments (e.g., ECG reports). 


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 
Dated and signed notes regarding adverse events (includng event description, severity, onset 
date, duration, relation to study treatment, outcome and treatment for adverse event). 
 
Dated notes regarding concomitant medications taken during the study (including start and stop 
dates). 
 
Subject condition upon completion of or withdrawal from the study. 
Study documentation includes all CRFs, data correction forms, source documents, monitoring logs and 
appointment schedules, sponsor-investigator correspondence and regulatory documents (e.g., protocol 
and amendments, IRB/IEC correspondence and approvals, approved and signed subject consent 
forms, Statement of Investigator form, and clinical study supplies receipts and distribution records). 
The Investigator will prepare and maintain complete and accurate study documentation in compliance 
with GCP guidelines and applicable federal, state, and local laws, rules and regulations; and, for each 
subject participating in the study, promptly complete all CRFs and such other reports as required by this 
protocol following completion or termination of the clinical study or as otherwise required pursuant to 
any agreement with the Lead PI and Duke Cancer Institute (DCI). 
The Investigator acknowledges that, within legal and regulatory restrictions and institutional and ethical 
considerations, study documentation will be promptly and fully disclosed to Lead PI or designee(s) by 
the Investigator upon request and also shall be made available at the Investigator’s site upon request 
for inspection, copying, review and audit at reasonable times by representatives of the Lead PI and DCI 
or responsible government agencies as required by law.  
The Investigator agrees to promptly take any reasonable steps that are requested by the Lead PI or 
designee(s) as a result of an audit to cure deficiencies in the study documentation and case report 
forms. 
11.6 Case Report Forms 
Subject data will be entered (ie. CRFs completed) into an electronic data capture (EDC) system called 
Medidata RAVE.  This database is maintained on a secure Duke University server and is accessible 
via internet with login and password.     
CRFs should be completed by trained study personnel according to guidelines provided by the Lead 
PI or designee(s) at the Duke GI Oncology Clinical Trials Office.  The Investigator or qualified 
designee is responsible for recording and verifying the accuracy of subject data.  The Investigator 
acknowledges that his/her electronic signature is the legally binding equivalent of a written signature. 
By entering his/her electronic signature, the Investigator confirms that all recorded data have been 
verified as accurate.   
In the event of discrepant data, the study monitor or study designee will request data clarification from 
the Investigator or designee for which may be resolved electronically in the EDC system. 
Accurate and reliable data collection will be ensured through verification and crosscheck of the CRFs 
against the Investigator’s study records (source document verification) by the study monitor or study 
designee. 
11.7 Monitoring and Audits/Inspections 
The study will be monitored both internally by the Lead PI and externally by the Duke Cancer Institute 
(DCI) Monitoring Team in accordance with their NCI-approved “Institutional Protocol Monitoring 
Procedures and Guidelines for NIH-sponsored Research Involving Human Subjects”.  


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In terms of internal review, the Lead PI and/or designee(s) will continuously monitor and tabulate 
adverse events.  Appropriate reporting to the DUHS IRB will be made. If an unexpected frequency of 
Grade 3 or 4 adverse events occurs, depending on their nature, action appropriate to the nature and 
frequency of these adverse events will be taken. This may require a protocol amendment, dose de-
escalation, or potentially closure of the study. The Lead PI of this study will also continuously monitor 
the conduct, data, and safety of this study to ensure that: 
 
Interim analyses occur as scheduled (if applicable); 
 
Stopping rules for toxicity and/or response are met; 
 
Risk/benefit ratio is not altered to the detriment of the subjects; 
 
Appropriate internal monitoring of adverse events and outcomes is done; 
 
Over-accrual does not occur; 
 
Under-accrual is addressed with appropriate amendments or actions; 
 
Data are being appropriately recorded on the CRF in a reasonably timely manner. 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety 
and to ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, 
standard operating procedures, GCP, and applicable regulatory requirements.  As specified in the DCI 
Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the 
third subject is enrolled, followed by annual monitoring of 1-3 subjects until the study is closed to 
enrollment and subjects are no longer receiving study interventions that are more than minimal risk.   
An external site monitoring plan addendum describes monitoring at participating sites. 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and 
DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the 
sponsor, the Principal Investigator, or the IRB.  All study documents must be made available upon 
request to the DCI Monitoring Team and other authorized regulatory authorities, including but not limited 
to the National Institute of Health, National Cancer Institute, and the FDA.  Every reasonable effort will 
be made to maintain confidentiality during study monitoring. 
The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the DCI 
Monitoring Team visit and additional safety and toxicity data submitted by the Principal Investigator. 
DCI Quality Assurance personnel, or designee, may conduct audits at sites.  Audits will include, but not 
be limited to: audit trail of data handling and processes, SOPs, drug supply, presence of required 
documents, the informed consent process, and comparison of case report forms/database with source 
documents.  The Investigator agrees to accommodate and participate in audits conducted at a 
reasonable time in a reasonable manner, as needed. 
Regulatory authorities may also audit an Investigator during or after the study.  The Investigator should 
contact the Lead PI and designee(s) at the Duke GI Oncology Clinical Trials Office as well as their local 
IRB, immediately if this occurs, and must fully cooperate with governmental (e.g., FDA) audits 
conducted at a reasonable time in a reasonable manner. 
The Duke University Compliance Program - Human Subject Research Compliance (HSRC) section may 
conduct confidential audits to evaluate compliance with the protocol and the principles of GCP.  The 


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Lead PI agrees to allow the HSRC auditor(s) direct access to all relevant documents and to allocate 
his/her time and the time of the study team at the Duke GI Oncology Clinical Trials Office to the CTQA 
auditor(s) in order to discuss findings and any relevant issues. 
11.8 Study Closeout 
Upon completion of the study (defined as all subjects have completed all follow-up visits, all CRFs are 
complete, and all queries have been resolved) the Lead PI or designee(s) at the Duke GI Oncology 
Clinical Trials Office will notify the Investigator of closeout and a study closeout visit will be performed.   
The study monitor or study designee will ensure that the Investigator’s regulatory files are up to date 
and complete, and that any outstanding issues from previous visits have been resolved.  Other issues 
to be reviewed at the closeout visit include: retention of study files, possibility of site audits, publication 
policy, and study closure with local IRB. 
11.9 Records Retention 
The Investigator will maintain the records of study drug disposition, worksheets and all other study-
specific documentation (e.g., study files, source documentation) until notified by the Lead PI or 
designee(s) at the Duke GI Oncology Clinical Trials Office that records may be destroyed.  If the 
application is not filed or is withdrawn, the Investigator will maintain the records for at least two (2) 
years after the formal discontinuation of the clinical development program for this product(s).  
To avoid error, the Investigator will contact the Lead PI or designee(s) at the Duke GI Oncology 
Clinical Trials Office before the destruction of any records pertaining to the study to ensure they no 
longer need to be retained.  In addition, the Lead PI or designee(s) will be contacted if the Investigator 
plans to leave the institution so that arrangements can be made for the transfer of records. 


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12.0 REFERENCES 
 
1. Kamangar, F., G. M. Dores, et al. (2006). "Patterns of cancer incidence, mortality, and prevalence across 
five continents: defining priorities to reduce cancer disparities in different geographic regions of the world." J 
Clin Oncol 24(14): 2137-2150. 
2. Altekruse, S., C. Kosary, et al. (2010). SEER Cancer Statistics Review, 1975-2007.  
 
Bethesda, MD, National Cancer Institute. 
3. Glimelius, B., K. Ekstrom, et al. (1997). "Randomized comparison between chemotherapy plus best 
supportive care with best supportive care in advanced gastric cancer." Ann Oncol 8(2): 163-168. 
4. Cutsem, E. V., Y. Kang, et al. (2009). Efficacy results from the ToGA trial: A phase III study of trastuzumab 
added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-
positive advanced gastric cancer (GC). ASCO Annual Meeting. Orlando, FL, J Clin Oncol. 27: suppl; abstr 
LBA4509. 
5. Kang, Y., A. Ohtsu, et al. (2010). AVAGAST: A randomized, double-blind, placebo- 
 
controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients 
with advanced gastric cancer (AGC). ASCO Annual Meeting. Chicago, IL, J Clin Oncol. 28: suppl; abstr 
LBA4007. 
6. Van Cutsem, E., V. M. Moiseyenko, et al. (2006). "Phase III study of docetaxel and cisplatin plus fluorouracil 
compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the 
V325 Study Group." J Clin Oncol 24(31): 4991-4997. 
7. Wagner, A. D., W. Grothe, et al. (2006). "Chemotherapy in advanced gastric cancer: a  
 
systematic review and meta-analysis based on aggregate data." J Clin Oncol 24(18): 2903-2909. 
8. Cunningham, D., N. Starling, et al. (2008). "Capecitabine and oxaliplatin for advanced  
 
esophagogastric cancer." N Engl J Med 358(1): 36-46. 
9. Saito H, Kuroda H, Matsunaga T, Osaki T, Ikeguchi M. (2013).  "Increased PD-1 expression on CD4+ and 
CD8+ T cells is involved in immune evasion in gastric cancer."J Surg Oncol 107(5):517-22. 
10. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with 
advanced cancer. N Engl J Med. Jun 28 2012;366(26):2455-2465. 
11. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells 
as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 
Apr 2005;54(4):307-314. 
12. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol. 2008;26:677-704. 
13. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on 
implications for chronic infections and tumor evasion. Cancer Immunol Immunother. May 2007;56(5):739-
745. 
14. Exolatin(R) [package insert]. Sanofi-aventis U.S. LLC., Bridgewater, NJ; October 2015. 
http://pi.lilly.com/us/byetta-pi.pdf. Accessed January 4, 2017. 
15. Xeloda(R) [package insert]. Hoffmann-La Roche, Inc., San Francisco, CA; December 2016. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020896s039lbl.pdf. Accessed January 4, 2017. 
16. Muro, K., Chung, H. C., et al. (2016). Pembrolizumab for patients with PD-L1-positive advanced gastric 
cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. The Lancet Oncology, 17(6), 717-726. 
17. NCCN Guidelines National Comprehensive Cancer Network.  Bone Cancer (Version I -  March 21, 2017). 
https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf.  Accessed April 5, 2017. 
18. Al-Batran, Salah-Eddin, et al. "Phase III trial in metastatic gastroesophageal adenocarcinoma with 
fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische 
Onkologie." Journal of Clinical Oncology 26.9 (2008): 1435-1442. 
19. Enzinger, Peter C., et al. "CALGB 80403 (Alliance)/E1206: A randomized phase II study of three 
chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers." 
Journal of Clinical Oncology 34.23 (2016): 2736-2742. 
20. Kim, Gun Min, et al. "A randomized phase II trial of S-1-oxaliplatin versus capecitabine–oxaliplatin in 
advanced gastric cancer." European Journal of Cancer 48.4 (2012): 518-526. 
21. Cunningham, David, et al. "Capecitabine and oxaliplatin for advanced esophagogastric cancer." New 
England Journal of Medicine 358.1 (2008): 36-46. 
22. A Study to Evaluate the Efficacy and Safety of Trastuzumab in Combination With Capecitabine and 
Oxaliplatin as First-line Chemotherapy for Inoperable, Locally Advanced or Recurrent and/or Metastatic  


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23. Gastric Cancer https://clinicaltrials.gov/ct2/show/NCT01364493 
24. Phase 3 Study of Xelox Followed by Maintenance Capecitabine in the Advanced Gastric Cancer 
https://clinicaltrials.gov/ct2/show/NCT02289547?term=capecitabine+oxaliplatin+gastric&recr=Open&rank=1
1 
25. Chemotherapy Options for the First Line Chemotherapy in Elderly Patient With Advanced Gastric Cancer 
https://clinicaltrials.gov/ct2/show/NCT02114359?term=capecitabine+oxaliplatin+gastric&recr=Open&rank=3
6 
26. Study of Oxaliplatin and Xeloda and Cetuximab as First Line Treatment for Metastatic or Unresectable 
Gastric or Gastroesophageal Junction Cancer https://clinicaltrials.gov/ct2/show/NCT00183898 
27. A Study of Pazopanib With CAPEOX in AGC Patients https://clinicaltrials.gov/ct2/show/NCT01130805 
28. Wang, Weiwei, et al. "Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades 
reduced tumor burden in colorectal cancer animal model." Biochemical and Biophysical Research 
Communications (2016). 
29. Hato, Stanleyson V., et al. "Molecular pathways: the immunogenic effects of platinum-based 
chemotherapeutics." Clinical Cancer Research 20.11 (2014): 2831-2837. 
30. Hirsch, Bradford R., and S. Yousuf Zafar. "Capecitabine in the management of colorectal cancer." Cancer 
Manag Res 3 (2011): 79-89. 
31. Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of 
fluoropyrimidines. J Clin Oncol. 2008;26(13):2118–2123. 
32. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine 
regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the 
TREE Study. J Clin Oncol. 2008;26(21):3523–3529.  
 
 
 


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Appendix A.  RECIST 1.1 
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. 
*E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. 
Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
Definitions 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Changes 
in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. Note: Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it does not 
provide additional meaning or accuracy. 
 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
 
 
10mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10mm)  
 
10mm caliper measurement by clinical exam (when superficial)  
 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung)  
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15mm 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 to <15 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques are all non-
measurable. 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 


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Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 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 organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be 
axial, saggital or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20mm x 30mm has a short axis of 20mm and qualifies 
as a malignant, measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 mm) should be 
considered non-target lesions. Nodes that have a short axis <10mm are considered non-
pathological and should not be recorded or followed. 
 
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 as noted above, 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 pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).  
 
Guidelines for Evaluation of Measurable Disease 


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All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
>10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at the 
end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung.  
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure from CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to be 
considered in complete response. Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup has 
developed CA125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer. 
 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, 


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where known residual benign tumors can remain). When effusions are known to be a potential 
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or stable 
disease in order to differentiate between response (or stable disease) and progressive disease. 
 
Response Criteria 
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 diameters of target lesions, 
taking as reference the baseline sum diameters.  
 
Progressive Disease (PD): At least a 20% increase in the sum of 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 progression).  
 
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.  
 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of <10 mm. Case report forms 
or other data collection methods may therefore be designed to have target nodal lesions recorded 
in a separate section where, in order to qualify for CR, each node must achieve a short axis <10 
mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included in the 
sum of target lesions. 
 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes which 
are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being ‘too small to measure’. 
When this occurs it is important that a value be recorded on the case report form.  If it is the opinion 
of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 
0mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded by fat such as 
in the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as well). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm. 
 


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Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’. 
 
Evaluation of Non-target Lesions   
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.  
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis).  
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).  
 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size 
of one or more non-target lesions is usually not sufficient to quality for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
 
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concept apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions are 
truly non-measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: i.e. an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic 
disease from localized to widespread, or may be described in protocols as ‘sufficient to require a 
change in therapy’. If ‘unequivocal progression’ is seen, the patient should be considered to have 
had overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so, therefore the 
increase must be substantial. 
 
New Lesions  
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not 
attributable to differences in scanning technique, change in imaging modality or findings thought to 
represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 


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lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.  
 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
 
 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
 
No FDG-PET at baseline and a positive FDG-PET at follow- up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, 
the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-
PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a response 
may not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response. Protocols must specify 
how any new therapy introduced before progression will affect best response designation. The 
patient’s best overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement. Specifically, in non-randomised trials where response is the primary 
endpoint, confirmation of PR or CR is needed to deem either one the “best overall response.”  
The best overall response is determined once all the data for the patient is known. Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment has 
a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-up 
after the first SD assessment would be considered inevaluable. 


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Appendix B.  Immune-Related Response Criteria 
 
The immune related response criteria* (irRC) has been developed to adequately characterize 
additional patterns of response and progression specific to patients treated with immunotherapy, that 
cannot be captured by the conventional criteria such as such as Response Evaluation Criteria in Solid 
Tumors (RECIST). 
 
*Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, 
Hodi FS. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. 
Clin Cancer Res. 2009;15(23):7412–7420. 
 
 
Antitumor response based on total measurable tumor burden.  
 
For the irRC, only index and measurable new lesions are taken into account (in contrast to 
conventional WHO criteria, which do not require the measurement of new lesions, nor do they 
include new lesion measurements in the characterization of evolving tumor burden). At the baseline 
tumor assessment, the sum of the products of the two largest perpendicular diameters (SPD) of all 
index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous index lesions) is 
calculated. At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (≥5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 
visceral lesions) are added together to provide the total tumor burden: 
 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
 
Time-point response assessment using irRC.   
 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the change in 
tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to 
baseline measurements (i.e., the SPD of all index lesions at screening). 
 
Overall response using the irRC.  
 
The overall response according to the irRC is derived from time-point response assessments 
(based on tumor burden) as follows:  
 
 
irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions) 
– 
confirmation by a repeat, consecutive assessment no less than 4 wk from the date first 
documented  
 
 
irPR, decrease in tumor burden ≥50%relative to baseline  
– 
confirmed by a consecutive assessment at least 4 wk after first documentation  
 
 
irSD, not meeting criteria for irCR or irPR, in absence of irPD  
 
 
irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) 
– 
confirmation by a repeat, consecutive assessment no less than 4 wk from the date first 
documented     
 


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Appendix C.  ECOG Performance Status 
 
The ECOG Scale of Performance Status, developed by the Eastern Cooperative Oncology Group, 
Robert L. Comis, MD, Group Chair*, describes a patient’s level of functioning in terms of their ability to 
care for themself, daily activity, and physical ability (walking, working, etc.). 
 
*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. 
 
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. 
 
 
 


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Appendix D.  Study Calendar 
 
Study Procedures 
Screening Period1 
Treatment Period2 
Follow-up Period3 
Days -28 to -1 
Day 125 
Weekly 
C1 Only  
Every 3 
cycles (+/-1 
week)21 
30 (±7) 
Days22  
Long     
Term 
Informed Consent 
X4 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical and Cancer History 
X 
 
 
 
 
 
Concomitant Medications 
X 
X --- (throughout study5) --- X    
 
Physical Examination 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
Vital Signs and Weight6 
X 
X 
X 
 
X 
 
ECOG Performance Status7 
X 
X 
X 
 
X 
 
CBC with Differential 
X8 
X10 
X 
 
X 
 
Chemistries including LFTs 
X8 
X10 
X 
 
X 
 
Thyroid Function Tests 
X 
 
 
X 
X 
 
Serum Pregnancy Test9 
X8, 9 
X26 
 
X9 
X9 
 
Pembrolizumab 
 
X11 
 
 
 
 
Oxaliplatin 
 
X12 
 
 
 
 
Capecitabine 
 
X13 
 
 
 
 
Adverse Event Assessment 
X 
X --- (throughout study 5) --- X    
 
Tumor Assessment14 
X 
 
 
X 
 
X23 
Blood Tumor Markers15  
X 
 
 
X 
 
X23 
Archived Tumor Tissue16 
X16 
 
 
 
 
X16 
Tumor Biopsy17 
X17 
 
X17 
 
 
 
PBMC18 
X18 
 
 
X18 
X18 
X27 
Plasma19 
X19 
 
 
X19 
X19 
X27 
Whole Blood20 
X20 
 
 
 
 
 
Survival 
 
 
 
 
 
X24 
 
1. 
Refer to Section 5.1. 
2. 
Refer to Section 5.2. Cycle length is 21 days. However, for dose expansion cohort, the first cycle (ie. biomarker cycle) is 28 days in 
length and subsequent cycles are 21 days in length. Visits for each cycle are Day 1 except for Cycle 1 when visits are weekly (ie. 
C1D8, C1D15 and for dose expansion cohort only, C1D22) and as clinically indicated. 
3. 
Refer to Section 5.3.    
4. 
May be completed more than 28 days prior to Cycle 1 Day 1. 
5. 
Document this data throughout study when changes or events occur. 
6. 
Obtain temperature (OC), blood pressure, heart rate, and weight (kg). 
7. 
At screening, obtain within 7 days to first dose of study treatment. Refer to Appendix C.  
8. 
Must perform within 7 days prior to Cycle 1 Day 1.  If completed within 7 days of Cycle 1 Day 1, no need to repeat.  If repeated on 
Cycle 1 Day 1, must wait for results to confirm eligibility prior to starting study drug.  
9. 
Only for women of childbearing potential. 
10. After Cycle 1, may perform up to 3 days prior to Day 1.   
11. Pembrolizumab (see Section 6.2) is administered on Day 1 of each cycle.   
12. Oxaliplatin (see Section 6.3) is administered on Day 1 of each cycle except for first cycle (ie. biomarker) cycle of dose expansion cohort 
only when administered on Day 8 (ie. pembrolizumab monotherapy lead-in period). 
13. Capecitabine (see Section 6.4) is taken on Days 1-14 of each cycle except for first cycle (ie. biomarker) cycle of dose expansion cohort 
only when taken on Days 8-22 (ie. pembrolizumab monotherapy lead-in period). 
14. Radiographic assessments (ie. restaging scans) include CT and/or MRI of chest, abdomen and pelvis after every 3 cycles (9 weeks). 
Same method for tumor assessment should be employed at every assessment.   
15. If clinically indicated (ex. CEA and/or CA19-9). 
16. If FFPE tumor tissue is available, refer to Section 8.1 and Study Manual. 


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17. For patients accrued to the dose expansion cohort with tumor lesion that is amenable to safe biopsy, pre-treatment (up to 1 week prior 
to pembrolizumab monotherapy lead-in) and on-treatment (C1 D7 or D8, prior to oxaliplatin and capecitabine/end of one week 
pembrolizumab monotherapy lead-in in Cycle 1) tumor biopsies will be performed in the first cycle (ie. biomarker cycle).  Refer to 
Section 8.1 and Study Manual. 
18. Peripheral blood collection for PBMCs (see Section 8.2 and Study Manual) at the following time points: baseline (may be obtained on 
Cycle 1 Day 1 prior to the first dose of study drug); end of monotherapy lead-in on Day 8 (biomarker cycle of dose expansion cohort 
only), end of first cycle of combination therapy on Day 29 (biomarker cycle of dose expansion cohort only), first restaging only (ie. after 
Cycle 3), and disease progression or treatment discontinuation. Note – There is no PBMC collection at 30-day off treatment follow-up.  
19. Peripheral blood collection for plasma (see Section 8.3 and Study Manual) at the following time points: baseline (may be obtained on 
Cycle 1 Day 1 prior to the first dose of study drug); end of monotherapy lead-in on Day 8 (biomarker cycle of dose expansion cohort 
only), end of first cycle of combination therapy on Day 29 (biomarker cycle of dose expansion cohort only), each restaging, disease 
progression or treatment discontinuation and 30-day off treatment follow-up. 
20. Peripheral blood collection for whole blood (see Section 8.4 and Study Manual at the following time point: baseline (may be obtained 
on Cycle 1 Day 1 prior to the first dose of study drug). 
21. After every 3 cycles. 
22. After the last dose of study drug.  
23. Subjects discontinued from study treatment with no documented disease progression and no subsequent anti-cancer treatment should 
have disease status and blood tumor markers (if clinically indicated) followed per standard of care schedule until disease progression 
or start of new anti-cancer treatment regimen is documented.  Disease status may be collected by personal interviews or review of 
medical records. 
24. Subjects are followed for survival up to 3 years after the last subject starts the study drug regimen or until the study is closed 
(whichever comes first).  Survival status may be collected by personal interviews or review of medical or public records. 
25. Treatment visits may occur within +/-3 days of D1 for C2 and all subsequent cycles. 
26. Cycle 1 day 1 only. After that, will redo at restaging visits.  
27. Only for subjects who achieved a complete response and have consented to the additional collection. 
 
 


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Appendix E. Laboratory Tests 
 
CBC with differential  
 
hematocrit  
 
hemoglobin 
 
platelet count 
 
WBC (total and differential) 
 
red blood cell (RBC) count 
 
 
absolute neutrophil count 
 
absolute lymphocyte count 
Chemistries with liver function tests (LFTs) 
 
albumin 
 
alkaline phosphatase (ALP) 
 
ALT 
 
AST 
 
Bicarbonate 
 
blood urea nitrogen (BUN) 
 
chloride 
 
creatinine 
 
glucose 
 
calcium 
 
potassium 
 
sodium 
 
total bilirubin 
 
total protein 
 
Thyroid Function Tests 
 
thyroid stimulating hormone 
(TSH) 
 
total thriiodothyronine (T3) 
 
 
free tyroxine (T4) 
Pregnancy Test 
 
serum β-HCG pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
 
 
 
 
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine 
in the First Line Treatment of Patients with Gastro-esophageal Cancer 
(KeyLARGO) 
 
 
Trial: NCT03342937 
 
 
Duke University Main Consent Form (May 18, 2020) 
Duke University Consent Addendum (January 9, 2023) 
 


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 1 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You are being asked to take part in this research study because you have adenocarcinoma of the 
esophagus or stomach.  Research studies are voluntary and include only people who choose to take part.  
Please read this consent form carefully and take your time making your decision. As your study doctor 
or study staff discusses this consent form with you, please ask him/her to explain any words or 
information that you do not clearly understand.  We encourage you to talk with your family and friends 
before you decide to take part in this research study.  The nature of the study, risks, inconveniences, 
discomforts, and other important information about the study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. Hope Uronis will conduct this Duke Cancer Institute study and it is funded by Merck & Co.  The 
supporting company for this study, Merck & Co., will pay Duke University to perform this research, and 
these funds may reimburse part of Dr. Uronis’ salary. One of the doctors working on this study, Dr. 
Michael Morse, receives personal compensation from Merck for consulting work.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. Uronis will be your doctor for the study and will be in contact with your 
regular health care provider throughout the time that you are in the study and afterwards, if needed.
Concise Summary
The purpose of this study is to assess the safety, tolerability, and efficacy of the combination of 
pembrolizumab, oxaliplatin and capecitabine in patients with previously untreated metastatic 
esophagogastric adenocarcinoma.
The study will be conducted in two stages: 1) safety validation and 2) dose expansion.  During 
the Study Drug Period, subjects will receive pembrolizumab and oxaliplatin intravenously (into 
your vein) on Day 1 and capecitabine orally (by mouth) on Days 1-14 of each 21-day cycle until: 
1) disease progression; 2) the occurrence of unacceptable treatment-related toxicity; or 3) other 
reason(s) for subject discontinuation. Your study drug regimen may last for up to 35 cycles 
(about 2 years).
Throughout the study you will have tests, exams and procedures as part of your standard of care 
as well as for study purposes. There are risks that may be associated with the use of the study 
drugs that are described in this document. Some of these risks include skin conditions, mouth 
sores, loose stool, changes to blood cells that fight infection and clot the blood, cough, nausea, 
vomiting and other possible side effects that could be serious and potentially life-threatening.
If you are interested in learning more about this study, please continue to read below.
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 2 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to find out what effects, good and/or bad, the combination of 
Pembrolizumab, Oxaliplatin, and Capecitabine has on you and your gastro-esophageal cancer.
HOW DO THESE DRUGS WORK?

Pembrolizumab (KEYTRUDA) is a drug that is given through a vein (intravenous, or I.V.) that 
targets a factor called “PD-1”. By blocking the interaction between PD-1 and its targets, PD-L1 
and PD-L2, it allows your immune system to attack your cancer more effectively. 
Pembrolizumab is FDA approved for indications including metastatic melanoma, advanced non-
small cell lung cancer, metastatic head and neck cancer, classical Hodgkin Lymphoma, urothelial 
carcinoma, and MSI-H or mismatch repair deficient solid tumors that have progressed following 
prior treatment, and in gastric and gastroesophageal junction (GEJ) adenocarcinoma whose 
tumors express PD-L1. However, pembrolizumab used in combination with other study drugs for 
(previously untreated) gastric and esophageal cancer is considered investigational. The word 
“investigational” means the study drugs are being tested in research studies and not approved by 
the U.S. Food and Drug Administration (FDA).

Oxaliplatin is a platinum-based anti-cancer agent given by infusion into the vein (IV), that 
inhibits tumor cell growth and replication. It is approved by the FDA for use in colorectal cancer. 
Its use in gastric and esophageal cancers is investigational. 

Capecitabine is an oral chemotherapy drug that works by damaging cancer cells, which causes 
them to grow more slowly and die. It is approved by the FDA for use in colorectal and breast 
cancers. Its use in gastric and esophageal cancers is investigational.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 50 people will take part in this study at Duke, and sites within the Duke Cancer 
Network. 
WHAT IS INVOLVED IN THE STUDY?
This study will involve the collection of the following research samples:
Blood 
Blood collected throughout the study will be used to assess your safety as well as your body’s response 
to the study drugs. This includes routine laboratory blood tests (blood counts, liver and kidney function, 
blood clotting ability, and other safety tests), biomarker (proteins in your blood) assessment, and genetic 
analysis to examine the effects of the study drug(s) on your cancer and your body’s response to the study 
drug(s).  
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 3 of 21                                                  Subject*Initials:______________
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Tumor Tissue
When you were first told you had cancer or at some other time during your illness, you may have had 
surgery or a biopsy to collect tissue containing a sample of your cancer.  Your tissue sample may hold 
important clues that might help researchers understand more about cancer and why people do or do not 
respond to the study drugs.  By signing this consent form, you give permission to obtain these (archived) 
samples for testing if they are available. In addition, a pre-study regimen, and on-study regimen biopsy 
will be taken 1 week before starting the study regimen, and on Day 8 prior to start of oxaliplatin and 
capecitabine study regimen, respectively. Biopsy is the removal of a small piece of your tissue for 
examination.  It can be done with a needle or small surgery, and it is usually done with local anesthesia 
(shots to numb the skin). Your study doctor will discuss with you the safest method and location to 
perform these biopsies.  You will only have biopsies that the study team believes to be not a significant 
risk to you.
Some portion of your archival tissue block and tumor biopsy tissue will be taken for biomarker (proteins 
and genes that tell you about your disease), and genetic analyses.  It may take many years to complete 
this research, so your samples will be stored indefinitely or until they are all used up.  Your tissue 
samples and related medical information will be used only for research and will not be sold.  Your 
samples will not be used for research involving human cloning (growing human tissue from this 
material). Information from this research will be from all the subjects who participate in this study as a 
group, not just from your samples.  You will not be informed of new analyses on retained samples.
Consent for future use of biomarker samples 
If there is any leftover tissue samples from your biopsies or archived tumor, you may opt to allow them 
to be retained for future research. Any unused samples will be stored and used to better understand the 
mechanisms of sensitivity and resistance to pembrolizumab in metastatic gastro-esophageal cancer.
Please initial below with whether you voluntarily agree to give your leftover tissue samples for future 
research
Yes _______ (initials)  No ________ (initials)
Screening:
If you agree to be in this study, you will be asked to sign this consent form.  You will have the following 
tests and procedures to make sure that you are eligible to participate and to ensure that the study drug 
does not pose a special risk to you: 

Physical exam and medical history

Vital signs (breathing rate, heart rate, temperature, blood pressure, height and weight)

Demographics

CT scans or MRI scans for tumor measurement.
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 4 of 21                                                  Subject*Initials:______________
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
Blood will be taken for the following:
o
Routine blood tests – these tests will evaluate blood cell counts, blood chemistry, liver 
and kidney function, thyroid function
o
Blood tumor markers – blood test that can indicate whether your tumor is responding to 
study drug.
o
Blood immune cells (cells that help the body fight infections and cancer) – the levels of 
some type of immune cells may be important in determining who may respond to 
different types of therapy. In this study, pembrolizumab may result in changes in these 
blood immune cells. Some of the blood collected may be used to study the effects of this 
drug on immune cells in order to better understand who might respond and what changes 
we can expect for patients on these therapies.
o
Biomarkers – these are factors in the blood that may help indicate how the study drug  is 
affecting your body
o
Pharmacogenomics – this test will help indicate how your genes affect your response to 
the study drugs by analyzing the genetic changes in your blood and immune cells.
o
If you are a woman able to bear children, you will also have a small blood sample taken 
for a pregnancy test

Tumor tissue – archived tumor from your primary diagnosis will be collected (if available) to be 
used for the following:
o
Biomarker testing and genetic analysis for expression of molecules which may be 
associated with sensitivity or resistance to the study drugs
Study Drugs 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, you 
will be enrolled in the study.
If you are in the Safety Validation group, you will be given pembrolizumab and oxaliplatin into a vein in 
your arm or central line on the first day of every 21 days. Capecitabine will be taken by mouth twice 
daily from Day1 to Day 14 of each 21-day cycle.
If you are in the Dose Expansion group, you will receive only pembrolizumab on the first day of study 
regimen. You will start to receive oxaliplatin and capecitabine on the eighth day of study regimen. The 
capecitabine will be taken by mouth on days 8 to 21, then you will take one week off drug. On day 29 of 
study regimen, you will start to receive pembrolizumab and oxaliplatin on day one of each 21 days and 
capecitabine on days 1 to 14 of each 21 days. This will continue for the duration of your participation in 
the study.
For both groups, pembrolizumab (200 mg) will be given over 30 minutes. Oxaliplatin (130 mg/m2) will 
be given over two hours. The two daily doses of capecitabine should be taken approximately 12 hours 
apart, within 30 minutes after eating and swallowed with approximately one cup of water. You will be 
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 5 of 21                                                  Subject*Initials:______________
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asked to complete a drug diary card each day while taking capecitabine. You will need to bring this drug 
diary with you each time you see your doctor.
For your safety, you will be monitored to be sure any side effects are prevented or minimized. This will 
require regular clinic visits, blood tests, and radiology tests. These tests to check you and your cancer are 
part of your routine care. You will continue to receive study drug until your cancer gets worse or if you 
experience excessive side effects or choose to withdraw from the study.
Assessments During Drug Regimen:
Cycle 1 of Safety Validation Group

Up to 7 days prior to starting study drug:
o
Routine blood tests, including blood cell count and blood chemistry

Day 1
o
Physical exam
o
Vital signs
o
Pembrolizumab administration over 30 minutes
o
Oxaliplatin administration over two hours
o
Begin taking capecitabine twice daily for days 1 to 14

Day 8 and Day 15
o
Physical exam
o
Vital signs
o
Routine blood tests

Day 22
o
Return to your doctor’s office for your next physical exam and to begin the next cycle.
Cycle 1 of Dose Expansion Group

Up to 7 days prior to starting study drug:
o
Routine blood tests, including blood cell count and blood chemistry
o
Urine sample
o
Pre-study regimen tumor biopsy (if amenable to safe biopsy) to be used for the following:

Biomarker testing and genetic analysis for expression of molecules which may be 
associated with sensitivity or resistance to the study drugs

Day 1
o
Physical exam
o
Vital signs
o
Pembrolizumab administration over 30 minutes

Day 8
o
Physical Exam
o
Vital signs
o
Routine blood tests
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 6 of 21                                                  Subject*Initials:______________
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o
Blood immune cells
o
Blood biomarkers
o
On-study regimen tumor biopsy (if amenable to safe biopsy) to be used for the following 
(can be completed on Day 7):

Biomarker testing and genetic analysis for expression of molecules which may be 
associated with sensitivity or resistance to the study drugs
o
Oxaliplatin administration over two hours
o
Begin taking capecitabine twice daily for days 8 to 21

Day 15 and Day 22
o
Physical Exam
o
Vital signs
o
Routine blood tests

Day 29
o
Blood immune cells
o
Blood biomarkers
o
Return to your doctor’s office for your next physical exam and to begin the next cycle.
All Remaining Cycles 

Up to 7 days prior to starting study regimen:
o
Routine blood tests, including blood cell count and blood chemistry

Day 1
o
Physical exam
o
Vital signs
o
Pembrolizumab administration over 30 minutes
o
Oxaliplatin administration over two hours
o
Begin taking capecitabine twice daily for days 1 to 14

Day 22
o
Return to your doctor’s office for your next physical exam and to begin the next cycle.
All Study Groups (Safety Validation and Dose Expansion)

Every 9 weeks (+/- 1 week)
o
Blood test to check thyroid function
o
Pregnancy test for women who are able to bear children
o
CT scan or MRI scan
o
Blood tumor marker test
o
Blood immune cells
o
Blood biomarkers

30 days (+/-7 days) after you stop the study drug regimen
o
Physical exam
o
Vital signs
o
Routine blood tests
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 7 of 21                                                  Subject*Initials:______________
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o
Blood test to check thyroid function
o
Pregnancy test for women who are able to bear children
o
Blood immune cells
o
Blood biomarkers

If you stop study drug regimen, but your disease did not get worse and you did not start new 
treatment
o
CT Scan or MRI scan every 12 weeks or until your disease gets worse
o
Blood tumor markers every 12 weeks or until your disease gets worse
HOW LONG WILL I BE IN THIS STUDY?
You will be asked to take pembrolizumab, oxaliplatin, and capecitabine as long as your disease does not 
get worse and you are able to tolerate the side effects of the study drug regimen. The maximum duration 
to receive pembrolizumab will be up 35 cycles (about 2 years). We would then like to keep track of your 
medical condition for up to 2 years after the last subject starts the study drug regimen (~January 2022) 
or until the study is closed (whichever comes first). We may review your medical record or contact you 
by phone every 12 weeks during this time. Keeping in touch with you and checking on your condition 
helps us look at the long-term effects of the study.
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first.
It is important to tell the study doctor if you are thinking about stopping so any risks from the study 
drugs can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. The study doctor 
may stop you from taking part in this study at any time if she believes it is in your best interest; if you do 
not follow the study rules; or if the study is stopped.
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with the study doctor and your regular health care provider if you choose. All anti-cancer 
treatments, including immune based therapies, may have side effects. Most side effects from the drugs 
used in this study are expected to be mild and reversible. However, side effects may rarely be severe, 
long lasting, and very rarely may even be lethal. Side effects may require additional treatments, 
procedures, hospitalization, or surgery. Because the body’s immune system is so multi-faceted, immune 
related side effects may affect essentially any part of the body. While the lists of side effects below are 
meant to be comprehensive, there can also be side effects not specifically listed or side effects that have 
not been seen before. We cannot predict in advance whether these or other medical problems may occur 
as the combination of oxaliplatin and capecitabine with pembrolizumab has not been tested thoroughly. 
For these reasons, you will be watched closely and you should also let your medical team know right 
away if you have any new problems.
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 8 of 21                                                  Subject*Initials:______________
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Side Effects Associated with PEMBROLIZUMAB:
Pembrolizumab, which is approved in the USA and some other countries, is available by prescription to 
treat several different cancers, but is not approved to treat your type of cancer. Pembrolizumab works by 
helping your immune system to fight your cancer. 
However, pembrolizumab can also cause your immune system to attack normal organs and tissues in 
your body and can affect the way they work, which can result in side effects that may become serious or 
life-threatening, and in some cases, may lead to death. These side effects may occur after stopping the 
drug. These side effects can affect more than one of your normal organs and tissues at the same time.
Very Likely (seen in 20% or more of patients)

Itching of the skin (Pruritus)

Loose or watery stools

Cough
Likely (seen in 5% to 20% of patients)

Joint pain 

Fever

Back pain

Rash

Pain in your belly 

Loss of skin color

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have infrequent or 
hard stools (also called hypothyroidism)

Low levels of salt in the blood that may cause you to feel tired, confused, have a headache, 
muscle cramps and/or feel sick to your stomach (hyponatremia)
Less Likely (seen in 1% to  less than 5% of patients)

Inflammation of the lungs so you may feel short of breath and cough. Sometimes this might lead 
to death (also called pneumonitis)

Too much thyroid hormone so you may feel anxious, angry, unable to sleep, weak, tremble, 
sweat, tired, have loose and watery stools (also called hyperthyroidism)

Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a fever, feel short 
of breath, experience a decrease in your blood pressure at the time of receiving your infusion 
(IV) or just after, or pain at the site of infusion

Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or watery 
stools, and black, tarry, sticky stools or stools with blood or mucus (also called colitis)
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 9 of 21                                                  Subject*Initials:______________
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
Inflammation of the skin so you may have peeling of the skin, itching, and/or skin 
redness. The skin inflammation (such as peeling, itching and redness) could also be 
widespread throughout your body. More severe skin reactions may involve the inside of 
your mouth, the surface of your eye and genital areas, and/or may cause the top layer of 
your skin to peel from all over your body which can cause severe infection(Severe skin 
reactions, including Stevens-Johnson syndrome/or toxic epidermal necrolysis). These 
severe conditions can sometimes lead to death.
Rare but Serious (less than 1% of patients)

Inflammation of the nerves that may cause pain, weakness or tingling in your hands and feet, and 
may spread to your legs, arms and upper body leading to severe muscle weakness and possible 
temporary paralysis (also called Guillain-Barré syndrome)

Inflammation of the muscles so you may feel weak or have pain in your muscles (also called 
myositis)

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you may 
have severe pain in the top part of your belly that may move to your back, feel sick to your 
stomach, and vomiting that gets worse when you eat (also called pancreatitis)

Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to light, eye 
pain, see floaters or have headaches (also called uveitis)

Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like not 
eating, feel tired, have a mild fever, have a pain in the right side of your belly, yellow eyes and 
skin, and dark urine (also called hepatitis)

Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick to 
your stomach or have headaches, changes in your behavior, double vision, few to no menstrual 
cycles, weakness, vomiting and dizziness or fainting (also called hypophysitis)

Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which could 
cause tiredness, weight loss, muscle weakness, feeling faint, joint, muscle and belly aches, 
nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes darkening of the skin 
like a suntan (also called Addison’s Disease)

Type 1 diabetes, a condition that can cause too much sugar in your blood, feeling thirstier than 
usual, frequent urination and weight loss. You are likely to need regular insulin shots.

Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, swelling 
and low back pain (also called nephritis)

Inflammation of the middle layer of your heart wall that may cause your heart to have difficulty 
pumping blood throughout your body, which can cause chest pain, shortness of breath and 
swelling of the legs. You may experience a fast or irregular heartbeat that may cause dizziness or 
fainting. Sometimes this condition can lead to death (also called myocarditis)

Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the rate at 
which food is converted into energy (also called thyroiditis)
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 10 of 21                                                  Subject*Initials:______________
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
A condition that may make you feel weak and tired and may cause drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and legs, 
or difficulty breathing (also called myasthenic syndrome)

The formation of small clusters of immune cells (called granulomas) in parts of your body such 
as your lymph nodes, eyes, skin, or lungs (also called sarcoidosis)

Inflammation of the brain such as confusion and fever. This may also include: disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, 
weakness or loss of movement in some parts of your body, and loss of consciousness (also called 
encephalitis)

Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the arms or legs, 
bladder or bowel problems including needing to urinate more frequently, urinary incontinence, 
difficulty urinating, and constipation (also called myelitis)
In addition to the above, if you have had an allogeneic stem cell transplant (a procedure in which a 
person receives blood-forming stem cells from a donor), you may experience graft versus host disease 
(GvHD), which may include diarrhea, skin rashes, and liver damage, after receiving pembrolizumab. 
Sometimes this condition can lead to death. 
If you have had a solid organ transplant (for example, if you have received a kidney or heart transplant), 
you may experience rejection of the transplanted organ. Your doctor will monitor you and should tell 
you what signs and symptoms you should report depending on the type of organ transplant you have 
had. 
Additionally, since pembrolizumab was approved in September 2014, the following side effects have 
been reported by people receiving pembrolizumab. These side effects were voluntarily reported from a 
group of people of unknown size. It is not possible to estimate the frequency of this side effect:

Inflammation of the joints which may include joint pain, stiffness and or swelling (arthritis).

Severe responses of the immune system that cause the body to attack its own blood cells, spleen, 
liver, lymph nodes, skin and brain. This may include fever, rash, inflammation of the liver, 
yellowing of the skin, an enlarged liver and spleen, low blood counts, and enlarged lymph nodes. 
The nervous system may also be affected and cause confusion, seizures and even coma. 

Changes in eyesight, eye pain, whitish patches on the skin and hearing loss (Vogt-Koyanagi-
Harada syndrome) 
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 11 of 21                                                  Subject*Initials:______________
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Side Effects Associated with OXALIPLATIN:
Very Likely (seen in 20% or more of patients)

Nerve damage that causes abnormal tingling sensation (Peripheral sensory neuropathy)

Decrease in a type of white blood cell called neutrophils (Neutropenia)

Decreased number of blood cells (platelets) that help to clot the blood, which could put you 
at increased risk of bleeding (Thrombocytopenia)

Decrease in red blood cells, which are the oxygen carrying cells, which could make you feel 
tired (Anemia)

Nausea

Abnormal liver function tests, which may indicate that your liver is not functioning properly 
(Increase in transaminases and alkaline phosphatase)

Diarrhea

Vomiting (Emesis)

Fatigue

Inflammation of the mouth, tongue, lips or throat (Stomatitis)

Fever

Constipation

Alteration in taste (Dysgeusia) 
Less Likely (seen in less than 20% of patients)

Cough

Trouble breathing (Dyspnea)

Nosebleed (Epistaxis)

Headache

Rash

Weight loss
Rare but Serious (seen in less than 3% of patients)

Serious allergic reactions, including anaphylaxis, that may be fatal. 

Rare event characterized by headache, confusion, seizures, high blood pressure and changes 
in vision (Reversible Posterior Leukoencephalopathy Syndrome)

Damage to lung tissue (Pulmonary fibrosis)

Abnormal heart rhythm that causes fast, chaotic heartbeats (QT prolongation)

Damage to muscle tissue that causes damage to the kidneys (Rhabdomyolysis) 
Side Effects Associated with CAPECITABINE:
Very Likely (seen in 20% or more of patients)
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 12 of 21                                                  Subject*Initials:______________
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
Loose stools (Diarrhea) 

Inflammation and/or sores in the mouth that may make swallowing difficult and are painful 
(Mucositis)

Feeling sick to your stomach (Nausea)

Redness or sores of the palms of the hands or soles of the feet (Palmar-plantar 
erythrodysesthesia- “hand-foot syndrome”) 

Dry skin (Xerosis)

Itching sensation (Pruitis)
Likely risks (seen in less than 20% of patients)

Decrease in red blood cells, which are the oxygen carrying cells, which could make you feel tired 
(Anemia)

Decreased white blood cells, which are the infection fighting cells, which could put you at risk 
for infection (Leukopenia)

Decreased number of blood cells (platelets) that help to clot the blood, which could put you at 
increased risk of bleeding (Thrombocytopenia)

Throwing up (Vomiting) 

Stomach or abdominal pain

Loss of appetite, not feeling hungry (Anorexia)

Difficulty passing stools (Constipation)

Heart burn (Dyspepsia)

Feeling tired (Fatigue)

Generalized weakness and loss of strength (Asthenia)

Hair loss (Alopecia)

Rash

Red, sore eyes

Fever (Pyrexia)

Sensation of lightheadedness, dizziness, or spinning sensation (Vertigo)

Headache

Pain, including joint (arthralgia), muscle (myalgia), or bone. 

Infection 
Rare but Serious (seen in less than 3% of patients)

Blood clots and/or bleeding

Excessive or abnormal loss of body fluids (Dehydration)

Abnormal liver function tests,which may indicate that your liver is not functioning properly

Lack of oxygen to the heart muscle which can cause damage to the heart (Heart attack)

Abnormal heartbeat (Arrhythmia) 
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 13 of 21                                                  Subject*Initials:______________
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For Those of Reproductive Potential:
 
Female
Being a part of this study while pregnant may expose the unborn child to significant risks, some of 
which may be currently unforeseeable.  Therefore, pregnant women will be excluded from the study.  If 
you are a woman of childbearing potential, a blood pregnancy test will be done (using 1 teaspoon of 
blood drawn from a vein by needle-stick), and it must be negative before you can continue in this study.  
If sexually active, you must agree to use appropriate contraceptive measures for the duration of the study 
and for 120 days afterwards. Medically acceptable contraceptives include: (1) surgical sterilization (such 
as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, 
patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a 
spermicide, or (4) an intrauterine device (IUD). Contraceptive measures such as Plan B (TM), sold for 
emergency use after unprotected sex, are not acceptable methods for routine use.  If you do become 
pregnant during this study or if you have unprotected sex, you must inform your study physician 
immediately.
Male
Your participation in this research may damage your sperm, which could cause harm to a child that you 
may father while on this study.  Such harm may be currently unforeseeable.  If you are sexually active, 
you must agree to use a medically acceptable form of birth control in order to be in this study and for 
120 days afterward. Medically acceptable contraceptives include: (1) surgical sterilization (such as a 
vasectomy), or (2) a condom used with a spermicide.  Contraceptive measures such as Plan B (TM), sold 
for emergency use after unprotected sex, are not acceptable methods for routine use. You should inform 
your partner of the potential for harm to an unborn child.  She should know that if pregnancy occurs, 
you will need to report it to the study doctor, and she should promptly notify her doctor.
Risks of Drawing Blood: 
Risks associated with drawing blood from your arm include momentary discomfort and/or bruising.  
Infection, excess bleeding, clotting, or fainting are also possible, although unlikely.
Risk of CT Scan: 
Computed Tomography (CT) is a way to make x-ray images of the inside of the body. The CT scanner is 
a doughnut-shaped machine that uses x-rays to create computer pictures that show structures inside your 
body more clearly than regular x-ray pictures. During the procedure, a technologist will take you into the 
CT scan room where you will lie down on the subject table (usually on your back) inside of the CT 
machine. You should get comfortable because it is very important that you not move during certain parts 
of the test.
CT examinations differ depending on the part of your body being studied. For example, if your abdomen 
is being studied, a series of pictures will be taken from your lower chest to your lower pelvis. During the 
study, you will be asked to hold your breath so that the pictures will not be blurred. The machine will 
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 14 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
make some noise, and the table will move during the scan. Also, you may receive signals from the 
technologist or from the machine about your breathing. Before or during the study, you may be given an 
injection of contrast liquid in your vein to allow the radiologist to obtain clearer images of your organs. 
If you have any discomfort during the test or after the injection, be sure to tell the technologist. 
Risk of MRI Scan:
Magnetic resonance imaging (MRI) uses a magnet and radio waves to make diagnostic medical images 
of the body. There have been no ill effects reported from exposure to the magnetism or radio waves used 
in this test. However, it is possible that harmful effects could be recognized in the future. A known risk 
is that the magnet could attract certain kinds of metal. Therefore, we will carefully ask you about metal 
within your body (this includes certain dyes found in tattoos). If there is any question about potentially 
hazardous metal within your body, you will be excluded from participation in this research study. We 
will also keep the examining room locked so that no one carrying metal objects can enter while you are 
in the scanner. 
The study involves entering a large room in which a magnet is present. You will be placed on a narrow 
bed and then slid into a small tunnel approximately 6 feet in length and 25 inches in diameter. You will 
be asked to lie still for about one hour on this bed. You will hear a loud machine-like noise. You may be 
asked to have a harmless monitoring device applied during the study. During the study, you can have 
voice contact and physical contact with someone in attendance if you desire. 
Risks of Radiation:
You will have a number of CT scans or MRI scans that are part of the regular care for your condition, 
and you would have them whether or not you participate in this research. These studies will not add to 
the risk due to participating in the research. However, if you have concerns about the overall radiation 
exposure or MRI safety issue, you should discuss them with your physician. 
Sometimes subjects have allergic reactions to the dyes used in imaging scans. This is rare. It can involve 
itching or rash. In severe cases, you may have difficulty breathing and dangerous lowering of your blood 
pressure. If you know that you have an allergy to the dye, or to iodine or shellfish, please let your study 
doctor and radiologist know.
Risks of Core Needle Biopsy:
You may experience pain from this procedure that could also include bruising, soreness or scarring at 
the biopsy site. Rarely, a subject may experience infection and/or internal bleeding,depending on the 
location of the biopsy. The biopsy procedure is usually performed while the patient is under local 
anesthesia (for example lidocaine), meaning that the skin site where the needle will be inserted is 
numbed. Side effects from the local anesthesia are rare but may include convulsions or seizures, 
breathing problems, chest pain, rapid heart rate, irregular heartbeat, dizziness, bluish lips and fingernails, 
drowsiness, headache, itching, nausea and/or vomiting, raised red swellings on the skin, lips, tongue, or 
in the throat, restlessness, unusual tiredness or weakness, back pain, difficulty in opening the mouth, 
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 15 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
inability to hold bowel movement and/or urine, loss of sexual function, temporary paralysis (loss of 
function) of legs, persistent or prolonged numbness or tingling (“pins and needles” sensations) of lips 
and mouth, and shivering.
Imaging equipment may be used to guide the needle to the desired site. This may involve ultrasound or 
CT. If CT is used, a subject will be exposed to a small dose of radiation. In addition, a patient may be 
injected with a contrast dye (for example iodine). This may cause some side effects including hives, 
itching, lightheadedness, nausea and a metallic taste in the mouth. Rarely, the iodine may result in a 
severe allergic reaction, including shock, very low blood pressure and cardiac arrest. 
Drug and Food Interactions: 
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 
taking before you start the study and before starting to take any of these products while you are on the 
study.
Potential Risks of Genetic Testing and the Genetic Information Non-Discrimination Act (GINA):
There is a potential risk of loss of confidentiality. Every effort will be made to protect your confidential 
information, but this cannot be guaranteed. The genetic information obtained as a result of your 
participation in this research will not be included in your medical record. Information from which you 
may be personally identified will be maintained in a confidential, secure location at DUHS, accessible 
only by authorized members of the study team, and will not be disclosed to third parties except as 
described in this consent form, with your permission, or as may be required by law. 
The Genetic Information Nondiscrimination Act (GINA) is a Federal law that will protect you in the 
following ways:
-Health insurance companies and group plans may not request genetic information from this research; 
-Health insurance companies and group plans may not use your genetic information when making 
decisions regarding your eligibility or premiums;
-Employers with 15 or more employees may not use your genetic information when making a decision 
to hire, promote, or fire you or when setting the terms of your employment.
There may be risks, discomforts, drug interactions or side effects that are not yet known.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, the investigational study drug regimen may help control your 
cancer. This may or may not make you feel better or live longer. We hope that in the future the 
information learned from this study will benefit other people with your condition.  
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY?
Your other choices may include the following:
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 16 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345

Getting treatment or care for your cancer without being in a study

Depending on the therapies that you have already received, there may be other potentially 
beneficial approved treatments available for your cancer. These treatments may shrink tumors, 
delay progression of cancer, provide symptom relief, or prolong your life and could include 
chemotherapy (for example, platinum-based chemotherapy) or drugs that target a specific 
abnormality in some cancers. You should discuss these options with your doctor.

Taking part in another study

Getting no treatment

Getting comfort care (also called palliative care) only. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by the cancer. It does not treat the 
cancer directly.
Talk to your doctor about your choices, including the risks and benefits of each choice, before you 
decide if you will take part in this study.
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
As part of the study, results of your study-related laboratory tests, x-rays, and procedures may be 
reported to Merck & Co. and its affiliates. In addition, your records may be reviewed in order to meet 
federal or state regulations.  Reviewers may include representatives from the Food and Drug 
Administration, representatives of the Office of Human Research Protection, representatives of the 
Department of Health and Human Services, representatives of the National Institutes of Health, 
representatives of Merck & Co (affiliates, collaborators, licensees, auditors, monitors), the Duke Cancer 
Institute, Duke Office of Audit, Risk, and Compliance, and the Duke University Health System 
Institutional Review Board.  If any of these groups review your research record, they may also need to 
review your entire medical record.
The supporting company (Merck & Co.) and those working for Merck, which may include affiliates, 
may use health data sent to them:

To see if the study drug works and is safe;

To compare the study drug to other drugs;

For other activities (such as development and regulatory) related to the study drug
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 17 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
For these uses, the supporting company may share this health data with others involved in these 
activities, as long as they agree to only use the health data as described here. Once the research team 
shares health data about you with others, it may no longer be covered by the federal privacy regulations. 
As part of this study, you will be asked to have certain tests and/or procedures performed. Some of these 
tests and/or procedures would have been done as part of your regular care. The study doctor will use 
these test results both to treat you and to complete this research.  These test results will be recorded in 
your medical record and will be reported to the research data office at Duke and representatives and 
affiliates of Merck & Co. Results of tests and studies done solely for this research study and not as part 
of your regular care will not be included in your medical record.
The study results will be retained in your research records for 6 years after the study ends.  At that time 
either the research information not already in your medical record may be destroyed or information 
identifying you will be removed from such study results at DUHS.  Any research information in your 
medical record will be kept indefinitely.
This information may be further disclosed by the funding company of this study.  If disclosed, the 
information is no longer covered by federal privacy regulations.
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by federal privacy regulations.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
WHAT ARE THE COSTS?
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 18 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
study with Dr. Uronis.  At your request, a Financial Counselor in the clinic may provide you with an 
estimate of costs for routine services.
Merck & Co., has agreed to pay for services and procedures that are done solely for research purposes.  
Please talk with the PI/study team about the specific services and procedures that the sponsor will pay 
for, and the ones for which you or your insurance will be responsible.
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately.  If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he/she can help find a resolution.
Merck & Co. will provide the pembrolizumab free of charge to you.  The cost of the pembrolizumab 
infusion, as well as the oxaliplatin and capecitabine, will be billed to you or your insurance. There will 
be no charges for research related visits, tests, or procedures. The physical examinations, radiographic 
evaluations (CT scans or MRI), and diagnostic procedures are considered part of the standard care for 
patients with your disease. The costs associated with each test will be charged to you or your insurance 
provider in the same manner as if you were not part of this research study. Therefore, you or your 
insurance provider will need to assume responsibility for these costs. You will be billed for all costs or 
co-payments that are not paid by your insurance provider.  Your study doctor may request that you 
return for a checkup before you stop your study drug/biologic if he/she thinks that stopping it suddenly 
may harm you and may ask you to complete the tests that would ordinarily occur when a person 
completes the study.
WHAT ABOUT COMPENSATION?
You will not be paid for participating in this study.
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., your Duke physicians, or the study supporter, 
Merck Sharp & Dohme Corp., to provide monetary compensation or free medical care to you in the 
event of a study-related injury.
For questions about the study or research-related injury, contact Dr. Uronis at (919) 668-1861 during 
regular business hours. After hours and on weekends and holidays, please call the Duke paging operator 
at (919) 684-8111, and ask the operator to page Dr. Uronis.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
Participation in this study is voluntary. You are free to withdraw your consent and to discontinue 
participation in the study at any time.
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 19 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
If you withdraw from the study, no new data about you will be collected for study purposes unless the 
data concern an adverse event (a bad effect) related to the study. If such an adverse event occurs, we 
may need to review your entire medical record. All data that have already been collected for study 
purposes, and any new information about an adverse event related to the study, will be sent to Merck.
If you decide to participate, you will be told of any important new information learned during the course 
of this research study that might affect your condition or your health, welfare, or willingness to stay in 
this study. If you agree to continue participation, you will be asked to sign an updated consent form.
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke. If you do 
decide to withdraw, we ask that you contact Dr. Uronis in writing and let her know that you are 
withdrawing from the study. Her mailing address is:
c/o Duke University Medical Center
Protocol Office
DUMC Box 2823
Durham, NC 27710
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.  The 
sponsor or regulatory agencies may stop this study at anytime without your consent. If this occurs, you 
will be notified and your study doctor will discuss other options with you.
We will tell you about new clinically relevant information that may affect your health, welfare, or 
willingness to stay in this study.
Your samples and/or data may be stored and shared for future research without additional informed 
consent if identifiable private information, such as your name and medical record number, are removed. 
If your identifying information is removed from your samples or data, we will no longer be able to 
identify and destroy them.
The use of your data and samples may result in commercial profit. You will not be compensated for the 
use of your data and samples other than what is described in this consent form.
A description of this clinical trial will be available on https://clinicaltrials.gov/  as required by U.S. Law.  
This Web site will not include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time.
 
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 20 of 21                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Uronis at (919) 668-1861 during regular business hours. 
After hours and on weekends and holidays, please call the Duke paging operator at (919) 684-8111, and 
ask the operator to page Dr. Uronis.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent to Participate in a Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line 
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
Page 21 of 21
                                                  *
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form."
__________________________________________
Printed Name of Subject
__________________________________________
___________     ____________
Signature of Subject
Date
   Time
“I have explained the research to the subject and answered all of his/her questions.”
__________________________________________
Printed Name of Person Obtaining Consent
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
   Time
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 05/18/2020
IRB EXPIRATION DATE: 12/21/2020


Consent To Participate In A Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
PI: Hope Uronis
Consent Form Addendum – Research Blood Collection
Page 1 of 2                                                  Subject*Initials:______________
Form
M0345
You are being asked to sign this consent addendum because you are participating in a research study at 
Duke entitled “A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the 
First LineTreatment of Patients with Gastro-esophageal Cancer (KeyLARGO)”.  
Please read this consent addendum carefully and take your time making your decision. As your study 
doctor or study staff discusses this addendum with you, please ask him/her to explain any words or 
information that you do not clearly understand.  We encourage you to talk with your family and friends 
before you decide to sign this consent addendum.   
Signing this addendum is optional.  You do not have to sign this addendum to remain in the study.
PURPOSE OF THIS ADDENDUM
The purpose of this addendum is to allow for the collection of additional research blood from subjects 
who completed the full course of study treatment and whose disease has remained in a complete 
response (no evidence of disease on your scans).
Except for the activities described in this addendum, the terms of your original consent form remain in 
full effect.
PROCEDURES
Every three months doing your regular clinic visits we will collect the below blood samples:

Blood immune cells (approximately 5 teaspoons)

Blood biomarkers (approximately 4 teaspoons)
These samples will be collected until the study closes in February 2023, you withdrawal your consent to 
sample collection, or until your disease progresses, whichever comes first.
QUESTIONS REGARDING THIS ADDENDUM 
If you have any questions, concerns or complaints concerning this consent addendum, please 
contact Dr. Hope Uronis, at (919) 668-1861 during regular business hours and at the Duke paging 
operator at (919) 684-8111 after hours and on weekends and holidays.
For questions about your rights as a research participant, or to discuss questions, concerns or suggestions 
related to the research or this consent addendum, or to obtain information or offer input about the 
research, please contact the Duke University Health System Institutional Review Board (IRB) Office at 
(919) 668-5111.
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 01/09/2023
IRB EXPIRATION DATE: 12/21/2023


Consent To Participate In A Research Study
A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line
Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
PI: Hope Uronis
Consent Form Addendum – Research Blood Collection
Page 2 of 2
                                                  *
Form
M0345
STATEMENT OF CONSENT
"The purpose of this consent addendum has been explained to me. I have been allowed to ask questions, 
and my questions have been answered to my satisfaction. I have been told whom to contact if I have 
questions, to discuss problems, concerns, or suggestions related to the research or this addendum, or to 
obtain information or offer input about the research. I have read this addendum and agree to the choices 
I have indicated above, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this addendum."
__________________________________________
Printed Name of Subject
__________________________________________
___________       ___________
Signature of Subject
Date                      Time
“I have explained the research to the subject and answered all of his/her questions.”
__________________________________________
Printed Name of Person Obtaining Consent
__________________________________________
___________        ____________
Signature of Person Obtaining Consent 
Date 
      Time
DUHS IRB
IRB NUMBER: Pro00080566
IRB REFERENCE DATE: 01/09/2023
IRB EXPIRATION DATE: 12/21/2023