Conditions: Esophagogastric Tumors Gastric Cancer Gastric Tumor Esophageal Cancer Esophageal Neoplasms Esophageal Tumor GastroEsophageal Cancer Gastroesophageal Junction Adenocarcinoma Gastroesophageal Junction Tumor Gastroesophageal Junction Cancer
Keywords: Esophagogastric Tumors Esophagogastric Cancers Gastric Cancer Esophageal Cancer Gastroesophageal Junction Cancer GEJ Tumor Pembrolizumab Trastuzumab 20-158 Memorial Sloan Kettering Cancer Center
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out whether treatment with trastuzumab combined with pembrolizumab will improve the clearance of tumor DNA from participants' bodies after surgery.

Detailed description:

Arms:
arm 1: Trastuzumab will be administered on an every 3 week dosing schedule, with initial loading dose of 8 mg/kg as a 90 minute infusion, followed by trastuzumab 6 mg/kg every 3 weeks.

The planned dose of pembrolizumab for this study is 200 mg every 3 weeks.

Interventions: intervention 1: Trastuzumab intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Trastuzumab (8mg/kg loading dose; 6mg/kg maintenance) will be administered on day 1 of each 3-week dosing cycle (21 days). intervention 2: Pembrolizumab 200 mg IV will be administered on day 1 of each 3-week dosing cycle (21 days).

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
 
 
 
MSK Protocol Cover Sheet 
 
A Single-Arm Pilot Study of Adjuvant Pembrolizumab plus Trastuzumab in HER2+ 
Esophagogastric Tumors with Persistent Circulating Tumor DNA Following 
Curative Resection 
 
Principal Investigator: Yelena Janjigian, MD in the Department of Medicine/ 
Gastrointestinal Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Page 1 of 46 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 2 of 46 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ............................................................................. 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ...................................................................................... 3 
3.0 
BACKGROUND AND RATIONALE ........................................................................................... 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................................ 8 
4.1 
Design ......................................................................................................................................... 8 
4.2 
Intervention ..................................................................................................................................... 8 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS ................. 9 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY .......................................................................... 10 
6.1 
Participant Inclusion Criteria ........................................................................................................ 10 
6.2 
Participant Exclusion Criteria ...................................................................................................... 11 
7.0 
RECRUITMENT PLAN .............................................................................................................................. 12 
7.1 
Research Participant Registration ............................................................................................... 14 
8.0 
INFORMED CONSENT PROCEDURES .......................................................................................... 14 
9.0 
PRE-TREATMENT/INTERVENTION ....................................................................................... 14 
10.0 
TREATMENT/INTERVENTION PLAN...................................................................................... 15 
11.0 
EVALUATION DURING TREATMENT/INTERVENTION ......................................................... 18 
12.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 19 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY ..................... 20 
14.0 
BIOSTATISTICS ...................................................................................................................... 21 
15.0 
TOXICITIES/RISKS/SIDE EFFECTS ............................................................................................. 23 
16.0 
PROTECTION OF HUMAN PARTICIPANTS ........................................................................... 40 
16.1 
Privacy ...................................................................................................................................... 40 
16.2 
Data Management ....................................................................................................................... 40 
16.3 
Quality Assurance ..................................................................................................................... 41 
16.4 
Data and Safety Monitoring ......................................................................................................... 41 
17.0 
REFERENCES .......................................................................................................................... 42 
18.0 
APPENDICES ......................................................................................................................... 44 
19.0 
MSK MULTICENTER TRIAL ADDENDUM 


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IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 3 of 46 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single arm pilot study of adjuvant trastuzumab and pembrolizumab in patients with HER2- 
positive gastric, esophageal or gastroesophageal junction (GEJ) tumors with persistent circulating 
tumor DNA (ctDNA) despite curative surgery and completion of standard perioperative and/or 
adjuvant therapy. This study will enroll 24 eligible patients over 2 years. The central hypothesis of 
this trial is that adjuvant trastuzumab + pembrolizumab will improve ctDNA clearance and disease- 
free survival (DFS) in patients with resected HER2+ tumors with minimal residual disease and very 
high risk of recurrence. This is based on recent data, which suggest potential synergy of 
trastuzumab with pembrolizumab. Patients with HER2+ esophagogastric cancer who are ctDNA 
positive (ctDNA+) will be consented within 8 months after curative surgery and completion of 
standard of care perioperative and/or adjuvant therapy. Patients with detectable ctDNA will receive 6 
months of trastuzumab + pembrolizumab (Figure 1). The primary objective of this trial is to 
determine the ctDNA clearance at 6 months with intensified adjuvant therapy. 
 
Figure 1: Study Schema 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 Primary Objective: 
 
To observe the rate of ctDNA clearance at 6 months with pembrolizumab + trastuzumab in patients 
with HER2+ esophagogastric tumors and persistent ctDNA following curative resection (R0 surgical 
resection) and standard perioperative and/or adjuvant therapy. 
2.2 Secondary Objectives: 
 
• 
To establish the safety of 6 months of adjuvant pembrolizumab + trastuzumab in patients 
with resected HER2+ esophagogastric tumors and persistent ctDNA. 
• 
To observe other measures of efficacy including DFS (median, 1-year and 2-year) and 
overall survival (median, 2-year and 5-year) in ctDNA-positive patients with resected HER2+ 
esophagogastric tumors. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 4 of 46 
 
 
 
 
2.3 Exploratory Objectives: 
 
• 
To collect archival tumor samples and post-recurrence tumor biopsies for correlative 
analysis, including TCR rearrangements, transcriptomic analysis and immunohistochemistry. 
• 
To utilize blood and tissue specimens collected during the course of study to explore the 
mechanisms of primary and acquired resistance to trastuzumab and pembrolizumab and 
their relationship to response, disease-free survival and overall survival. 
• 
To bank tumor and blood material for future correlative analysis, including but not limited to 
whole exome analysis to determine mutation load and specific neoantigen landscape. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Introduction 
Esophagogastric cancer is a significant global health burden, representing the fifth most common 
cancer worldwide with over one million new cases each year, and the third leading cause of cancer 
death1. Approximately half of patients present with metastatic disease, but even those that present 
with resectable disease have a high probability of recurrence. Even with adequate resection and 
aggressive standard of care perioperative therapy, 3-year overall survival in locoregionally advanced 
disease is only 57-58%2,3. 
 
Improving therapy for locally advanced esophagogastric cancer has been challenging. Differing 
perioperative approaches are utilized, including neoadjuvant chemoradiotherapy2,4, perioperative 
chemotherapy3, adjuvant chemotherapy5  and adjuvant chemoradiotherapy6, all followed by 
guideline-driven  radiographic and clinical surveillance. Notably, there are no established biomarkers 
to guide adjuvant therapy. Therefore, this trial utilizes ctDNA detection at the conclusion of 
perioperative therapy—regardless of the modality—as a method of identifying  patients at highest risk 
of recurrence to further escalate their therapy and delay recurrence. 
Approximately 25% of esophagogastric tumors overexpress the receptor tyrosine kinase human 
epidermal growth factor receptor 2 (HER2, also known as ERBB2), which has emerged as a critical 
oncogenic driver and biomarker7. In the metastatic setting, targeting this protein with the anti-HER2 
antibody trastuzumab demonstrates considerable clinical benefit8. Limited data suggest that 
perioperative trastuzumab is safe and well-tolerated in patients with locally advanced 
esophagogastric cancer9,10. However, results from randomized trials studying perioperative or 
adjuvant trastuzumab (RTOG-1010, INNOVATION)  have not been reported, and a role for adjuvant 
trastuzumab in locally advanced disease has not been established. Thus, the current 
recommendation for patients with locally advanced HER2-positive esophagogastric cancer is 
observation after completion of standard perioperative/adjuvant  therapy. 
Since development of these trials, a growing body of data suggests potential synergy between 
trastuzumab and immunotherapy. Trastuzumab activity is enhanced by immune cell recruitment 
leading to dendritic cell priming, cytotoxic T cell activation and programmed death-ligand 1 (PD-L1) 
upregulation. Based on these data, a recent phase II study combining pembrolizumab and 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 5 of 46 
 
 
 
 
trastuzumab in patients with metastatic esophagogastric adenocarcinoma demonstrated a 
remarkable 89% objective response rate 100% disease control rate11. Notably, a decrease in ctDNA 
was observed after only one dose of pembrolizumab and trastuzumab in 83% of patients. More 
recently, final results of this phase II trial (N=37) demonstrated that 70% of patients were 
progression-free at 6 months and the combination of pembrolizumab with trastuzumab and 
chemotherapy is safe and has promising activity in HER2-positive metastatic esophagogastric 
cancer. This led to the ongoing KEYNOTE-811 study, a global multicenter, randomized, placebo- 
controlled phase 3 study in which patients with previously untreated unresectable or metastatic 
HER2+ gastric/GEJ cancer are randomized 1:1 to chemotherapy + trastuzumab with pembrolizumab 
or placebo. 
Given these promising data, the proposed trial will evaluate the efficacy of adjuvant combined 
trastuzumab/pembrolizumab in ctDNA+ patients at high risk for recurrence. 
3.2 Clinical activity of pembrolizumab in esophagogastric cancer 
Programmed death-1 (PD-1) is a surface molecule on T cells that binds its ligand PD-L1 and 
suppresses antitumor immunity. Pembrolizumab is a humanized monoclonal antibody that inhibits 
PD-1 and has been shown to have activity in several malignancies, including esophagogastric 
cancer. In the phase II KEYNOTE-059 study, patients with metastatic esophagogastric cancer who 
had previously received two or more lines of systemic therapy were given pembrolizumab 
monotherapy12. This trial demonstrated an objective response rate of 12% regardless of PD-L1 
status, which improved to 16% in PD-L1-positive patients. Based on these results, pembrolizumab 
was approved in the metastatic setting for chemotherapy-refractory patients with a combined  
positive score (CPS) score > 1. The KEYNOTE-061 study randomized patients receiving second-line 
therapy for metastatic esophagogastric cancer to chemotherapy or pembrolizumab. Patients with a 
PD-L1 CPS score >1 achieved a 12-month overall survival of 40% with a median duration of 
response of 18 months13. Both of these trials demonstrated that a significant subset of PD-L1- 
expressing patients derived considerable clinical benefit from pembrolizumab monotherapy. 
 
3.3 Clinical activity of trastuzumab in esophagogastric cancer 
In the metastatic setting, trastuzumab was the first targeted therapy approved in esophagogastric 
cancer based on results from the Trastuzumab for Gastric Cancer (ToGA) trial8. In this double- 
blinded phase III  study, 594 patients were randomized to receive chemotherapy with or without 
trastuzumab. The primary endpoint was reached with a superior mOS of 13.8 vs 11.1 months when 
trastuzumab was added. Of note, the survival benefit was more pronounced in patients who fulfilled 
current HER2+ criteria (IHC 3+ or IHC 2+ in combination with FISH positivity). Numerous 
subsequent phase III trials targeting HER2 in esophagogastric cancer using small molecules like 
lapatinib (LOGiC, TYTAN) or antibodies like pertuzumab or T-DM1 (JACOB, GATSBY) have failed14– 
17. One possibility for the lack of benefit for other HER2-targeted agents is that trastuzumab may 
induce non-canonical immune stimulation, in addition to its canonical inhibition of HER2 signaling. 
 
3.4 Mechanistic rationale for the combination of trastuzumab and pembrolizumab 


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IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
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New York, New York 10065 
Page 6 of 46 
 
 
 
 
Both preclinical and clinical data suggest that trastuzumab modulates antitumor immunity through 
various mechanisms. For example, trastuzumab promotes immune cell recruitment and activation  
via antibody-dependent  cellular cytotoxicity (ADCC) and antibody-dependent  cellular phagocytosis 
(ADCP). Trastuzumab increases uptake of HER2 by dendritic cells, leading to cytotoxic T cell 
activation and proliferation18, and promotes NK cell recruitment via increased MHC class I 
expression. Both of these mechanisms lead to the production of cytokines such as IFN 19, resulting 
in the upregulation of PD-L1 on tumor cells, which can be inhibited by concurrently blocking PD120,21. 
 
These observations have led to clinical studies combining HER2 blockade with anti-PD1 therapy. An 
investigator-initiated  trial conducted at Memorial Sloan Kettering Cancer Center (MSKCC) 
(NCT2954536) demonstrated that pembrolizumab in combination with trastuzumab and 
chemotherapy was both safe and efficacious in metastatic esophagogastric cancer patients with an 
objective response rate of 89% and disease control rate of 100%11. Grade 3/4 non-immune toxicities 
included anemia, transaminitis, diarrhea, rash, mucositis, lymphopenia, and neutropenia, which were 
all likely due to concurrent chemotherapy. Immune-related toxicities included colitis and 
transaminitis. These preliminary results demonstrate both efficacy and safety of combined 
pembrolizumab and trastuzumab in esophagogastric cancer patients. 
3.5 Circulating tumor DNA 
Circulating tumor DNA (ctDNA) obtained from plasma during a routine blood draw—a technique 
known as “liquid biopsy”—can be used to detect minimal residual disease (MRD). Whereas 
histopathologic or molecular characteristics of tumors that are associated with a higher recurrence 
risk indicate a propensity for metastasis, the presence of circulating DNA molecules containing 
somatic mutations found in an individual’s tumor is a direct indication that occult tumor cells remain 
after surgery. ctDNA has been detected across diverse tumor types: in patients with localized 
tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, 
gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively22. Notably, 
ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these 
two biomarkers are distinct entities. Given that ctDNA is a relatively new area of investigation, the 
frequency of positive ctDNA samples after perioperative chemotherapy is not well established, and 
the ctDNA clearance rate among tumor types is not known. However, several studies have shown 
that ctDNA can be used to detect MRD and determine those at highest risk for recurrence22–24. 
 
For example, recently published data suggest that patients with resected stage II colon cancer and 
detectable ctDNA have residual disease with very high recurrence risk. In this study, 1,046 plasma 
samples from a prospective cohort of 230 patients with resected stage II colon cancer were used to 
evaluate the utility of ctDNA to assess the risk of recurrence post-resection23. In patients not treated 
with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 patients (7.9%), 11 of 
whom (79%) recurred at a median follow-up of 27 months; by contrast, recurrence occurred in only 
16 of 164 patients (9.8%) with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 
7.9 to 40; p < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion 
of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 
to 68; p = 0.001). Taken together, these studies suggest a positive predictive value (PPV) for 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 7 of 46 
 
 
 
 
cancer recurrence of >83% in patients who have 
detectable ctDNA following surgical resection. More 
recent data also validate that persistent ctDNA after 
 
 
 
 
 
100 
 
prognostic for recurrence. In one study, 10 out of 94 
patients with stage I-III  colorectal cancer had positive 
ctDNA at day 30 post-resection, all of whom received 
standard adjuvant chemotherapy25. Of these 10 
patients, 7 patients experienced relapse and all had 
positive ctDNA throughout or shortly after completion of 
adjuvant therapy. Among the 8 patients with positive 
ctDNA after surgery and serial ctDNA sampling, 4 of 8 
patients (50%) demonstrated ctDNA clearance with 
adjuvant treatment; two of these patients remained 
ctDNA negative and did not have disease recurrence 
within the follow-up period. CtDNA profiling from the 75 
 
 
 
 
50 
 
 
 
 
 
 
 
 
 
 
 
 
0 
0 
5 
10 
15 
20 
25 
Time (months) 
patients with serial ctDNA sampling suggest that ctDNA positivity persists in longitudinal samples in 
the absence of clinical intervention. While data for ctDNA positivity after standard therapy for 
locoregionally advanced esophagogastric cancer are limited, recent reports suggests that ctDNA is 
also prognostic for recurrence. For example, in one study of 46 patients with resected gastric  
cancer, ctDNA was detected in 45% of pretreatment samples26. All patients with detectable ctDNA in 
the post-operative period experienced relapse, and ctDNA positivity during follow-up was associated 
with worse disease-free survival (HR, 14.78; 95% CI, 7.991 – 61.29; p < 0.0001) and overall survival 
(HR, 7.664; 95% CI, 2.916 – 21.06, p < 0.002). 
 
 
Figure 3. Variant allele frequencies (VAF) in 2 patients with matched ctDNA 
enrolled on protocol 18-399. 
 
We are conducting an 
ongoing single arm pilot study of adjuvant pembrolizumab in patients with MSI-H solid tumors and 
positive ctDNA, similar in design to this protocol (IRB #18-399).  From the time of study initiation in 
2018, through August 2020, we screened 750 patients and identified 153 with stage II and III MSI-H 
disease treated with curative intent eligible for this protocol. After exclusion we performed ctDNA 
testing on 73 patients, of which 7 had positive results, and 5 patients enrolled on study. Among the 
63 patients who were ctDNA-negative or unmatched, 2 were lost to follow up, 1 is deceased, and the 
remainder are alive with no evidence of disease (NED) (Figure 2). Preliminary results from two 
     ctDNA- (n=58) 
ctDNA+ (n=5) 
Figure 2. Progression-Free Survival by 
ctDNA result (N=63). PFS was compared 
between patients with positive (matched) ctDNA 
(red) and negative (mismatched or not detected 
ctDNA (blue) (Protocol 18-399). 
Probability of Progression-Free Survival 


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IRB Number: 20-158 A(2) 
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Page 8 of 46 
 
 
 
 
patients receiving pembrolizumab show a striking decrease in variant allele frequency (VAF) 
detected in plasma (Figure 3), with patients achieving ctDNA clearance after 5 and 8 months of 
treatment, respectively. 
 
While the recurrence rate for patients with esophagogastric cancer with persistent ctDNA after 
resection and standard adjuvant therapy is not known, available data suggest that the large majority 
of these patients will have disease recurrence, and therefore we estimate the null ctDNA clearance 
rate with surveillance to be ~5% in this population. 
 
MSK has developed our own method of detecting ctDNA in plasma derived from whole blood 
samples.  This method, called MSK-ACCESS, is a next-generation sequencing assay that can 
accurately detect down to 0.3% mutant allele fraction and will be used in the ctDNA assessments for 
this study (see Section 10.1.2). 
This trial explores adjuvant HER2 and PD-1 blockade patients with HER2+ esophagogastric tumors 
who have positive ctDNA following completion of standard-of-care surgery and perioperative 
therapy, a population at extremely high risk for recurrent disease. As administration of trastuzumab 
and pembrolizumab in the adjuvant setting is not currently approved by the FDA, these drugs will be 
provided as investigational. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single arm pilot study of adjuvant pembrolizumab + trastuzumab in patients with HER2+ 
(IHC 3+ or IHC 2+/FISH ratio >2.0) esophageal, GEJ or gastric cancer and detectable ctDNA after 
completion of standard perioperative therapy and surgery. Using mutations or amplifications 
identified in the primary resected tumors (as determined by next-generation sequencing (NGS)), 
ctDNA levels will be measured in plasma collected up to eight months after curative surgery, and 
standard perioperative and/or adjuvant therapy and assessed for alterations shared between the 
tumor and plasma. Eligible patients with at least one shared mutation between tumor and plasma 
will be enrolled in this study and and receive 6 months of pembrolizumab/trastuzumab. The primary 
endpoint of the study is to determine ctDNA clearance at 6 months. 
4.3 
Intervention 
 
This study will be conducted as a single arm pilot study including 24 participants.  Treatment will be 
administered on an outpatient basis as possible to the date of enrollment. Trastuzumab (8mg/kg 
loading dose; 6mg/kg maintenance) in combination with pembrolizumab 200 mg IV will be 
administered on day 1 of each 3-week dosing cycle (21 days). One cycle is defined as 21 days. In 
esophagogastric cancers, standard of care for patients who have completed surgery and 
perioperative therapy is surveillance. However, in patients with detectable ctDNA, the expected 
ctDNA clearance rate is close to zero and our data suggest that these patients are essentially 
metastatic, which justifies our investigation of intensified adjuvant therapy. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
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Page 9 of 46 
 
 
 
 
Treatment will be performed on the scheduled day (± 7 day treatment window). Adverse events will 
be monitored and graded in severity according to the guidelines outlined in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
Patients will be assessed with a CT scan and ctDNA assessment at baseline and every 3 months for 
the first 12 months post-enrollment, then a CT scan and ctDNA assessment every 6 months in year 2 
and year 3 post-enrollment, and then every 12 months in year 4 and year 5 post-enrollment. Patients 
will be on this study for up to 5 years. ctDNA assessments for all timepoints will be performed in a 
CLIA-approved  laboratory. Anytime a patient has intolerable toxicity or declines further treatment, 
they will go to the event monitoring phase and will be followed with a CT scan and ctDNA assessment 
every 3 months for the first 12 months post-enrollment, then a CT scan and ctDNA assessment every 
6 months in years 2 and 3 post-enrollment, and then every 12 months in years 4 and 5 post- 
enrollment.  In the event of disease recurrence during the treatment phase, the patients will be taken 
off treatment and followed for overall survival. In the event of disease recurrence during the follow- 
up period, the patients will be followed for overall survival. 
We believe that ctDNA detection of MRD after surgery and/or adjuvant therapy portends a high risk 
of recurrence, and current literature suggests a PPV of > 83% independent of the assay used. 
Overall, we believe that our proposed approach will result in reduced recurrence and improved 
overall survival for patients with resected HER2+ esophagogastric tumors with persistent ctDNA. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS 
 
5.1 Trastuzumab Dose 
For this study, a trastuzumab biosimilar, trastuzumab-qyyp, will be provided by Pfizer at no charge. 
Trastuzumab will be administered on an every 3 week dosing schedule, with initial loading dose of 8 
mg/kg as a 90 minute infusion, followed by trastuzumab 6 mg/kg every 3 weeks, administered as a 
30 minute infusion if the initial loading dose was well tolerated. Trastuzumab infusion will be 
prepared and administered in accordance to institutional guidelines. 
 
Trastuzumab-qyyp will be provided and shipped by Pfizer directly to MSKCC. Receipt and 
dispensing of trial medication must be recorded by an authorized person at the trial site. The 
investigator is responsible for keeping accurate records of the clinical supplies received from Pfizer 
or designee, the amount dispensed to and returned by the subjects and the amount remaining at the 
conclusion of the trial. 
 
5.2 Pembrolizumab Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks. 
 
5.2.1 Pembrolizumab Storage and Accountability 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Receipt and dispensing of trial medication must be recorded by an 


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IRB Number: 20-158 A(2) 
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Page 10 of 46 
 
 
 
 
authorized person at the trial site. Clinical supplies may not be used for any purpose other than that 
stated in the protocol. 
 
5.2.2 Dispensing of Pembrolizumab 
Pembrolizumab will be provided by Merck at no charge. Pembrolizumab will be provided in 
100mg/4mL vials and shipped by Merck directly to the MSKCC. Receipt and dispensing of trial 
medication must be recorded by an authorized person at the trial site. The investigator is responsible 
for keeping accurate records of the clinical supplies received from Merck or designee, the amount 
dispensed to and returned by the subjects and the amount remaining at the conclusion of the trial. 
 
MSK will submit a cross reference application to the FDA for the use of pembrolizumab in 
combination with trastuzumab. 
 
5.2.3 Preparation and Administration of Pembrolizumab 
Investigators should consult the manufacturer’s instructions for pembrolizumab for complete 
prescribing information and follow institutional procedures for the administration of pembrolizumab. 
Pembrolizumab should be administered on Day 1 of each 21 day cycle after all procedures and 
assessments have been completed as detailed on the Trial Flow Chart (Section 11.0). 
Pembrolizumab 200mg will be administered as a 30-minute IV infusion every 3 weeks. Variation in 
infusion time is permitted per institutional standards. 
 
5.2.4. Timing of Administration 
Treatment will be administered in the following order: pembrolizumab will be administered first, 
followed by trastuzumab infusion. 
 
6.1 
CRITERIA FOR PARTICIPANT ELIGIBILITY 
 
6.2 
Participant Inclusion Criteria 
 
• 
Age 18 years or older. 
• 
ECOG performance status 0-2. 
• 
Sign informed consent within 8 months after curative surgery and completion of standard 
of care perioperative and/or adjuvant therapy. 
• 
HER2+ esophageal, GEJ, or gastric adenocarcinoma biopsy or resection specimen as 
defined by local HER2 IHC3+ or IHC 2+/FISH>2.0 expression. 
• 
Must have genetic testing of DNA from primary tumor for somatic genomic alterations 
across a minimum of 50 genes. 
• 
Must have undergone a complete curative surgical resection (R0). 
• 
Must have completed standard of care (SOC) surgery, neoadjuvant or adjuvant therapy 
• 
CtDNA will be tested at a minimum of four weeks after completion of surgery and 
standard perioperative and/or adjuvant therapy. To be eligible for 
trastuzumab/pembrolizumab therapy, the patients must have positive ctDNA (as defined 
in section 7.0) within 8 months after completion of appropriate standard of care therapy 


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IRB Number: 20-158 A(2) 
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Page 11 of 46 
 
 
 
 
(surgery, chemotherapy, radiation as appropriate). For all patients, if the initial ctDNA has 
a negative result, ctDNA can be re-tested 4 weeks later, within 9 months of completion of 
standard therapy. 
• 
Demonstrate adequate organ function as defined in Table 1. 
 
Table 1 – Organ Function Requirements for Eligibility 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL 
Renal 
Serum creatinine 
≤1.5 X upper limit of normal (ULN) 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN. Except patients with Gilbert’s disease (≤3xULN) 
AST and ALT 
≤ 2.5 X ULN 
Albumin 
>3 mg/dL 
 
 
6.3 
Participant Exclusion Criteria 
 
• 
Patients who have not recovered from serious adverse events (as determined by treating MD) 
related to surgery. 
• 
Presence of metastatic or recurrent disease. 
• 
Had R1 (microscopic residual tumor) or R2 resection (macroscopic residual tumor at resection 
margin). 
• 
Left   ventricular   ejection   fraction   <50%   within   1   month   of   screening  by   MUGA 
or 
echocardiogram. 
• 
Is currently participating and receiving study therapy  or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
• 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
• 
Patients who have received acute, low dose, systemic immunosuppressant medications 
(e.g., dexamethasone containing antiemetic regimen or steroids as CT scan contrast 
premedication) may be enrolled. 
• 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients 
with orthostatic hypotension or adrenocortical insufficiency is allowed. 
• 
Has a known history of active TB (Bacillus tuberculosis) 
• 
Hypersensitivity to pembrolizumab or any of its excipients. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
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• 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
o Note:   If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy. 
• 
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis 
• 
Has known history of, or any evidence of active, non-infectious pneumonitis. 
• 
Has an active infection requiring systemic therapy. 
• 
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of 
the trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator. 
• 
Has known psychiatric or substanceabuse disorders that would interfere with cooperation with 
the requirements of the trial. 
• 
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after 
the last dose of trial treatment. 
• 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 agent. 
• 
Has received prior therapy with an anti-HER2 agent 
• 
Active or  prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease; systemic lupus erythematosus; Wegener syndrome [granulomatosis with 
polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis) 
within the past 3 years prior to the start of treatment. The following are exceptions to this 
criterion: 
o Subjects with vitiligo or alopecia 
o Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone 
replacement or psoriasis not requiring systemic treatment. 
• 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
• 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
• 
Has received a live vaccine within 30 days of planned start of study therapy. 
o Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed;  however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
• 
Is unwilling to give written informed consent, unwilling to participate, or unable to comply with 
the protocol for the duration of the study. 
 
7.0 
RECRUITMENT PLAN 
 
The sample size will be 24 patients with ctDNA-positive HER2+ EG cancer. Although we initially 
anticipated that we would need to screen 175 patients to identify 24 HER2+ patients (25% of 
esophagogastric cancers) with detectable ctDNA after adjuvant therapy (57%, unpublished data), 


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Page 13 of 46 
 
 
 
 
based on our experience to date, we anticipate that we will need to screen closer to 400 patients to 
identify 24 patients who meet all enrollment criteria. Given ~240 esophagectomies and 
gastrectomies annually at MSKCC, an accrual duration of ~2 years is expected. 
 
In order to be eligible, the patient must be ctDNA-positive following standard of care therapy 
(surgery, chemotherapy, radiation as appropriate). If the initial ctDNA has a negative result, ctDNA 
can be re-tested 4 weeks later, within 9 months of completion of standard therapy. ctDNA will be 
defined as positive if at least one mutation is shared between the tumor and ctDNA sequence, as 
described in a manuscript that is in-preparation for publication. In a review of relatedness among 
mutations found in ctDNA sequenced with MSK-ACCESS (the novel next-generation sequencing 
assay designed at MSK to detect and identify ctDNA) and MSI tumors sequenced with MSK- 
IMPACT,  one shared mutation will provide an estimated relatedness of 68.2% [95% CI 46.6% to 
98.8%]; if two mutations are shared, the estimated relatedness is 93.3% [95% CI 82.6% to 99.6%]. 
The mutation(s) of interest can be assessed as changes at the nucleotide or protein level (i.e. KRAS 
c.35G>A vs. KRAS G12D). 
 
In the event that a patient has multiple concurrent tumors, all resectable tumors identified through 
imaging will be sequenced with IMPACT (or similar as outlined in this protocol), as per standard of 
care. Mutations derived from ctDNA data will be interpreted in the context of tumor sequencing data 
independently.  Only ctDNA that has achieved acceptable relatedness with mutations found in 
tumors (as defined in section 7.0 of this protocol) will used for assessment in this trial. 
 
All eligible patients, regardless of sex and race, will be approached for participation. No additional 
measures, e.g. advertisement or payment to patients, will be employed to recruit patients. 
 
During the initial conversation between the investigator/research staff and the patient, the patient  
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical records 
at MSKCC in order to further assess eligibility. They will use the information provided by the patient 
and/or medical record to confirm that the patient is eligible and to contact the patient regarding study 
enrollment. If the patient turns out to be ineligible for the research study, the research staff will 
destroy all information collected on the patient during the initial conversation and medical records 
review, except for any information that must be maintained for screening log purposes. 
 
Participation in the study is completely voluntary. Patients/LAR will be required to read, agree to, 
and sign an IRB-approved informed consent form prior to registration on this trial. Patients will not 
receive payment for their participation on this study. Patients are free to withdraw from the study 
without consequence at any time. 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at MSKCC. If the investigator is a member of the treatment 
team, s/he will screen their patient’s medical records for suitable research study participants and 


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IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
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New York, New York 10065 
Page 14 of 46 
 
 
 
 
discuss the study and their potential for enrolling in the research study. Potential subjects contacted 
by their treating physician will be referred to the investigator/research staff of the study. 
 
7.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. During 
the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. The individual signing the Eligibility Checklist is confirming whether the 
participant is eligible to enroll in the study. Study staff are responsible for ensuring that all 
institutional requirements necessary to enroll a participant to the study have been completed. See 
related Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
 
8.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
9.1 
PRE-TREATMENT/INTERVENTION 
 
Pretreatment evaluation will be performed within 2 weeks of study entry and will include: 
• 
History, concomitant medications, and toxicity assessment. 
• 
Physical exam, vital signs, and performance status (ECOG). 
• 
Serum or urine pregnancy test for women of childbearing potential (WOCBP) 


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Page 15 of 46 
 
 
 
 
 
In addition, all WOCBP should be instructed to contact the Principal Investigator 
immediately if they suspect they might be pregnant (e.g. late or missed period) at any 
time during study participation. 
• 
Laboratory evaluation including complete blood count, comprehensive chemistry panel 
(includes  BUN,  creatinine,  sodium,  potassium,  chloride,  CO2,  calcium,  glucose, 
bilirubin, total, protein, total, albumin, alkaline phosphatase, AST, ALT), TSH and free 
T4. 
• 
Research blood tests including whole blood collection for peripheral blood mononuclear 
cells (PBMC) and peripheral blood lymphocytes (PBLC). 
• 
Tumor Markers: CEA, LDH (per clinically indicated) 
• 
Electrocardiogram (ECG) 
 
The following must be obtained within 28 days prior to starting protocol therapy: 
• 
CT scan of chest, abdomen and pelvis within 4 weeks of study entry 
• 
Collection of archival tumor tissue for correlative testing 
• 
ctDNA collection 
• 
Echocardiogram or MUGA scan 
 
To be completed any time prior to starting therapy: 
• 
Histological confirmation of cancer diagnosis at MSKCC prior to study enrollment. 
 
10.0 TREATMENT/INTERVENTION PLAN 
 
Study treatment in all arms will begin on Day 1 of each 3-week dosing cycle (21 days). This study 
will be conducted as a single arm pilot study. Trastuzumab (8mg/kg loading dose; 6mg/kg 
maintenance) will be administered on day one of each 3 week cycle according to standard-of-care. 
Pembrolizumab will be prepared by the research pharmacy staff and administered intravenously. 
Pembrolizumab will be given as follows: pembrolizumab 200 mg IV every 3 weeks over 30 minutes. 
Treatment should begin as close as possible to the date on which the participant is enrolled. 
Treatment will be performed on the scheduled day (± 7-day treatment window) on an outpatient 
basis. Adverse events will be monitored throughout the study and graded in severity according to the 
guidelines outlined in the NCI CTCAE version 5. 
CT scan and ctDNA assessment will be performed at baseline, and every 3 months for the first 12 
months post-enrollment. Follow-up will start at the time of disease recurrence, removal from study 
any reason other than recurrence, or completion of treatment. If the patient is removed for disease 
recurrence, they will be followed for overall survival every 3 months for the first-year post enrollment, 
every 6 months for years 2 and 3 post-enrollment, and then every 12 months for years 4 and 5 post- 
enrollment. If the patient is removed for toxicity or completion of pembrolizumab + trastuzumab 
therapy, they will be followed with a CT scan and ctDNA assessment every 6 months for years 2 and 
3 post-enrollment and then every 12 months for years 4 and 5 post-enrollment. Each subject will be 
on study from the time of enrollment for up to 5 years. 
10.1 Exploratory Correlative Studies 


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Details for correlative collection are listed in Appendix 1. Patients will be offered the option of 
consenting to 06-107 and corresponding Biospecimen Research Protocols (optional). For consented 
patients, upon completion of all exploratory correlative studies, any leftover blood or tissue samples 
will be re-banked for future use in unspecified research. 
10.1.1 Collection of peripheral blood mononuclear cells (PBMC), plasma for peripheral blood 
lymphocytes  (PBLC), and immunologic analyses 
Whole blood will be used for isolation of PBMCs. Flow cytometry will be performed on PBMCs at 
baseline and during treatment to assess changes in composition/activation status of lymphocyte 
subsets, including CD8+ and CD4+ T-cell subsets (activated; effector/memory; regulatory) and 
populations of those cells as defined by the expression of activation, exhaustion, or signaling 
markers such as ICOS, HLA-DR, PD-1, CTLA-4, and/or intracellular IFNγ. 
Approximately 16 ml of whole blood per visit (baseline, C1D1, C2D1, C3D1, C4D1, at every imaging 
timepoint and treatment discontinuation) will be collected at ambient temperature into 2 x 8-ml BD 
sodium heparin Cell Preparation Tubes (CPT) for density gradient centrifugation and isolation of 
PBMC and plasma for banking according to institutional procedures at the MSKCC Ludwig Center 
for Cancer Immunotherapy Immune Monitoring Core Facility. After centrifugation, the plasma 
supernatant will be collected and then the PBMC monolayer isolated and washed. PBMC will 
resuspended at ~6-8 million cells per vial in cell freezing medium, frozen at –80 degrees C in 
controlled rate cooling containers, and then cryopreserved in liquid nitrogen freezers. Plasma will be 
frozen in 1.5 ml aliquots and stored at –20 degrees C. 
10.1.2 Collection of blood for ctDNA 
 
DNA extracted from plasma will be assessed at baseline, every imaging timepoint, and at the time of 
treatment discontinuation for the presence of mutations. Testing may be performed using digital PCR 
or next-generation sequencing but must be able to reliably identify genomic alterations (excluding 
copy number changes or fusions) at or below a minimum allele frequency of 0.25%. 
Testing must be performed by a CLIA-certified laboratory or equivalent. We will limit ctDNA testing to 
the following assays: 
• 
Guardant 360, Guardant Health, Redwood City, CA 
 
• 
MSKCC Access, MSKCC, New York, NY 
 
Approximately 40-60 ml of whole blood per visit will be collected at ambient temperature into 4-66x 
10mL cell free DNA BCT tubes for plasma isolation. Minimum requirements are at least 10cc of 
plasma or 10ng of isolated cfDNA. Appendix 1 outlines the number of tubes required for ctDNA 
collection at each timepoint. 
 
The same assay used to detect ctDNA at baseline should be used for all subsequent timepoints. 


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MSK-ACCESS is a next-generation sequencing assay designed to detect mutations in cell free  
DNA.  This assay uses custom DNA probes and unique molecular indexes (Integrated DNA 
Technologies, US) that were designed to capture selected exons and introns in 129 genes.  The 
selected genes in this panel were chosen to interrogate at least 1 mutation in 84% of >20,000  
tumors analyzed with MSK-IMPACT.   These libraries are sequenced using the Illumina HiSeq 
system with paired end reads (2 x 100bp), to achieve >20,000x average total coverage and a 
collapsed unique coverage of >1,000x.  After bioinformatic pipeline filtering the data are pushed 
through a custom read collapsing algorithm, resulting in a cfDNA consensus read. These consensus 
reads will be aligned back to the human genome followed by variant calling using VarDict.  MSK- 
ACCESS allows for detection of somatic mutations down to 0.3% mutation allele fractions at 1000x 
uniquely collapsed coverage per loci.  For all time points, ctDNA testing will be performed at the 
Department of Molecular Pathology at MSK.  This is a CLIA-certified laboratory and all testing will be 
in accordance to the Clinical Laboratory Improvement Amendments of 1988. 
 
10.1.3 T-cell receptor (TCR) Sequencing 
 
DNA extracted from formalin-fixed or frozen primary tumor tissue will need to be sequenced to 
identify somatic mutations across all or a subset of the coding regions for at least 50 genes. 
Sequencing must be performed by a CLIA-certified laboratory or equivalent and may be performed 
using tumor only or tumor with matched normal. Tumor sequencing will be performed in the 
Memorial Sloan Kettering Molecular Genetics Laboratory. 
The presence of tumor infiltrating lymphocytes (TILs) and TCR clonality will be assessed by TCR 
sequencing of tumor and serially collected PBLC using ImmunoSEQTM (Adaptive  Biotechnologies), 
or similar assay if updated. This assay identifies unique TCRβ-chains by sequencing the rearranged 
CDR3 regions in the β-chain gene locus. The relative abundance of unique TCRβ CDR3 regions 
across the repertoire and interference of T cell quantity within each sample is estimated from 
sequence data. This will allow us to quantify the presence and relative clonality of specific TCR 
clones in the tumor and peripheral blood. 
 
The number of antigens on tumors that are recognized by the immune system have been defined at 
the molecular level, including both tumor-associated antigens and tumor-specific antigens. These 
antigens can be recognized by the adaptive immune system and serve to direct an immunologic 
response to cancers. Techniques including intracellular cytokine staining, IFNy release assays and 
tetramer assays, will be used for quantification and functional characterization of antigen-specific T 
cells in human peripheral blood and tumors samples. These functional, tumor antigen-specific T 
cells may be relevant markers of disease response. 
 
Cytokines and chemokines are readily detected in serum samples from patients and may provide 
evidence of an ongoing immune response. The type(s) of cytokines or chemokines, the kinetics and 
magnitude of changes, and the corresponding clinical events may be used to characterize the 
ctDNA clearance and immune response. The MSKCC Immune Monitoring  Facility has a specialized 


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Page 18 of 46 
 
 
 
 
platform, the Meso Scale Delivery System, to detect cytokines and chemokines in patient samples 
sensitively and accurately. 
10.1.4 PD-L1 testing of archival tissue 
 
PD-L1 expression in tumor tissue will be characterized by IHC to explore the relationship between 
PD-L1 expression and response to pembrolizumab. Other exploratory biomarkers including but not 
limited to PD-1 expression and markers of T-cell phenotype may also be evaluated. Testing will be 
done at the Memorial Sloan Kettering Cancer Center Pathology lab. 
10.1.5 Tumor microenvironment analysis 
 
FFPE sections of pre-treatment tumors will be analyzed using multi-parameter IHC Vectra platform, 
focusing on the specific components of the tumor microenvironment (e.g. CD4, CD8, CD68, FoxP3) 
as well as immune-inhibitory markers (e.g. PD-L1, IDO). RNA will be extracted from archival tumors 
and analyzed for broad expression of genes related to immune function (e.g. type I and type II IFN 
signatures) using RNAseq, Affymetrix microarray, or targeted multiparameter PCR (e.g. Nanostring). 
11.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
Screening 
Cycle  1 
(21 days) 
Cycle 2 & 
thereafter  (21 
days) 
End of 
Treatment 
Follow-up  (Every  3 months 
year 1 post-enrollment,  6 
months years 2 and 3 post- 
enrollment,  then every  12 
months years 4 and 5 post- 
enrollment) 
≤28 
days 
≤14 
days 
Day 1 
Day 1 
Informed  consent 
X 
Pembrolizumab1 
X 
X 
Trastuzumab 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
History and exam, 
vitals,  weight, 
ECOG PS 
X 
X 
X 
X 
X 
CT assessment2 
X 
X- Every  3 months 
X 
2 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
CBC with diff,  plts 
X 
X 
X 
X 
X 
Chemistry3 
X 
X 
X 
X 
X 
TSH, Free T4 
X 
X 
X 
X 
Pregnancy  test4 
X 
ECG 
X 
ECHO/MUGA5 
X 
X- Every  3 months 
Tissue Collection6 
X 
PBMC and PBLC7 
X 
X 
X7 
X 


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Page 19 of 46 
 
 
 
 
 
Tumor  Markers8 
X 
X 
X 
ctDNA9 
X9 
X- Every  3 months9 
X 
X9 
Fresh Biopsy 
X10 
1. 
Patients will receive  pembrolizumab  200 mg IV every  3 weeks +/-7days off for one year, until 
disease recurrence,  intolerable toxicity or patient refusal. 
2. 
CT scan chest, abdomen and pelvis  with IV contrast ≤28 days prior to registration, then once every 
3 months for the first 12 months post-enrollment,  every  6 months in years 2 and 3 post enrollment, 
and then every  12 months in years 4 and 5 post enrollment. This CT schedule should occur until 
documented recurrence  of disease. Patients in whom IV contrast is contraindicated are 
recommended  to have MRI abdomen  and non-contrast  chest CT scan. A given  CT or MRI may be 
+/- 14 days of time points for specific administrative  reasons, in particular clinic closure for holidays 
or patient’s preference. 
3. 
Chemistry panel:   BUN, creatinine, sodium, potassium, chloride, CO2, calcium, glucose, bilirubin, 
total protein, albumin, alkaline phosphatase,  AST, ALT 
4. 
For women of childbearing  potential only, serum or urine pregnancy  test within 14 days of starting 
treatment. 
5. 
Baseline ECHO/MUGA must be obtained within one month prior to starting protocol therapy. ECHO 
with speckle tracking will be the preferred modality for LVEF assessment. When possible, the same 
method used to measure LVEF at baseline (either ECHO or MUGA) should be used throughout the 
study. Repeat LVEF assessments will be performed every 3 months after initiating protocol therapy. 
Window of +/-14 days for ECHO/MUGA. 
6. 
Tissue collection (Archival)  within 28 days of starting treatment. 
7. 
PBMC and PBLC collection should be done at screening,  C1D1, C2D1,  C3D1, C4D1,  each imaging 
timepoint (every  3 months up to 48 weeks), and end of treatment (EOT) 
8. 
Tumor markers to be drawn as appropriate  for tumor type at each visit (CEA, LDH) 
9. 
ctDNA collection should be done  at the following frequency  if the subject is actively  receiving 
treatment, removed  from  study for any reason other than recurrence  or completes treatment: 
baseline (at screening or pre-treatment  D1), each imaging timepoint, EOT, in follow-up  (every  3 
months for the first 12 months post-enrollment,  every 6 months in years 2 and 3 post enrollment, and 
then every  12 months in years 4 and 5 post enrollment). ctDNA is not required for collection after a 
patient is removed  from study for disease recurrence. 
10. Post recurrence  biopsy (optional) 
 
12.0   CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops radiographic disease recurrence, defined by radiographic evidence 
of recurrence by CT imaging, the patient will be taken off study and followed for overall survival. If at 
any time the patient develops unacceptable toxicity that fails to resolve after a maximum treatment 
delay of 9 weeks, he/she will be removed from treatment and followed for survival. At the end of 
treatment visit, patients will be scanned and have ctDNA drawn to assess the response. 
 
A patient will be withdrawn from the study treatment in the following circumstances: 
 
• 
The patient is no longer able to participate in the study (e.g., AE, surgery, concomitant 
diagnoses, concomitant therapies or administrative reasons); in such a case the treating 
investigator’s reason for a patient’s removal must be recorded in CRDB. 
• 
Patient withdrawal of consents or election to discontinue participation in the trial 


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• 
Significant deviation from the protocol or eligibility criteria; such patients will be considered 
protocol violations and removed from study 
• 
Non-compliance with study or follow-up procedures 
• 
Drug related AE(s) have not resolved after 9 weeks of treatment interruption. Exception to 
this in patients who derive obvious clinical benefit according to the investigator’s judgment 
could be considered upon discussion with Principal Investigator. The dose reduction scheme 
provided should be followed in this case. 
• 
Repeated episodes of drug related toxicity appropriate management. 
• 
Documented disease recurrence by CT imaging. 
 
As soon as a patient is removed from the study treatment, the End of Treatment (EOT) visit has to be 
performed within 1-14 days after off treatment date. Every effort should be made to follow up patients 
in case an adverse event is still ongoing at the time of withdrawal. Patients with radiologically 
documented disease recurrence should be removed from the study. 
 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
 
13.1 Criteria for Therapeutic Response/Outcome Assessment 
The primary endpoint of the study is the proportion of patients with ctDNA clearance at 6 months 
with trastuzumab/pembrolizumab in patients with HER2+ esophagogastric cancer with persistent 
ctDNA despite curative surgery and standard perioperative/adjuvant  therapy. CtDNA clearance is  
the conversion of detectable to undetectable ctDNA (as defined in section 7.0). The secondary 
endpoints include safety, DFS and OS. The patients will be assessed with a CT scan and ctDNA 
assessment at baseline and every 3 months for first 12 months post-enrollment, every 6 months in 
years 2 and 3 post-enrollment, and then in years 4 and 5 post-enrollment. CtDNA recurrence is 
defined as the detection of ctDNA after prior non-detectable ctDNA; however, only recurrence by 
standard radiographic criteria will be used for removal from study and secondary endpoints of DFS.  
If the scan shows disease recurrence, the patient will enter the event monitoring phase and will be 
followed for overall survival. Anytime a patient has intolerable toxicity, or declines further treatment 
they will go to event monitoring phase and will be followed with a CT scan and ctDNA assessment 
every 3 months for first 12 months post-enrollment, every 6 months in years 2 and 3 post-enrollment, 
and then every 12 months in years 4 and 5 post-enrollment. Patients will be considered as responders 
if they have ctDNA clearance at 6 months. Patients will be considered as non- responders                   
if they do not experience ctDNA clearance at 6 months or If imaging shows disease recurrence 
before or at 6 month assessment. 
13.2 Criteria for Study Endpoint Evaluability 
Patients who were enrolled but not treated with trastuzumab + pembrolizumab will be replaced by a 
new patient. Patients are evaluable for the primary endpoint if they receive at least one dose of 
trastuzumab/pembrolizumab and will be assessed for therapeutic response as per Section 13.1. All 
patients who receive at least one dose of trastuzumab + pembrolizumab or will be evaluable for the 
secondary endpoints of safety, DFS and OS, as well as the exploratory endpoints. OS is defined as 


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the time from treatment start until death or last follow up, whichever comes first, while DFS is 
defined as the time from treatment start until recurrence or death, whichever comes first. 
 
 
14.0 
BIOSTATISTICS 
 
This is a single arm pilot study in which HER2+ patients with MRD (defined by detection of ctDNA in 
their plasma after completion of curative surgery with R0 resection and standard perioperative 
therapy) receive trastuzumab + pembrolizumab. Patients with HER2+ esophagogastric cancer will 
be consented within 8 months after curative surgery and completion of standard of care adjuvant 
therapy (if appropriate), and will undergo ctDNA testing at a minimum of 4 weeks after completion of 
definitive therapy. Patients with positive ctDNA (as defined per Section 7.0) will be enrolled to 
receive 6 months of trastuzumab in combination with pembrolizumab. 
 
The statistical analysis of the data obtained will be the responsibility of the MSKCC Biostatistics 
department. The official, final database will not be analyzed until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and  
complete. The primary endpoint is clearance of ctDNA at 6 months post-enrollment. CtDNA 
clearance is defined as the conversion of detectable to undetectable ctDNA (as per in section 7.0). 
Patients who have ctDNA clearance at 6 months will be considered responders, and patients who do 
not have ctDNA clearance at 6 months or have disease recurrence by CT scan before or at 6  
months will be considered non-responders. Patients are evaluable for the primary endpoint if they 
receive at least one dose of trastuzumab + pembrolizumab. Patients will receive therapy for 6 
months and will be followed on study for 5 years after enrollment for survival. The patients will be 
assessed with a CT scan and ctDNA assessment at baseline and every 3 months for first 12 months 
post-enrollment, every 6 months in years 2 and 3 post enrollment, and then every 12 months in years 4 
and year 5 post enrollment. Patients who received at least one dose of study drug and come off 
therapy before 6 months for reasons other than disease recurrence will be followed with scans and 
ctDNA levels. Anytime a patient has intolerable toxicity or declines further treatment, they will go to 
event monitoring phase and will be followed with a CT scan and ctDNA assessment every 3 months  
for the first 12 months post-enrollment, every 6 months in years 2 and year 3 post enrollment, and 
then every 12 months in year 4 and year 5 post enrollment. In the event of disease recurrence by CT 
imaging, the patient will be followed for overall survival. Patients that are lost to follow up without a 6- 
month evaluation will be treated as events (non-responder). 
 
A Simon’s two-stage optimal design will be used to differentiate 6-month clearance rates of 5% vs 
25%. We are using a null ctDNA clearance rate of 5% because the expected ctDNA clearance rate 
with observation alone is extremely low, as nearly all patients with positive ctDNA after surgery and 
adjuvant chemotherapy relapse. The chosen design has a type I and type II error rate of 0.1 each. 
We plan to treat 9 patients in the first stage. If one or more patients demonstrate ctDNA clearance at 
6 months, then we would enroll 15 more patients (total of 24 patients). We will not hold accrual after 
the first 9 patients, but we will monitor these patients for 6-month ctDNA clearance to assess for 
futility and early termination of the arm based on the decision rule. If we observe three or more 


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Page 22 of 46 
 
 
 
 
patients with ctDNA clearance among the 24 patients, then the treatment will be considered worthy 
for further investigation. 
 
Clearance rate of ctDNA at 6 months will be evaluated using binomial proportions, and exact 95% 
confidence interval will be provided. With 24 patients we can estimate the 6-month clearance rate to 
within +/-  20% margins of error with 95% confidence. As we will need to screen approximately 400 
patients to accrue this study, we anticipate enrollment will take 2 years. 
 
 
Secondary endpoints of the study include: 
 
• 
Safety of 6 months of adjuvant trastuzumab in combination with pembrolizumab in HER2+ 
patients. AEs of any grade considered related to trastuzumab and pembrolizumab will be 
summarized descriptively using percentages separately for each treatment arm. 
• 
DFS (median, 1-year and 2-year) and OS (median, 2-year and 5-year) will be analyzed 
separately in each arm. DFS is defined as the time from treatment start till recurrence or 
death, whichever comes first. OS is defined as the time from treatment start until death or 
last follow up, whichever comes first. Survival curves will be estimated using the Kaplan- 
Meier method. 
Exploratory endpoints of the study include: 
 
• 
Perform correlative analyses including whole exome analysis in order to determine mutation 
load and specific neoantigen landscape with strong association in patients with ctDNA 
clearance. The Mann–Whitney test will be used to compare mutational loads of tumors 
among responders and non-responders. 
• 
Plasma samples taken at sequential time points during this trial will be used to evaluate the 
role of trastuzumab and pembrolizumab in reducing or delaying disease recurrence. Multiple 
plasma collection timepoints to monitor ctDNA clearance is integral to generate sufficient 
data to establish the effect of HER2-targeted therapy and immunotherapy in the adjuvant 
setting for samples with MRD as determined with ctDNA. PBMC and ctDNA levels will be 
summarized at each timepoint using descriptive statistics including median and interquartile 
range. Due to the limited sample size, these analyses are exploratory. 
• 
To describe the independent and inter-dependent associations between other assays such 
as gene expression, TCR sequencing, immunophenotyping, as well as their association with 
ctDNA clearance. Gene set enrichment analysis will explore pathways associated with 
response as determined by ctDNA clearance. Deconvolution of immune gene expression to 
estimate the relative proportion of immune cell subtypes in the tumor microenvironment will 
be explored using CIBERSORT. 
• 
Descriptive statistics of the longitudinal ctDNA levels and changes in the immune landscape 
using PBMC from timepoints taken from enrollment to end-of-study will be used to explore 
the mechanisms of primary and acquired resistance. 


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Page 23 of 46 
 
 
 
 
• 
Perform correlative analyses on archival tumor samples and post-recurrence tumor biopsies, 
including TCR rearrangements and whole exome sequencing to compare any changes in 
tumor mutational burden in HER2+ tumors. Changes in tumor mutational burden between the 
pre- and post- recurrence will be assessed using Wilcoxon sign rank test. 
• 
DFS and OS for ctDNA responders and non-responders will be assessed using the Kaplan 
Meier method and log-rank test. 
These analyses are exploratory in nature and hypothesis generating due to limited sample 
size. Exploratory endpoints will be evaluated in each treatment arm separately. 
15.0 TOXICITIES/RISKS/SIDE EFFECTS 
 
The treating investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart (Section 11.0) and more frequently if clinically 
indicated. AEs will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 5.0. Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatm ent. For subjects 
receiving treatment with pembrolizumab all AEs of unknown etiology associated with pembrolizumab 
exposure should be evaluated to determine if it is possibly an event of clinical interest (ECI) of a 
potentially immunologic etiology (termed immune-related adverse events, or irAEs). 
 
15.1 Trastuzumab 
Principal AEs of trastuzumab include the following: 
 
Cardiomyopathy 
Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, 
cardiomyopathy, cardiac death or asymptomatic decline in left ventricular ejection fraction (LVEF). 
Caution should be exercised in treating patients with increased cardiac risk (e.g., hypertension, 
documented coronary artery disease, CHF, diastolic dysfunction, older age). Monitoring  and 
management is described below in 15.1.2. 
 
Infusion reactions 
Infusion/administration-related  reactions (ARRs) and hypersensitivity are known to occur with the 
administration of trastuzumab. Pre-medication may be used to reduce risk of occurrence of infusion 
reactions. 
 
Pulmonary toxicity 
Serious and fatal pulmonary toxicity has been reported with trastuzumab. Pulmonary toxicity 
includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic 
pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and 
pulmonary fibrosis. 
 
Embryo-fetal toxicity 


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IRB Number: 20-158 A(2) 
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Page 24 of 46 
 
 
 
 
Trastuzumab can cause fetal harm when administered to a pregnant woman. In post-marketing 
reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios. 
 
Other toxicities 
Most common adverse reactions ( ≥ 10%) include neutropenia, diarrhea, fatigue, anemia, stomatitis, 
weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, 
nasopharyngitis, and dysgeusia. 
 
15.1.1 Trastuzumab Dose Delays or Modifications 
There will be no dose modifications of trastuzumab. Trastuzumab dose delays are permitted for 
Grade 3/4 clinical toxicity or at the treating investigator’s discretion. Dose delays are not required for 
laboratory abnormalities unless associated with clinical symptoms. Omitted doses of trastuzumab 
are not replaced or restored; instead, the patient should resume the planned treatment cycles. 
Patients who develop signs and symptoms of congestive heart failure (CHF) should have 
trastuzumab held and should receive treatment for CHF. Patients with an asymptomatic absolute 
decrease in LVEF of >16 percentage points or an absolute decrease in LVEF of 10 to 15 percentage 
points to below the lower limit of normal should have trastuzumab held as outlined below. 
 
15.1.2 Congestive Heart Failure and other Cardiac Dysfunction Associated with Trastuzumab 
All patients must have a baseline evaluation of cardiac function including a measurement of LVEF 
by ECHO (with speckle tracking) prior to entry into the study. If an ECHO cannot be performed or is 
technically limited, a MUGA scan can alternatively be performed. Patients with a normal LVEF 
(>50%) are eligible for entry into the study. 
 
All patients will undergo regular cardiac monitoring throughout the study, including at baseline and 
every 12 weeks after initiating trastuzumab. During the course of trastuzumab therapy, patients 
should be monitored for signs and symptoms of CHF (i.e., dyspnea, tachycardia, new unexplained 
cough, neck vein distention, cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, 
orthopnea, peripheral edema, and rapid unexplained weight gain). Patients who develop signs or 
symptoms of CHF will be further evaluated with a repeat LVEF assessment using the same method 
selected at baseline (either ECHO or MUGA)  if possible. 
 
Management of Symptomatic Cardiac Changes 
Patients who develop signs and symptoms of CHF should have trastuzumab held and should  
receive treatment for CHF as recommended by the American Heart Association (AHA)/American 
College of Cardiology (ACC) (e.g., ACE inhibitors, angiotensin-II receptor blockers, beta-blockers, 
diuretics, and cardiac glycosides, as needed) with referral to cardiology for consultation. If the 
symptoms of CHF resolve with treatment, and/or cardiac function improves to baseline, reinitiation of 
trastuzumab can be considered at the discretion of the treating investigator after discussion with the 
patient concerning the risks and benefits of continued therapy and in consultation with a cardiologist. 
If trastuzumab is restarted, continued surveillance with noninvasive measures of LVEF (MUGA or 
ECHO) will resume as regularly scheduled. Additional LVEF assessments prior to the next regularly 
scheduled LVEF measurement may be performed at the treating investigator‘s discretion. 


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Page 25 of 46 
 
 
 
 
 
 
Management of asymptomatic Decreases in LVEF 
Trastuzumab can be continued in patients experiencing an asymptomatic absolute decrease in  
LVEF of <16 percentage points from baseline, when the LVEF remains within the imaging center's 
range of normal limits. Repeat measures of LVEF should be obtained using the methodology 
selected at baseline if possible. Close follow-up of such patients is recommended. Patients with an 
asymptomatic absolute decrease in LVEF of >16 percentage points or an absolute decrease in  
LVEF of 10 to 15 percentage points to below the lower limit of normal should have trastuzumab held. 
Referral to cardiology should be considered for evaluation and management of left ventricular 
systolic dysfunction with adherence to ACC/AHA guidelines. In light of the variability inherent in the 
assessment of ejection fraction, consideration should be given to repeating the study within 4-7 days 
to confirm an observed decline. Repeat measures of LVEF should be obtained using the same 
methodology selected at baseline if possible, but at the discretion of the treating investigator or 
consulting cardiologist. If trastuzumab has been held for an asymptomatic decline in LVEF, a repeat 
measure of LVEF will be obtained within 1 month to evaluate for recovery of LVEF. If LVEF does not 
improve after repeat assessment within 1 month, the patient should be monitored with monthly or as 
clinically indicated ECHOs/MUGAs until LVEF is improved. If cardiac function improves and LVEF  
no longer meets hold criteria as defined above, trastuzumab may be restarted. If trastuz umab is 
restarted, continued surveillance with noninvasive measures of LVEF (MUGA or ECHO), using the 
optimal methodology as determined by the treating investigator or consulting cardiologist, will resume 
per the standard schedule. 
 
15.2 Pembrolizumab 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizum ab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per table 2 below. Most common adverse reactions 
(≥20%) are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, 
pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. 
 
Table 2: Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose. 
3-4 
Permanently  discontinue 
Permanently  discontinue 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Type 1 diabetes 
mellitus  (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab  for new onset 
Type 1 diabetes mellitus or Grade 3- 
4 hyperglycemia associated w ith 
evidence of beta cell failure. 
Resume pembrolizumab  w hen patients are clinically and 
metabolically  stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
Hypothyroidism 
2-4 
Therapy w ith pembrolizumab  can be 
continued w hile treatment for the 
thyroid disorder is instituted 
Therapy w ith pembrolizumab  can be continued w hile 
treatment for the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently  discontinue 
Permanently  discontinue 
Pneumonit is 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
3-4 
Permanently  discontinue 
Permanently  discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
3-4 
Permanently  discontinue 
Permanently  discontinue 
All Other Drug- 
Related Toxicity1 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 Patients w ith intolerable or persistent Grade 2 drug-related AEmay hold study medication at treating physician discretion. Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment w ith study drug has been held, that do not recover to Grade 
0-1 w ithin 12 w eeks of the last dose. 
 
 
15.2.1 Supportive Care 
 
• 
Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• 
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 


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Page 27 of 46 
 
 
 
 
 
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For  Grade  2  diarrhea/colitis  that  persists  greater  than  3  days,  administer  oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
o Pembrolizumab can be held until the patient is off corticosteroids. 
 
• 
Type 1 diabetes mellitus (DM) (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
 
o For Type 1 DM or Grade 3-4 Hyperglycemia 
▪ 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
▪ 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
• 
Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
• 
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ 
In 
hyperthyroidism, 
non-selective 
beta-blockers 
(e.g. propranolol) 
are 
suggested as initial therapy. 
▪ 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine  or 
liothyronine, is indicated per standard of care. 


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Approval date: 07-Jul-2021 
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Page 28 of 46 
 
 
 
 
o Grade 3-4 hyperthyroidism 
▪ 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
• 
Hepatic: 
o For Grade 2 events,  monitor liver  function  tests more frequently  until  returned  to 
baseline values (consider weekly). 
▪ 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
▪ 
Treat with IV methylprednisone 1-4 mg/kg at investigator’s discretion 
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade  1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
 
15.2.2 Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology.   These 
immune-related adverse events (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may 
be included as part of the evaluation.  Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.  Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab are provided in Table 3. 
Please refer to the IB for a complete list of reported AEs.  Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 3. 
Table 3: Dose Modification and Toxicity Management Guidelines for Immune-Related 
AEs Associated With Pembrolizumab 


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General instructions: 
Corticosteroid taper should be initiated upon AE improving  to Grade 1 or less and continue to taper 
over  at least 4 weeks. 
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. 
For severe and life-threatening  irAEs, IV corticosteroid should be initiated first followed  by oral steroid. 
Other immunosuppressive  treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-relat 
ed AEs 
Toxicity 
grade or 
conditio 
ns 
(CTCAE 
v5.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other  therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer 
corticosteroids  (initial 
dose of 1-2mg/kg 
prednisone  or 
equivalent)  followed  by 
taper 
Monitor participants for 
signs and symptoms of 
pneumonitis 
Evaluate  participants with 
suspected pneumonitis  with 
radiographic  imaging and 
initiate corticosteroid 
treatment 
Add prophylactic  antibiotics 
for opportunistic  infections 
Grade 3 
or 4, or 
recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea  / 
colitis 
Grade 2 
or 3 
Withhold 
Administer 
corticosteroids  (initial 
dose of 1-2mg/kg 
prednisone  or 
equivalent)  followed  by 
taper 
Monitor participants for 
signs and symptoms of 
enterocolitis (i.e., diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever)  and of bowel 
perforation  (i.e., 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. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation  or 
Grade 2 
Withhold 
Administer 
corticosteroids  (initial 
dose of 0.5- 1mg/kg 
Monitor with liver function 
tests (consider weekly or 
more frequently  until liver 


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Page 30 of 46 
 
 
 
 
 
General instructions: 
Corticosteroid taper should be initiated upon AE improving  to Grade 1 or less and continue to taper 
over  at least 4 weeks. 
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. 
For severe and life-threatening  irAEs, IV corticosteroid should be initiated first followed  by oral steroid. 
Other immunosuppressive  treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-relat 
ed AEs 
Toxicity 
grade or 
conditio 
ns 
(CTCAE 
v5.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other  therapies 
Monitor and follow-up 
increased 
Bilirubin 
prednisone  or 
equivalent)  followed  by 
taper 
enzyme value  returned to 
baseline or is stable). 
Grade 3 
or 4 
Permanently 
discontinue 
Administer 
corticosteroids  (initial 
dose of 1-2 mg/kg 
prednisone  or 
equivalent)  followed  by 
taper 
T1DM  or 
hyperglycemia 
Newly 
onset 
T1DM or 
Grade 3 
or 4 
hyperglyc 
emia 
associate 
d with 
evidence 
of b-cell 
failure 
Withhold 
Initiate insulin 
replacement  therapy for 
participants with T1DM 
Administer 
anti-hyperglycemic  in 
participants  with 
hyperglycemia 
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids  and 
initiate hormonal 
replacements  as 
clinically indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including  hypopituitarism 
and adrenal  insufficiency) 
Grade 3 
or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidis 
m 
Grade 2 
Continue 
Treat  with non-selective 
beta-blockers  (e.g., 
propranolol)  or 
thionamides  as 
appropriate 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 
or 4 
Withhold or 
Permanently 
discontinue1 


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IRB Number: 20-158 A(2) 
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Page 31 of 46 
 
 
 
 
 
General instructions: 
Corticosteroid taper should be initiated upon AE improving  to Grade 1 or less and continue to taper 
over  at least 4 weeks. 
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. 
For severe and life-threatening  irAEs, IV corticosteroid should be initiated first followed  by oral steroid. 
Other immunosuppressive  treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-relat 
ed AEs 
Toxicity 
grade or 
conditio 
ns 
(CTCAE 
v5.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other  therapies 
Monitor and follow-up 
Hypothyroidis 
m 
Grade 
2-4 
Continue 
Initiate thyroid 
replacement  hormones 
(e.g., 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  1-2mg/kg 
or equivalent)  followed 
by taper. 
Monitor changes of renal 
function 
Grade 3 
or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
or 2 
Withhold 
Based on severity  of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation  to confirm 
etiology and/or exclude 
other causes 
Grade 3 
or 4 
Permanently 
discontinue 
All Other 
immune-relate 
d AEs 
Intolerabl 
e/ 
persisten 
t Grade 2 
Withhold 
Based on severity  of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation  to confirm 
etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Guillain-Barre 
Syndrome  and 
encephalitis 
Grade 4 
or 
Permanently 
discontinue 


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IRB Number: 20-158 A(2) 
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Page 32 of 46 
 
 
 
 
 
General instructions: 
Corticosteroid taper should be initiated upon AE improving  to Grade 1 or less and continue to taper 
over  at least 4 weeks. 
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. 
For severe and life-threatening  irAEs, IV corticosteroid should be initiated first followed  by oral steroid. 
Other immunosuppressive  treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-relat 
ed AEs 
Toxicity 
grade or 
conditio 
ns 
(CTCAE 
v5.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other  therapies 
Monitor and follow-up 
recurrent 
Grade 3 
AE=adverse event; ALT=alanine aminotransferase; AST= aspartate aminotransferase; CTCAE= Common Toxicity 
Criteria for Adverse Events; GI=gastrointestinal; irAE=immune related adverse event; IV=intravenous ; 
T1DM=Type  1 diabetes mellitus. 
1 Withhold or permanentlydiscontinue pembrolizumab is at the discretion of the investigator or treating physician; 
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathywhere withhold of pembrolizumab is 
required, pembrolizumab maybe resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapyor achieved metabolic control (in case of T1DM). 
 
15.2.3 Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction are 
provided in Table 4. 
Table 4: Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption  not 
indicated;  intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires  therapy or 
infusion interruption but 
Stop Infusion. 
Additional appropriate  medical therapy may 
include but is not limited to: 
Participant may be 
premedicated  1.5 h 
(±30 minutes) prior to 


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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
responds  promptly to 
symptomatic  treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids);  prophylactic 
medications  indicated 
for ≤24 hrs 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion,  the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise,  dosing will be 
held until symptoms resolve and the participant 
should be premedicated for the next scheduled 
dose. 
Participants who develop  Grade 2 toxicity 
despite adequate premedication  should be 
permanently  discontinued from further study 
drug treatment. 
infusion  of pembrolizumab 
with: 
Diphenhydramine  50 mg po 
(or equivalent  dose of 
antihistamine). 
Acetaminophen 
500-1000  mg po (or 
equivalent  dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged  (i.e., not 
rapidly responsive  to 
symptomatic 
medication and/or brief 
interruption  of infusion); 
recurrence  of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae  (e.g., renal 
impairment, pulmonary  
infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support  indicated 
Stop Infusion. 
Additional appropriate  medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine  should 
be used immediately. 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Participant is permanently discontinued 
from further study drug treatment. 
CTCAE=Common  Toxicity Criteria for Adverse Events ;  IV=intravenous;  NCI=  National  Cancer Institute; 
NSAID=non-steroidal  anti-inflammatory  drug;  po=per OS (orally) 
Appropriate  resuscitation equipment  should be available  at the bedside and a physician readily available 
during the period of drug administration. 
For further information,  please refer  to the CTCAE  v5.0 at http://ctep.cancer.gov 
 
 
 
15.2.4 Other allowed dose interruption for pembrolizumab 
 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / 
surgical events or logistical reasons not related to study therapy. Participants should be placed back 
on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the 
study PI. The reason for interruption should be documented in the participant’s study record. 
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between 
pembrolizumab doses for non-study medication-related or administrative reasons require 
consultation between the investigator and the study PI. 
15.3 Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Subjects should be 
informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if 
pregnancy were to occur during the study. In order to participate in the study subjects of childbearing 
potential must adhere to the contraception requirement (described in Table 5) from the day of study 
medication initiation (or 14 days prior to the initiation of study medication for oral contraception) 
throughout the study period up to 120 days after the last dose of trial therapy. If there is any question 
that a subject of childbearing potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below) 
 
Women in the following categories are not considered WOCBP: 
 
• 
Premenarchal 
• 
Premenopausal female with 1 of the following: 


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o Documented hysterectomy 
o Documented bilateral  salpingectomy 
o Documented bilateral  oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
 
• 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required. 
o Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 
Male Participants: 
 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame: 
• 
Be abstinent from penile-vaginal  intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
• 
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per 
year as described in Table 9 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile- 
vaginal intercourse or use a male condom during each episode of penile penetration. 
Female Participants: 
 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception that has a low user dependency consistently and correctly as 
described in Table 4 during the protocol-defined time frame. 
Table 5. Contraceptive Methods 
 
 
Acceptable Contraceptive  Methods 
Failure rate of >1% per year when  used consistently and correctly. 
● 
Male or female condom with or without spermicide 


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● 
Cervical  cap, diaphragm  or sponge with spermicide 
Highly Effective  Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when  used consistently and correctly. 
• 
Combined  (estrogen- and progestogen-  containing ) hormonal  contraception  b 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
• 
Injectable 
• 
Progestogen-only  hormonal  contraception b 
• 
Oral 
• 
Injectable 
Highly Effective  Methods That Have Low User  Dependency 
Failure rate of <1% per year when  used consistently and correctly. 
• 
Progestogen-  only contraceptive  implant b, c 
• 
Intrauterine  hormone-releasing   system (IUS)  b 
• 
Intrauterine  device (IUD) 
• 
Bilateral tubal occlusion 
Vasectomized  partner 
A vasectomized partner is a highly effective  contraception method provided  that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional 
highly effective  method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective  method only if defined as refraining  from 
heterosexual  intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated  in relation to the duration of the study and the 
preferred  and usual lifestyle of the participant.) 
 
 
Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment, the subject will immediately be 
removed from the study. The site will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated. The outcome of the 
pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours to the 
Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother 
or newborn). 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to Merck. 
 
Use in Nursing Women 
 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 


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15.4 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention.  SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event.  All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 


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• 
If the SAE is an Unanticipated Problem 
 
 
15.5 Merck Global Safety Reporting 
 
For the time period beginning when the consent form is signed until treatment 
allocation/enrollment, any AE, or follow up to a serious AE, including death due to any cause 
that occurs to any participant must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety if it causes the participant to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet or a procedure. 
For the time period beginning at treatment allocation/enrollment through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates 
new anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a 
serious adverse event, including death due to any cause whether or not related to the Merck 
product, must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified in 
the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally, investigators will submit a copy of these reports to Merck  & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
 
15.6 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215-661-6229). 
For the time period beginning when the consent form is signed until treatment 
allocation/enrollment, any ECI, or follow up to an ECI, that occurs to any participant must be 
reported within 2 working days to Merck Global Safety if it causes the participant to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure. 


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For the time period beginning at treatment allocation/enrollment through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates 
new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 2 working days to Merck Global Safety. 
Events of clinical interest for this trial include: 
 
1. an overdose of Merck product, as defined in Section 15.7 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
15.7 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) 
15.8 Pfizer Global Safety Reporting 


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16.1 PROTECTION OF HUMAN PARTICIPANTS 
 
The responsible principal investigator will ensure that this study is conducted in agreement 
with the declaration of Helsinki. The study will seek to protect the rights of human subjects in 
every way. The potential risks, including adverse drug reactions and potential benefits in 
terms of pain control will be discussed in detail with the patients. 
Potential side effects as outlined above will be discussed with the patients. No patient will be 
required to participate in the study and participation, or refusal to do so, will not affect the 
patient’s care or treatment. 
The patient will not incur any financial cost as a result of participation in the study. Patients 
will be given up to $100 per treatment visit (for up to 1 year) for travel related expenses 
incurred while on study. 
Participation will be purely voluntary, patient confidentiality will be maintained. No results of 
the study will be presented or discussed in a fashion that will allow identification of a 
particular patient in the study. All adverse events will be fully reported to the IRB in a timely 
fashion as required. 
16.1 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals/entities described in the 
Research Authorization form. A Research Authorization form must be approved by the IRB 
and Privacy Board (IRB/PB). 
The consent indicates that individualized  de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with others at 
the time of study publication. 
 
16.2 
Data Management 
 
Data to be collected include documentation from all outpatient visits, laboratory, pharmacy, 
and treatment records. Data will be collected and stored in Medidata. 
At MSKCC a Clinical Research Associate (CRA) and/or Clinical Research Coordinator (CRC) 
will be assigned to the study. The responsibilities of the CRA and/or CRC include 
confirmation of patient eligibility,  project compliance, data collection, abstraction and entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and coordination 
of the activities of the protocol study team. Source documentation will be available to support 
computerized patient records. 


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Final data sets for publication are required to be locked and stored centrally for potential 
future access requests from outside entities. 
16.3 
Quality Assurance 
 
Data and project enrollment will be monitored on an ongoing basis by the Principal 
Investigator. The CRA or CRC will inform the PI about the number of patients enrolled, the 
number of patients in follow-up, and any other outstanding issues. A log will be maintained of 
eligible vs. enrolled patients. The study data will be assessed for completeness. Random - 
sample data quality and protocol compliance audits will be conducted by the study team at 
minimum of two times per year or more frequently if problems are encountered. 
16.4 
Data and Safety Monitoring 
 
The Data and Safety Monitoring Plan utilized for this study must align with the MSK DSM  
Plan, where applicable. 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by 
the National Cancer Institute in August 2018. The plans address the new policies set forth by 
the NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety  
Monitoring  of Clinical Trials.” 
There are several different mechanisms by which clinical studies are monitored for data, 
safety and quality. At a departmental/PI level there exists procedures for quality control by 
the research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA 
and two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Deputy Physician-in-Chief,  Clinical Research. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials.  The 
DSMB/C have oversight over the following trials: 
• 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
• 
External studies where MSK is the data coordinating center 
• 
Low risk studies identified as requiring DSMB/C review 
 
The DSMC will initiate review following the enrollment of the first participant/or by the end of 
the year one if no accruals and will continue for the study lifecycle until there are no 
participants under active therapy and the protocol has closed to accrual. The DSMB will 
initiate review once the protocol is open to accrual. 


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17.0 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 44 of 46 
 
 
 
 
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18.0 
APPENDICES 
 
Appendix 1. Correlative Collection Table 
Appendix 2. Investigational Scan Considerations 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 45 of 46 
 
 
 
 
 
 
Specimen 
Collection 
Time Points 
Mandatory 
or 
Optional? 
SOC or 
Research? 
Collection 
Amount 
Specimen 
Processing 
Location 
Shipping Details 
Analysis 
(reason for 
specimen 
collection) 
Storage 
Tumor 
tissue 
SCR, 
Progression 
Screening 
(Mandatory 
), 
Recurrenc 
e (optional) 
RNB 
(screening), 
SOC at 
recurrence 
TISSUE 
SECTIONING 
REQUESTS ARE 
TO BE MADE IN 
BATCH ONLY 
TCR:  10 x 5µm 
FFPE tissue curls 
are to be collected 
fromeach biopsy. 
Curls are to be cut 
serially and kept in 
a DNAse/RNAse 
free screw-top 
microtube. 
PD-L1, IHC 
Vectra: 10 x 5µm 
serial sections are 
to be cut from 
each biopsy. 
Sections are to be 
mounted on 
charged slides, 
one section per 
slide. Slides 
should be 
numbered to 
differentiate 
section sequence 
(e.g. 1/5, 2/5, etc). 
TCR sequencing: 
MSK IMF lab 
PD-L1: MSK 
Pathology Lab 
Tumor 
environment 
analysis via IHC 
Vectra: Dr. Taha 
Merghoub/Wolcho 
k lab 
TCR sequencing: 
FFPE tissue 
samples ship 
ambient, Fresh- 
frozen tissue 
shipped on dry ice. 
PD-L1, IHC 
Vectra: FFPE 
tissue samples 
ship ambient, 
Fresh-frozen 
tissue shipped on 
dry ice 
TCR sequencing 
PD-L1 via IHC 
Tumor 
environment 
analysis via IHC 
Vectra 
Yes to 
future 
use 
Blood for 
SOC labs 
SCR, all D1, 
EOT 
Mandatory 
SOC 
Variable 
MSK 
N/A 
CBC, chemistry, 
thyroid function, 
pregnancy test 
(as required) 
N/A 
Plasma 
for ctDNA 
SCR, 
imaging 
timepoint, 
EOT, 
Follow -up 
Mandatory 
RNB 
4x 10mL cell free 
DNA BCT tubes 
(screening) 
6x 10mL cell free 
DNA BCT tubes 
(all other time 
points) 
Department of 
Molecular 
Pathology at MSK 
Ambient, shipped 
immediately by 
courier to 
Department of 
Molecular 
Pathology at MSK 
ctDNA 
Yes to 
future 
use 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-158 A(2) 
Approval date: 07-Jul-2021 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 46 of 46 
 
 
 
 
 
 
Specimen 
Collection 
Time Points 
Mandatory 
or 
Optional? 
SOC or 
Research? 
Collection 
Amount 
Specimen 
Processing 
Location 
Shipping Details 
Analysis 
(reason for 
specimen 
collection) 
Storage 
Whole 
blood for 
PBMC 
PBLC 
SCR, C1D1, 
C2D1, 
C3D1, 
C4D1, Each 
imaging 
timepoint(up 
to 48 
w eeks), 
EOT 
Mandatory 
RNB 
2 x 8-ml BD 
sodium heparin 
Cell Preparation 
Tubes 
MSK: Center 
Ludw ig Center for 
Cancer 
Immunotherapy 
Immune 
Monitoring Core 
Facility 
Ambient, shipped 
immediately  by 
courier to IMC 
Facility at MSK 
Ludw ig Cancer for 
processing 
Density gradient 
centrifugation 
and isolation of 
PBMC/PBLC 
and plasma 
PBMC/PBLC  w ill 
resuspended at 
~6-8 million cells 
per vial in cell 
freezing 
medium, frozen 
at –80 degrees 
C in controlled 
rate cooling 
containers, and 
then 
cryopreserved in 
liquid nitrogen 
freezers 
Plasma w ill be 
frozen in 1.5 ml 
aliquots and 
stored at –20 
degrees C. 
Yes to 
future 
use 
 
 
Appendix 2:  Investigational Scan Considerations 
 
All disease assessment scans will be performed per standard of care. 
 
Patients on study will have a biopsy at time of recurrence.  Patients undergoing investigational CT- 
guided biopsies are exposed to an additional 0.626 Gy (+/- 0.132) dermatologically, an additional 
29.9 mSv in for scan done in helical mode and an additional 18.9 mSv for scans done in axial mode. 
It is estimated that each patient will have up to 1 additional scan for CT-guided biopsies. 
The informed consent will include the necessary risk language on contrast use and low-level 
radiation.