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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.
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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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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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title

A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line Treatment of Patients with Gastro-esophageal Cancer (KeyLARGO)
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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.
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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.
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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.
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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.
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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.  
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.
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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.
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estimated length of study participation

Estimated duration of subject enrollment is 12 months.  
Patients will continue to receive study treatment until they experience unacceptable drugrelated 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 drugrelated 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 anticancer 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.
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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.  
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.
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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.
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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.
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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.  
KeyLARGO
PI: Uronis
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table of contents

| 1.0 INTRODUCTION                                                                                                                                             |                                                                                                                                                   |              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| 1.1                                                                                                                                                          | Background .                                                                                                                                      |              |
| 1.2                                                                                                                                                          | Study Drugs                                                                                                                                       |              |
| 1.2.1                                                                                                                                                        | Pembrolizumab .................................................................................................................12                 |              |
| 1.2.1.1                                                                                                                                                      | Pharmaceutical and Therapeutic Background ...................................................... 13                                               |              |
| Preclinical and Clinical Trial Experience .................................................................. 14                                              |                                                                                                                                                   |              |
| 1.2.1.2                                                                                                                                                      |                                                                                                                                                   |              |
| 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                                                                                                                                   |              |
| 2.0 OBJECTIVES                                                                                                                                               |                                                                                                                                                   |              |
| 2.1                                                                                                                                                          | Primary Objective                                                                                                                                 |              |
| 2.2                                                                                                                                                          | Secondary Objectives .                                                                                                                            |              |
| 2.3                                                                                                                                                          | Exploratory Objectives .                                                                                                                          |              |
| 3.0 STUDY DESIGN .                                                                                                                                           |                                                                                                                                                   |              |
| Study Description                                                                                                                                            |                                                                                                                                                   |              |
| 3.1                                                                                                                                                          |                                                                                                                                                   |              |
| 3.2                                                                                                                                                          | Safety Validation                                                                                                                                 |              |
| 3.2.1                                                                                                                                                        | Dose Limiting Toxicity .....................................................................................................28                    |              |
| 3.3                                                                                                                                                          | Dose Expansion Cohort                                                                                                                             |              |
| 4.0 SUBJECT SELECTION                                                                                                                                        |                                                                                                                                                   |              |
| 4.1                                                                                                                                                          | Inclusion Criteria .                                                                                                                              |              |
| 4.2                                                                                                                                                          | Exclusion Criteria .                                                                                                                              |              |
| 4.3                                                                                                                                                          | Inclusion of Women and Minorities                                                                                                                 |              |
| 5.0 STUDY ASSESSMENTS                                                                                                                                        |                                                                                                                                                   |              |
| 5.1                                                                                                                                                          | Screening Period                                                                                                                                  |              |
| 5.2                                                                                                                                                          | Treatment Period .                                                                                                                                |              |
| 5.3                                                                                                                                                          | Follow-up Period .                                                                                                                                |              |
| 5.4                                                                                                                                                          | Laboratory Assessments                                                                                                                            |              |
| 5.5                                                                                                                                                          | Adverse Event Assessment .                                                                                                                        |              |
| T Tumor Assessments                                                                                                                                          |                                                                                                                                                   |              |
| 5.6                                                                                                                                                          |                                                                                                                                                   |              |
| 5.6.1                                                                                                                                                        | RECIST version 1.1 ..........................................................................................................34                   |              |
| 5.6.2                                                                                                                                                        | Immune-Related Response Criteria .............................................................................35                                  |              |
| 5.7                                                                                                                                                          | Subject Discontinuation                                                                                                                           |              |
| 6.0  STUDY DRUGS .........................................................................................................................................37 |                                                                                                                                                   |              |
| Treatment Compliance and Study Drug Accountability ..................................................... 37                                                  |                                                                                                                                                   |              |
| 6.1                                                                                                                                                          |                                                                                                                                                   |              |
| 6.2                                                                                                                                                          | Pembrolizumab                                                                                                                                     |              |
| 6.2.1                                                                                                                                                        | Storage and Handling .................................................................................................38                          |              |
| 6.2.2                                                                                                                                                        | Administration ...............................................................................................................38                  |              |
| 6.3                                                                                                                                                          | Oxaliplatin                                                                                                                                       |              |
| Version Date_30Mar2022                                                                                                                                       | CONFIDENTIAL                                                                                                                                      | Page 8 of 83 |  
| KeyLARGO                                                                                                                                       | PI: Uronis                                                                                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.3.1                                                                                                                                          | Storage and Handling ...................................................................................................39                     |
| 6.3.2                                                                                                                                          | Administration ................................................................................................................39              |
| 6.4                                                                                                                                            | Capecitabine .                                                                                                                                 |
| 6.4.1                                                                                                                                          | Storage and Handling ..............................................................................................40                          |
| 6.4.2                                                                                                                                          | Administration .........................................................................................................40                     |
| 6.5                                                                                                                                            | Concomitant Medications/Vaccinations                                                                                                           |
| 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 .                                                                                                                           |
| 7.1.1                                                                                                                                          | Pembrolizumab Dose Modifications  .............................................................................43                              |
| 7.1.2                                                                                                                                          | XELOX Dose Modifications .........................................................................................45                           |
| 7.2                                                                                                                                            | Toxicity Management                                                                                                                            |
| 7.2.1                                                                                                                                          | Pneumonitis ................................................................................................................................52 |
| 7.2.2                                                                                                                                          | Diarrhea/Colitis                                                                                                                               |
| 7.2.3                                                                                                                                          | Diabetes                                                                                                                                       |
| Mellitus                                                                                                                                       | 53 .                                                                                                                                           |
| 7.2.4                                                                                                                                          | Hypophysitis                                                                                                                                   |
| 7.2.5                                                                                                                                          | Hyperthyroidism or Hypothyroidism ..................................................................................53                         |
| 7.2.6                                                                                                                                          | Hepatic                                                                                                                                        |
| Renal Failure or Nephritis ....................................................................................................54              |                                                                                                                                                |
| 7.2.7                                                                                                                                          |                                                                                                                                                |
| 7.2.8                                                                                                                                          | Infusion Reactions                                                                                                                             |
| 8.0 CORRELATIVES .                                                                                                                             |                                                                                                                                                |
| 8.1                                                                                                                                            | Tumor Tissue Biomarkers                                                                                                                        |
| 8.2                                                                                                                                            | Circulating Immune Cells (PBMC)                                                                                                                |
| 8.3                                                                                                                                            | Protein Multiplex Arrays (Plasma)                                                                                                              |
| Pharmacogenomics (Whole Blood)                                                                                                                 |                                                                                                                                                |
| 8.4                                                                                                                                            |                                                                                                                                                |
| 8.5                                                                                                                                            | Future Use of Patient Samples                                                                                                                  |
| 8.6                                                                                                                                            | Correlative Collaborations                                                                                                                     |
| 8.6.1                                                                                                                                          | Duke-Personalis Collaboration ......................................................................................................57         |
| 8.6.2                                                                                                                                          | Duke-Olink Collaboration                                                                                                                       |
| 9.0 STATISTICAL ANALYSIS ...................................................................................................................60 |                                                                                                                                                |
| General Analysis Considerations                                                                                                                |                                                                                                                                                |
| 9.1                                                                                                                                            |                                                                                                                                                |
| 9.1.1                                                                                                                                          | Primary Endpoint                                                                                                                               |
| 9.1.2                                                                                                                                          | Secondary Endpoints ...........................................................................................................60              |
| 9.1.3                                                                                                                                          | Exploratory Endpoints ....................................................................................................61                   |
| 10.0  SAFETY                                                                                                                                   |                                                                                                                                                |
| 10.1                                                                                                                                           | Adverse Events .                                                                                                                               |
| 10.2                                                                                                                                           | Serious Adverse Events .                                                                                                                       |
| 10.3                                                                                                                                           | Events of Clinical Interest                                                                                                                    |
| 10.4                                                                                                                                           | Other Safety Considerations                                                                                                                    |
| 10.4.1                                                                                                                                         | Pregnancy and Lactation .............................................................................................65                        |
| 10.4.2                                                                                                                                         | Medication Overdose and Error ...................................................................................65                            |  
| 1.0 ADMINISTRATIVE RESPONSIBILITIES                                                                                                                  |                                                                                                                                                 |
|------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|
| 11.1                                                                                                                                                 | Institutional Review Board/Independent Ethics Committee .......................................... 65                                           |
| 11.2                                                                                                                                                 | Protocol and Protocol Revisions ......................................................................................................... 65    |
| 1.3                                                                                                                                                  | Protocol Deviations and Violations ......................................................................................................... 65 |
| 1.4                                                                                                                                                  | Informed Consent                                                                                                                                |
| 11.5                                                                                                                                                 | Source and Study Documentation .                                                                                                                |
| 1.6                                                                                                                                                  | Case Report Forms                                                                                                                               |
| 1.7                                                                                                                                                  | Monitoring and Audits/Inspections                                                                                                               |
| 11.8                                                                                                                                                 | Study Closeout                                                                                                                                  |
| 1.9                                                                                                                                                  | Records Retention                                                                                                                               |
| 12.0 REFERENCES                                                                                                                                      |                                                                                                                                                 |
| Appendix A.  RECIST 1.1                                                                                                                              |                                                                                                                                                 |
| 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 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-PD1 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.
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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 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 FDAapproved 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 FDAapproved 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.
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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 CTLA4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1 has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumors. Both ligands are type I transmembrane receptors containing both IgVand 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 Tcell 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 Tcell 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.
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1.2.1.2 preclinical and clinical trial

For complete study information, refer to the current Pembrolizumab Investigator's Brochure (IB).
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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, 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).
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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.
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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.
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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 analysis included HNSCC subjects previously exposed to platinum therapy.  
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.
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1.2.1.3 safety profile

Pembrolizumab is safe and well tolerated, as evidenced by a low rate of toxicity Grade 3 to 5 drugrelated 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).
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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.  
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 nnecrosis 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.
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table 1.2.1.3.1 all aeosi adverse

| Frequencies                                           |       |        |
|-------------------------------------------------------|-------|--------|
| Reference Safety Dataset for MK-3475*                 |       |        |
| Averse Reaction                                       | (%)   |        |
| Rash prurition                                        | (0.0) |        |
| Rash pustular                                         | l     | (0.0)  |
| Skin lesion                                           | 1     | (0.0)  |
| Stevens-Johnson Syndrome                              | (0.0) |        |
| l                                                     |       |        |
| Hepatitis                                             | 19    | (0.7)  |
| Autoimmune hepatitis                                  | 12    | (0.4)  |
| Hepatitis                                             | 6     | (0.2)  |
| Drug-induced liver injury                             | 2     | (.0.1) |
| Hypophysitis                                          | 17    | (0.6)  |
| Hypophysitis                                          | 9     | (0.3)  |
| Hypopituitarism                                       | 8     | (0.3)  |
| Uveitis                                               | 14    | (0.5)  |
| Uveitis                                               | 10    | (0.4)  |
| Iridocyclitis                                         | 2     | (.0.1) |
| Iritis                                                | 2     | (0.1)  |
| Myositis                                              | 11    | (0.4)  |
| Myositis                                              | 7     | (0.3)  |
| Myopathy                                              | 3     | (.0.1) |
| Rhabdomyolysis                                        | l     | (0.0)  |
| Pancreatitis                                          | 9     | (0.3)  |
| Pancreatitis                                          | 7     | (0.3)  |
| Autoimmune pancreatitis                               | l     | (0.0)  |
| Pancreatitis acute                                    | l     | (0.0)  |
| Type 1 diabetes mellitus                              | 6     | (0.2)  |
| (0.2)                                                 |       |        |
| Type 1 diabetes mellitus                              | s     |        |
| Diabetic ketoacidosis                                 | 2     | (.0.1) |
| Nephritis                                             | 4     | (0.1)  |
| (0.1)                                                 |       |        |
| Tubulointerstitial nephritis                          | 4     |        |
| (Presented by Decreasing Frequency of AEOSI Category) |       |        |  
Version Date_30Mar2022 cont. Table 1.2.1.3.1 All AEOSI Adverse Reactions Considered Expected for Pembrolizumab  
| (Presented by Decreasing Frequency of AEOSI Category)                                                                         | Frequencies   |        |
|-------------------------------------------------------------------------------------------------------------------------------|---------------|--------|
| Reference Safety Dataset for MK-3475*                                                                                         |               |        |
| Adverse Reaction                                                                                                              | (%)           |        |
| Guillain-Barre Syndrome                                                                                                       | 2             | (0.1)  |
| Axonal neuropathy                                                                                                             | 1             | (0.0)  |
| Guillain-Barre syndrome                                                                                                       | l             | (0.0)  |
| Secondary adrenal insufficiency                                                                                               | i             | (0.0)  |
| Secondary adrenocortical insufficiency                                                                                        | l             | (0.0)  |
| Non Immune-Mediated Adverse Reactions                                                                                         |               |        |
| Infusion related reactions                                                                                                    | 70            | (2.5)  |
| Infusion related reaction                                                                                                     | 29            | (1.0)  |
| Hypersensitivity                                                                                                              | 22            | (0.8)  |
| Drug hypersensitivity                                                                                                         | 13            | (0.5)  |
| Anaphylactic reaction                                                                                                         | 3             | (.0.1) |
| Cytokine release syndrome                                                                                                     | 2             | (0.1)  |
| Serum sickness                                                                                                                | l             | (0.0)  |
| KN = KEYNOTE; MedDRA = Medical Dictionary for Regulatory Activities                                                           |               |        |
| Every subject is counted a single time for each applicable row and column.                                                    |               |        |
| MedDRA version used is 18.1.                                                                                                  |               |        |
| a Includes all subjects who received at least one dose of MK-3475 in KN001 Part B1, B2, B3, D, C, F1, F2, F3; KN002 (original |               |        |
| phase), KN006, and KN010 .                                                                                                    |               |        |
| (KN001 Database Cutoff Date for Melanoma: 18APR2014).                                                                         |               |        |
| (KN001 Database Cutoff Date for Lung Cancer: 23JAN2015).                                                                      |               |        |
| (KN002 Database Cutoff Date: 28FEB2015).                                                                                      |               |        |
| (KN006 Database Cutoff Date: 03MAR2015).                                                                                      |               |        |
| (KN010 Database Cutoff Date: 30SEP2015).                                                                                      |               |        |  
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%) 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 infusionrelated 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.
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table 1.2.1.3.2 all additional adverse

| Frequencies                                                                                                                       |      |        |
|-----------------------------------------------------------------------------------------------------------------------------------|------|--------|
| Reference Safety Dataset for MK-3475*                                                                                             |      |        |
| Preferred Term                                                                                                                    | (%)  |        |
| Subjects in population                                                                                                            | 2799 |        |
| Diarrhoca                                                                                                                         | 625  | (22.3) |
| Cough                                                                                                                             | 615  | (22.0) |
| Pruritus                                                                                                                          | 562  | (20.1) |
| Arthralgia                                                                                                                        | 504  | (18.0) |
| Rash                                                                                                                              | 49   | (17.8) |
| Pyrexia                                                                                                                           | 357  | (12.8) |
| Back pain                                                                                                                         | 349  | (12.5) |
| Abdominal pain                                                                                                                    | 274  | (9.8)  |
| Vitiligo                                                                                                                          | 171  | (6.1)  |
| Hyponatraemia                                                                                                                     | 146  | (5.2)  |
| KN = KEYNOTE; MedDRA = Medical Dictionary for Regulatory Activities                                                               |      |        |
| Every subject is counted a single time for each applicable row and column.                                                        |      |        |
| MedDRA version used is 18.1.                                                                                                      |      |        |
| Individual PTs were identified from KN002, KN006, and KN010. Each PT occurred at a rate of ≥ 10% in at least one of these studies |      |        |
| in patients treated with MK-3475 and at a higher incidence than in the control arm (Between Arm Difference of ≥ 5% [All Grades]   |      |        |
| or ≥ 2% [Grade 3 or higher])                                                                                                      |      |        |
| ' Includes all subjects who received at least one dose of MK-3475 in KN001 Part B1, B2, B3, D, C, F1, F2, F3; KN002 (original     |      |        |
| phase), KN006, and KN010.                                                                                                         |      |        |
| (KN001 Database Cutoff Date for Melanoma: 18APR2014).                                                                             |      |        |
| (KN001 Database Cutoff Date for Lung Cancer: 23JAN2015).                                                                          |      |        |
| (KN002 Database Cutoff Date: 28FEB2015).                                                                                          |      |        |
| (KN006 Database Cutoff Date: 03MAR2015).                                                                                          |      |        |
| (KN010 Database Cutoff Date: 30SEP2015).                                                                                          |      |        |
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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 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.
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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.
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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 nonspecific.  
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)].
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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.
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neuropathy oxaliplatin is associated with

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 5fluorouracil/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 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 5fluorouracil/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 5fluorouracil/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 FDAapproved 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).
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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.
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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.  
**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 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 postbaseline tumor assessment that showed disease response. The median duration of response 40 weeks, 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.
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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.
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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.
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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

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 treatmentrelated toxicity (e.g. disease progression or inter-current illness) are considered nonevaluable for DLT.  
| 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* |     |               |     |
| Cohort                                                                                                        | No. Evaluable Subjects                    |     |               |     |
| 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. |                                           |     |               |     |
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table 3.1 cohorts

*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.
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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.
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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 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.
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4.0 subject selection 4.1 inclusion

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
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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 antitumor 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.  
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.  
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.
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4.3 inclusion of women and

Men and women of all races and ethnic groups are eligible for this trial.
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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.
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refer to appendix d for

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)
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.
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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**:
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 Physical examination Vital signs and weight Concomitant medications ECOG performance status Adverse event assessment CBC with differential Chemistries including LFTs For **dose expansion cohort only**, the following study procedures must be completed **pre-dose on**
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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
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cycle 1 day 29 (i.e.

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.
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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.  
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.
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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.
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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 NCICTCAE version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-0614_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.
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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.
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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 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.
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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 documented
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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:
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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
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the following treatment-related discontinuation criteria

- 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:
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 treatmentrelated 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
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6.0 study drugs 6.1 treatment

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.
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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.
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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.
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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

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.
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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.
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incompatibilities

Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5fluorouracil) 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.
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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 peachcolored 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.
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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.
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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).  
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.
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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.
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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.
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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
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.
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7.0 dose modification and toxicity

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).
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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.  
All dose modifications and reasons for modification must be recorded in the CRF.
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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 Immunerelated AEs Toxicity  grade or  conditions  (CTCAEv4.0) Action taken to  irAE management with  pembrolizumab 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 /                            | Grade 2 or 3                                                                                                          | Withhold |                                                                                                                                                                           | Administer                                                                                            |    |                                                              |
| Colitis                               | 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                                                                                              |          |                                                                                                                                                                            |                                                                                                       |    |                                                              |  
| Immunerelated AEs                                                       | Toxicity  grade or  conditions  (CTCAEv4.0)                                                                                                                                                                              | Action taken to                                                                                         | irAE management with                                                               |                                                                                            |    |                                                                                                          |
|-------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|----|----------------------------------------------------------------------------------------------------------|
| pembrolizumab                                         | 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         | 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                                                                                                                                                                                                              | Administer corticosteroids                                                                              |                                                                                    |                                                                                            |    |                                                                                                          |
| discontinue                                           | (initial dose of 1-2 mg/kg  prednisone or equivalent)  followed by taper                                                                                                                                                 |                                                                                                         |                                                                                    |                                                                                            |    |                                                                                                          |
| Grade 2                                               | Withhold                                                                                                                                                                                                                 | Administer corticosteroids  (initial dose of 0.5- 1 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 antihyperglycemic in  participants with  hyperglycemia                                                                                                                                                                                                                          |                                                                                                        | Monitor participants for  hyperglycemia or other  signs and symptoms of  diabetes. |                                                                                            |    |                                                                                                          |
| Hypophysitis                                          | Grade 2                                                                                                                                                                                                                  | Withhold                                                                                                |                                                                                   | Administer  corticosteroids and  initiate hormonal  replacements as  clinically indicated. |   | Monitor for signs and  symptoms of  hypophysitis (including  hypopituitarism and  adrenal insufficiency) |
| Grade 3 or 4                                          | Withhold or  permanently  discontinue1                                                                                                                                                                                   |                                                                                                         |                                                                                    |                                                                                            |    |                                                                                                          |
| Hyperthyroidis                                        | Grade 2                                                                                                                                                                                                                  | Continue                                                                                                | Treat with non-selective                                                           |                                                                                            |    |                                                                                                          |
| m                                                     | beta-blockers (eg,                                                                                                                                                                                                       |                                                                                                         |                                                                                    |                                                                                            |    |                                                                                                          |
| propranolol) or thionamides  as appropriate           |                                                                                                                                                                                                                         | Monitor for signs and  symptoms of thyroid  disorders.                                                  |                                                                                    |                                                                                            |    |                                                                                                          |
| Grade 3 or 4                                          | Withhold or permanently  discontinue1                                                                                                                                                                                    |                                                                                                         |                                                                                    |                                                                                            |    |                                                                                                          |  
Version Date_30Mar2022 CONFIDENTIAL Page 44  
| Immunerelated AEs                                                                                                                                                                                                                                                                                                                                                                                                       | Toxicity  grade or  conditions  (CTCAEv4.0)                                                                                                                         | Action taken to                                               | irAE management with                                                                  |    |                                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------------------|----|------------------------------------|
| pembrolizumab                                                                                                                                                                                                                                                                                                                                                                                         | corticosteroid and/or other  therapies                                                                                                                              | Monitor and follow-up                                         |                                                                                       |    |                                    |
| Hypothyroidis                                                                                                                                                                                                                                                                                                                                                                                         | Grade 2                                                                                                                                                             | Continue                                                      | Initiate thyroid replacement                                                          |    |                                    |
| m                                                                                                                                                                                                                                                                                                                                                                                                     | 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                                                               |   | Ensure adequate                    |
| administer corticosteroids                                                                                                                                                                                                                                                                                                                                                                            | evaluation to confirm  etiology and/or exclude  other causes                                                                                                        |                                                               |                                                                                       |    |                                    |
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                          | Permanently  discontinue                                                                                                                                            |                                                               |                                                                                       |    |                                    |
| All other  immune                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                     |                                                               |                                                                                       |    |                                    |
| related AEs                                                                                                                                                                                                                                                                                                                                                                                           | Intolerable/  persistent  Grade 2                                                                                                                                   |                                                              | 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                                                                                                                                                                                                                                                                                                                                                                        | Withhold                                                                                                                                                            | Based on type and severity  of AE administer  corticosteroids |                                                                                       |    |                                    |
| 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). |                                                                                                                                                                     |                                                               |                                                                                       |    |                                    |