Clinical trial NCT04089904
Conditions: Gastroesophageal Junction Adenocarcinoma Gastric Adenocarcinoma Esophageal Adenocarcinoma
Sponsor: University of Chicago
Start date: 2019-10-11; Completion date: 2023-03-11
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To determine the pathologic complete response (pCR) rate in patients with cT1b-T2N0 GEA treated with neoadjuvant pembrolizumab followed by surgical resection.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Pembrolizumab Injection
Intervention descriptions: intervention 1: Patients will receive 3 cycles of pembrolizumab at 200mg intravenously on day 1 of a 3 week cycle. After 3 cycles the patients will undergo surgery

Protocol documents:
Prot_SAP_000.pdf: 
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Local Protocol #: 
IRB19-0310 
 
TITLE:  A Phase II Trial of Neoadjuvant Pembrolizumab for Resectable Early Stage 
Gastroesophageal Adenocarcinoma 
 
 
Coordinating Center: 
 
The University of Chicago 
 
Principal Investigator: 
Ardaman Shergill, M.D. 
 
The University of Chicago Medicine  
5841 S. Maryland Ave 
 
 
 
 
 
MC2115 
 
 
 
 
Chicago, IL  60637 
 
Phone: (773) 702-4274 
ashergill@medicine.bsd.uchicago.edu 
 Co-Investigators:  
 
 
  Surgeons:  
 
Mitchell Posner, MD 
Mark Ferguson, MD 
Kevin Roggin, MD 
Jessica Donington, MD 
University of Chicago Medicine 
5841 S. Maryland Ave, Room G209, MC 5094 
Chicago IL 60637 
mposner@surgery.bsd.uchicago.edu 
mferguso@surgery.bsd.uchicago.edu 
kroggin@surgery.bsd.uchicago.edu  
jdonington@surgery.bsd.uchicago.edu  
 
  Gastroenterologists:  
  Uzma Siddiqui, MD Irving Waxman, MD 
  Irving Waxman, MD 
 
  Christopher Chapman, MD 
  The University of Chicago Medicine Center for Care and Discovery 
  5700 S. Maryland Avenue MC 8043 
  Chicago, IL 60637 
  Phone: (773) 702-145 
  Fax: (773) 834-8891 
  usiddiqui@bsd.uchicago.edu  
  iwaxman@medicine.bsd.uchicago.edu 
  Christopher.Chapman@uchospitals.edu  
 
 
  
 
  Pathologists 
John Hart, MD 


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Shu-Yuan Xiao, MD 
Namrata Setia, MD 
Lindsay Alpert, MD 
University of Chicago Medical Center 
Department of Pathology 
Chicago, IL 60637 
Phone: 773 702 9319 
John.Hart@uchospitals.edu 
sxiao@bsd.uchicago.edu 
Namrata.Setia@uchospitals.edu 
Lindsay.Alpert@uchospitals.edu 
 
 Statistician:  
 Theodore Karrison, Ph.D. 
    University of Chicago 
 5841 S. Maryland Ave. MC 2007 
 Chicago, IL 60637 
 Phone: 773-702-9326 
 tkarrison@health.bsd.uchicago.edu  
 
 
 
Version Date: 01/25/2022  
 
 
 
This study will be managed by the Personalized Cancer Care Consortium (PCCC).  


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DOCUMENT HISTORY 
 
 
Protocol Version Date  
Summary of Changes  
5/12/21 
• Biopsy/Endoscopy language added to 
Section 8.1.2.6.2  
• Standard PCCC Language added to: 
- 
Section 5: Registration Procedures  
- 
Section 8.2.3.2: UChicago/PCCC 
SAE reporting language  
- 
Section 11.0: Regulatory 
management language added to  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0 TRIAL SUMMARY ..................................................................................................................6 
2.0  TRIAL DESIGN .......................................................................................................................6 
3.0 
OBJECTIVES & HYPOTHESES .......................................................................................7 
3.1 
Primary Objective & Hypothesis  Objective: ...........................................................7 
3.2 
Secondary Objectives & Hypotheses  Objectives: ...................................................7 
3.3 
Exploratory Objectives ............................................................................................8 
4.0 
BACKGROUND & RATIONALE......................................................................................8 
4.1 
Background ..............................................................................................................8 
4.2 
Rationale ................................................................................................................10 
5.0 REGISTRATION PROCEDURES .........................................................................................14 
5.1 General Guidelines.......................................................................................................14 
5.2 Registration Process .....................................................................................................14 
6.0 
METHODOLOGY ............................................................................................................14 
6.1 
Study Population ....................................................................................................14 
6.2 
Trial Treatments .....................................................................................................18 
6.3 
Randomization or Treatment Allocation ...............................................................26 
6.4 
Concomitant Medications/Vaccinations (allowed & prohibited) ..........................26 
6.5 
Participant Withdrawal/Discontinuation Criteria ...................................................28 
6.6 
Participant Replacement Strategy ..........................................................................29 
6.7 
Clinical Criteria for Early Trial Termination .........................................................29 
7.0 
TRIAL FLOW CHART .....................................................................................................30 
7.1 
Study Flow Chart ...................................................................................................30 
8.0 
TRIAL PROCEDURES .....................................................................................................32 
8.1 
Trial Procedures .....................................................................................................32 
8.2 
Assessing and Recording Adverse Events .............................................................40 
9.0 
STATISTICAL ANALYSIS PLAN ..................................................................................49 
9.1 
Statistical Analysis Plan Summary ........................................................................49 
10.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ...50 
10.1 
Investigational Product ..........................................................................................50 
10.2 
Packaging and Labeling Information .....................................................................50 
10.3 
Clinical Supplies Disclosure ..................................................................................50 
10.4 
Storage and Handling Requirements .....................................................................50 
10.5 
Returns and Reconciliation ....................................................................................51 
11.0 STUDY MANAGEMENT AND REGULATORY AFFAIRS .............................................52 
11.1  Multicenter Guidelines...........................................................................................52 
11.2 
Institutional Review Board (IRB) Approval and Consent .....................................52 


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11.3 Required Documentation ...........................................................................................52 
11.4 
Data and Safety Monitoring ...................................................................................53 
11.5  Auditing .................................................................................................................53 
11.6 
Amendments to the Protocol ..................................................................................54 
11.7 
Annual IRB Renewals, Continuing Review and Final Reports .............................54 
11.8 
Record Retention ...................................................................................................54 
11.9 
Obligations of Study Site Investigators .................................................................55 
12.0 APPENDICES ......................................................................................................................55 
13.0 REFERENCES .....................................................................................................................64 
 
 
 
 


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1.0 TRIAL SUMMARY 
 
Abbreviated Title 
Neoadjuvant pembrolizumab for resectable early stage gastroesophageal 
adenocarcinoma 
Trial Phase 
IIa 
Clinical Indication 
Resectable cT1b-2N0M0 gastroesophageal adenocarcinoma 
Trial Type 
Prospective clinical trial 
Type of control 
Historical controls 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups 
1 
Number of trial participants 
33 
Estimated enrollment period 
24 months 
Estimated duration of trial 
36 months 
Duration of Participation 
Until 5 years post-surgical resection, death, or study closure 
Estimated average length of 
treatment per patient 
8-11 weeks (pembrolizumab IV q 3 weeks x 3 cycles followed by surgery 
within 8-11 weeks from first dose of pembrolizumab) 
 
 
2.0  TRIAL DESIGN 
2.1 Trial Design  
This is a prospective, single-arm phase IIa study enrolling patients with cT1b-2N0Mx esophageal 
and gastric adenocarcinoma. Patients will receive 3 cycles of pembrolizumab 200mg intravenously 
on day 1 of a 3-week cycle. After 3 cycles, patients will undergo surgery. The target surgery date 
is 8-11 weeks after the first dose of pembrolizumab. Surgical approach will vary based upon tumor 
location but would entail tumor resection with either D2 or two-field lymphadenectomy. The 
primary objective is to determine the pathologic complete response (pCR) rate in patients with 
cT1b-T2N0 gastroesophageal adenocarcinoma (GEA) treated with neoadjuvant pembrolizumab 
followed by surgical resection. A sample size of 33 patients will provide 90% power with one- 
sided alpha 0.1 to detect a pCR rate of 15% using neoadjuvant pembrolizumab. Secondary 
endpoints include R0 resection rate, safety and tolerability, disease-free survival (DFS), and 
overall survival (OS). Diagnostic tissue biopsy and surgical resection specimen pre- and post- 
pembrolizumab therapy will be assessed for panel DNA/RNA next generation sequencing (NGS), 
programmed death-ligand 1 (PD-L1) combined positive score (CPS) testing, Epstein-Barr virus 
(EBV) testing, microsatellite instability (MSI) testing and tumor mutation burden (TMB). Plasma 
circulating tumor DNA (ctDNA) samples will be collected for panel NGS (73 gene in real time, 
and more stored for larger 550 gene and smaller higher depth panels) prior to pembrolizumab 
therapy, after neoadjuvant pembrolizumab therapy but prior to surgery, after surgery, and upon 
recurrence if/when this occurs. Stool samples will also be obtained at these time points and 
subjected to Fecal 16S RNA seq. 


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2.2 Trial Diagram 
 
3.0 OBJECTIVES & HYPOTHESES 
 
3.1  Primary Objective & Hypothesis 
Objective: 
To determine the pathologic complete response (pCR) rate in patients with cT1b-T2N0 GEA 
treated with neoadjuvant pembrolizumab followed by surgical resection. 
 
Regression of the primary tumor will be documented by the amount of viable tumor versus the 
amount of fibrosis (Becker Criteria), ranging from no evidence of any treatment effect to a 
complete response with no viable tumor identified, as previously described[1] [Grade 1a: 
complete remission (pCR), no residual tumor/tumor bed; Grade 1b: subtotal remission, <10% 
residual tumor/tumor bed; Grade 2: partial remission, 10-50% residual tumor/tumor bed; Grade 
3: minor/no remission, >50% residual tumor/tumor bed]. 
 
Hypothesis: 
 
The pCR rate (Grade 1a+b response) in patients with cT1b-T2N0 GEA who receive 
neoadjuvant pembrolizumab followed by surgical resection will be 15%, whereas historical 
patients treated with surgery alone have a pCR rate of virtually 0%.[2, 3] 
 
3.2  Secondary Objectives & Hypotheses 
Objectives: 
a. To determine the R0 resection rate in patients with cT1b-2N0 GEA treated with 
neoadjuvant pembrolizumab. Proximal, distal, and circumferential margins will be 
assessed to determine the completeness of resection. The absence of tumor cells at the 
proximal and distal margins will be required to be classified as an R0 resection. 
b. To determine rates of Grade 1a (complete); 1b (minimal residual disease); 2 (partial 
response); and 3 (no response) pathologic response grades (PRG). 
c. To evaluate the safety/ tolerability of pembrolizumab in patients with cT1b-2N0 GEA 
d. To determine the DFS measured from the time of first pembrolizumab dose 
e. To determinate OS measured from the time of first pembrolizumab dose 
Pts with 
cT1bN0Mx or 
cT2N0Mx GEA, 
eligible for 
curative intent 
surgery 
Pembrolizumab 
200mg IV q3w x 
3 cycles 
Surgical 
resection 
Endpoints 
1°: pCR rate 
2°: R0 resection 
rate, safety, DFS, OS 
8‐11 weeks 
Surveillance 


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Hypotheses: 
 
a. R0 resection rate will be greater than 95%. 
b. A subset of cases will be G1b and G2 responses. 
c. Pembrolizumab will be safe and tolerable. Patients will successfully complete 
neoadjuvant therapy and undergo surgery 8-11 weeks after first dose of 
pembrolizumab. 
d. The DFS rate will be improved compared to historical controls. 
e. OS will be improved compared to historical controls. 
 
3.3 
Exploratory Objectives 
 
a. To evaluate rates of PD-L1 positive expression (by CPS score ≥1 and ≥10), MSI 
status, TMB and EBV status in pre-treatment biopsy specimens. 
b. To evaluate whether PD-L1 expression, MSI status, TMB and/or EBV status in pre- 
treatment biopsy specimen is a predictive biomarker for pCR/PRG/R0 to 
pembrolizumab and other clinical outcomes. 
c. To evaluate interval change in PD-L1 expression (by CPS score) pre/post 
pembrolizumab therapy in resected pathological specimens (if residual tumor is 
present). 
d. To determine the somatic genomic changes of actionable cancer related genes 
(mutation, amplification, indels, and translocation) using targeted deep next- 
generation sequencing (NGS) oncopanel in pre-treatment specimen and in resected 
specimen (if tumor is still present) and correlate with clinical outcomes (pCR/PRG, 
R0 rate, DFS, OS) and other molecular markers. 
e. To evaluate ctDNA NGS pre-pembrolizumab, post-pembrolizumab, post-surgery, and 
if applicable at time of recurrence, and correlate with clinical outcomes (pCR/PRG, 
R0 rate, DFS, OS) and molecular markers. 
f. To determine baseline and interval changes in whole-exome RNAseq expression 
analysis pre-/post- therapy. 
g. To evaluate fecal flora via Fecal 16S RNA seq pre-pembrolizumab, post- 
pembrolizumab, post-surgery, and if applicable at time of recurrence, and correlate 
with clinical outcomes. 
 
4.0 BACKGROUND & RATIONALE 
 
4.1 
Background 
 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of


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indications because of its mechanism of action to bind the PD-1 receptor on the T cell. For more 
details on specific indications refer to the Investigator brochure. 
 
Pembrolizumab is FDA approved for third line treatment of recurrent locally advanced or 
metastatic CPS >1 PD-L1+ GEA [4, 5] and for second line treatment of unresectable or 
metastatic microsatellite high (MSI-H) or mismatch repair deficient (dMMR) GEA. [5, 6] As 
the role of pembrolizumab continues to be investigated in the metastatic setting, newer trials are 
investigating the use of checkpoint blockade in the perioperative setting. KEYNOTE-585 is 
examining whether the addition of pembrolizumab to chemotherapy improves outcomes in the 
neoadjuvant or adjuvant setting in untreated patients with cT3 or cN+ GEA (NCT03221426). 
[7] CheckMate 577 is enrolling patients with stage II or III carcinoma of the esophagus of EGJ 
(squamous cell carcinoma and AC) treated with chemoradiation followed by surgery, who have 
an R0 resection yet residual disease, to receive nivolumab or placebo adjuvantly 
(NCT02743494).[8] 
 
4.1.1 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades. [9] Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma. [10, 11] 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte- 
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2). [12, 13] 
 
The structure of murine PD-1 has been resolved.[14] PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade.[13, 15-17] The mechanism by which PD-1 down-modulates T-cell responses 
is similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping 


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set of signaling proteins. [18, 19] As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in gastroesophageal adenocarcinoma. 
 
4.1.2 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 
Rationale 
 
4.2.1 Rationale for the Trial and Selected Population 
 
Gastroesophageal cancer is the second leading cause of cancer mortality worldwide. [20] Surgery 
and endoscopic resection are the only curative options for patients with early stage and/or locally 
advanced operable GEA. Survival is highly dependent on the extent of disease at presentation, in 
particular the depth of invasion and nodal status, as well as ability to obtain a complete (R0) 
resection and pCR. [21] The role of perioperative chemotherapy is clear in ≥cT3 and/or ≥cN1 
disease where R0 resection rates are 80-90% and pCR 15-25%. However, the benefit of such 
therapy in cT2N0 disease is less certain, and in cT1bN0 disease even less well studied. This is in 
part due to significant heterogeneity that exists in the enrollment criteria for the major clinical trials 
that have guided the use of neoadjuvant therapy. Trials have varied in their inclusion of cT2N0 
disease, use of EUS for staging, use of AJCC staging system, and reporting of outcomes by T and 
N status. There is thus great heterogeneity across treatment centers regarding the inclusion of 
cT1b-2N0 patients in perioperative therapy approaches. A recent retrospective analysis of 1704 
patients with cT2N0 gastric cancer found that there was no overall survival benefit derived from 
neoadjuvant and/or perioperative chemotherapy compared to surgery alone.[22] 
 
However, patients with cT2N0 esophageal adenocarcinoma (AC) (clinical stage IIB based on the 
AJCC 8th edition) have a 5-year risk-adjusted survival of only ~42% [23], a dismal number, and 
actually comparable to patients with stage III colon cancer where routine adjuvant therapy is 
implemented. Patients with cT1N0 esophageal AC (clinical stage I), have a 5-year risk-adjusted 
survival of only approximately 68%. Patients with cT1-2N0M0 gastric AC (clinical stage I) have 
an estimated 5-year survival of 57%. [24] There is a clear need to improve on outcomes in patients 
with operable GEA. It is quite evident that the optimal treatment of cT1-2N0 GEA is controversial 
without widespread implementation of any perioperative therapy, yet with acknowledged 
relatively poor outcomes. At the University of Chicago and many other centers, the standard of 
care for cT1-2N0 GEA is surgical or (endoscopic mucosal resection/dissection if early stage I 
cT1a) followed by observation. 
 
Recently, immune checkpoint blockade has emerged as a promising therapeutic strategy in GEA 
as discussed above. An unexplored area of research is whether neoadjuvant checkpoint blockade 
can improve outcomes in patients with cT1-2N0 GEA. In KEYNOTE-012, a phase 1b trial of 
pembrolizumab in recurrent or metastatic PD-L1+ GEA, the median time to response was 8 
weeks.[25] This median time to response has been now observed in other follow up studies of 
checkpoint inhibition in this disease. Thus, in cT1b-2N0 patients who would ordinarily undergo 
surgery alone, neoadjuvant pembrolizumab could, in a short amount of time, induce a response 
and still allow for surgery to be performed in a timely manner. Furthermore, the proportion of 


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MSI-H tumors (which are more sensitive to PD-1 blockade) appears to be enriched in the early 
stage setting compared to the metastatic setting in which pembrolizumab is currently approved. 
Moreover, the rate of PD-L1 positivity has been reported to be generally higher in earlier stage 
disease. Thus, these early stage patients, who otherwise have a moderate chance of recurrence with 
surgery alone, may in particular be worth targeting with neoadjuvant pembrolizumab. 
 
A potential concern may be that neoadjuvant pembrolizumab could delay curative surgery, 
allowing an early stage GEA to progress. However, a non-concurrent long term follow up study 
of patients with early gastric cancer elucidated the natural history of this disease and found that 
the median duration of those remaining in the early stage was 44 months. [26] Thus it is unlikely 
that delaying surgery by 8-11 weeks in order to obtain 3 doses of pembrolizumab would result in 
a clinically meaningful progression. Furthermore, in practice, surgery is often not scheduled for 
approximately 2-6 weeks after staging is complete, so the incremental delay attributed to receiving 
pembrolizumab is likely even less. Finally a recent neoadjuvant study in lung cancer demonstrated 
feasibility and safety in a similar setting.[27] This pilot study will provide early efficacy of 
pembrolizumab monotherapy using a pCR surrogate endpoint, and will also lend important pre- 
and post-pembrolizumab tissue for biomarkers analyses. 
 
4.2.2 Justification for Dose 
 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W) for 3 doses, 
neoadjuvantly. Based on the totality of data generated in the Keytruda development program, 
200 mg Q3W is the appropriate dose of pembrolizumab for adults across all indications and 
regardless of tumor type.  As outlined below, this dose is justified by: 
 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and exposure- 
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied. Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 


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the tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
 
4.2.3 Rationale for Endpoints 
 
4.2.3.1 Efficacy Endpoints 
 
There is compelling evidence that pathologic complete response rate is an early surrogate endpoint 
for survival in GEA. In patients with gastric cancer treated with neoadjuvant platinum-based 
chemotherapy, complete or subtotal tumor regression has been showed to be a prognostic factor 
independent from ypT and ypN stage.[28] In a large meta-analysis of patients with resectable GEA 
treated with neoadjuvant chemotherapy followed by surgery, those who achieved a pCR had 
improved survival than patients who did not achieve a pCR.[29] Thus, histopathologic regression 
measured as pCR rate is an appropriate endpoint for this phase 2 trial. 
 
4.2.3.2 Biomarker Research 
 
GEA is a heterogeneous group of diseases with variable benefit from pembrolizumab. The 
identification of biomarkers that predict response to immunotherapy may help guide selection of 
patients that are most likely to benefit from PD-1 blockade. Assuming adequate tissue and 
resources, the biomarker assessment outlined in the exploratory objectives (Section 3.3) will be 
performed. 
 
PD-1 and PD-L1 staining has been studied as predictive response biomarkers in several tumor 
types. In advanced NSCLC, PD-L1 expression of at least 50% of tumor cells correlates with 
prolonged PFS and OS with pembrolizumab treatment.[30] In KEYNOTE-059, patients with 
previously treated advanced GEA received pembrolizumab monotherapy and PD-L1 positive 
(CPS≥1) patients had a higher ORR compared to PD-L1 negative patients.[31] It is unknown if in 
the curative neoadjuvant setting, if PD-L1 expression is predictive for response to immunotherapy 
and whether PD-L1 expression changes pre- and post-pembrolizumab therapy. 


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The Cancer Genome Atlas research network recently reported the molecular characteristics of 
untreated gastric adenocarcinomas as part of The Cancer Genome Atlas project.[32] Gastric cancer 
was classified into the following four subtypes: MSI tumors (22%), EBV+ tumors (9%), tumors 
exhibiting chromosomal instability (CIN) (50%), and genomically stable (GS) tumors (20%). MSI 
has also been reported in 6.6% of untreated resected Barrett esophagus-associated EGJ AC.[33] 
MSI-H tumors and EBV+ tumors are thought to be sensitive to PD-1 blockade. This is due to high 
neoantigen levels in MSI-H tumors and due to high degree of PD-L1 positive T cell infiltration in 
both MSI-H and EBV+ tumors. Pembrolizumab is FDA-approved for patients with unresectable 
or metastatic MSI-H or dMMR of any solid tumor type, including GEA, that has progressed 
following prior treatment and who have no satisfactory alternatives.[6] The proportion of MSI-H 
tumors appears to be enriched in the early stage setting. Patients with EBV+ GC have improved 
survival which has been in part attributed to the associated rich CD8+ T-cell infiltrate present as 
part of the immune response against EBV[34-36] and increased PD-L1 and PD-L2 expression.[32] 
Recently reported was a patient with metastatic EBV+ esophagogastric cancer who had a durable 
complete response to immunotherapy.[37] It is unknown if MSI-H status or EBV positivity is 
predictive of response to PD-1 blockade in the neoadjuvant curative setting. 
 
TMB quantifies mutations present in tumor cells and is currently under investigation as a potential 
immunotherapy biomarker in several cancer types. In patients with stage IV NSCLC, an 
exploratory analysis found patients with high TMB had a improved response rate and progression 
free survival compared to low/medium TMB, when treated with nivolumab versus platinum-based 
chemotherapy.[38] There was no association between level of TMB and level of tumor PD-L1 
expression, however patients with PD-L1 expressions of <1% were excluded. The role of TMB as 
a predictive biomarker to PD-1 blockade in the early stage setting remains unknown. 
 
The Gajewski lab has previously demonstrated a correlation between fecal flora composition and 
response to immunotherapeutics.[39, 40] In this trial, patient fecal microbiomes will be 
characterized before pembrolizumab therapy, after pembrolizumab therapy, after surgery, and at 
time of recurrence (if applicable) in order to evaluate the relationship between fecal flora and 
therapeutic response. 
 
Patients who do not respond to immunotherapy may have various mechanisms of primary and/or 
acquired resistance. Genomic alterations will be characterized using targeted NGS in the pre- 
treatment specimen as well as in the resected specimen (if residual tumor is present) to evaluate if 
non-responders have particular mechanisms of resistance to therapy. Additional ctDNA will be 
evaluated before pembrolizumab therapy, after pembrolizumab therapy, after surgery, and at time 
of recurrence (if applicable) to characterize genomic alterations at diagnosis, identify temporal 
trends, identify ctDNA alterations that may be predictive of outcomes, and determine if presence 
of residual tumor ctDNA post-operatively is predictive of outcomes. 


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5.0 REGISTRATION PROCEDURES 
 
 
5.1 General Guidelines 
 
Prior to registration and any study-specific evaluations being performed, all patients must have given 
written informed consent for the study and must have completed the pre-treatment evaluations.  Patients 
must meet all of the Participant Inclusion Criteria in Section 6.1.1. Eligible patients will be entered on study 
centrally by the University of Chicago study coordinator. All sites should contact the study coordinator at 
PhaseIICRA@medicine.bsd.uchicago.edu to verify availability of a slot.  
 
 
5.2 Registration Process 
 
When a potential patient has been identified, notify the CRA via email at 
PhaseIICRA@medicine.bsd.uchicago.edu to ensure a reservation on the study. Reservations for 
potential subjects will only be held for subjects who have signed consent for that particular study. 
 
When registering a subject, the following must occur:  
 
• 
Confirm that the institution has a current IRB approval letter for the correct version of 
protocol/consent and has an annual update on file, if appropriate.  
• 
Submit all required materials (Eligibility Checklist, Source documentation, and signed consent 
form) to confirm eligibility and required pre-study procedures to the CRA a minimum of 48 
hours prior to the subject’s scheduled therapy start date.  
• 
Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source documentation but 
rather as a checklist that original source documentation exists for each criterion. 
• 
Communicate with the CRA to ensure all necessary supporting source documents are received 
and the potential subject is eligible to start treatment on schedule. If there are questions about 
eligibility, the CRA will discuss it with the Study Lead PI, Dr. Ardaman Shergill . Dr. Shergill 
may clarify, but not overturn, eligibility criteria.  
• 
Affiliate sites must confirm registration of subjects by obtaining a subject study ID number from 
the CRA via phone, fax or email.  
• 
If a subject does not start on the scheduled day 1 treatment date, promptly inform the CRA as the 
delay in start may deem the subject ineligible and/or require further or repeat testing to ensure 
eligibility.  
• 
If randomization is involved, the date the patient is randomized will be considered the patient’s 
“On Study Date.”  If randomization is not involved, the first time the patient receives treatment 
will be considered the patient’s “On Study Date.” The patient’s subject ID will be assigned and a 
confirmation of registration will be issued by the CRA on this date. Subjects that sign consent 
and do not go “On Study” will be recorded in the database with the date they signed consent and 
the reason for not going “OnStudy” (e.g., Ineligible, Screen Failure or Withdrawn Consent).  
 
6.0 METHODOLOGY 
 
6.1 
Study Population 
 
6.1.1 Participant Inclusion Criteria 


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Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of untreated esophageal adenocarcinoma 
(AC) (including Siewert type I and II esophagogastric junction AC) or gastric AC 
(including Siewert type III esophagogastric junction AC), with clinical stage T1b-T2, N0, 
and M0. Tumors that are adenosquamous are allowed if they are predominantly 
adenocarcinoma. 
 
2. Patients must undergo EUS, CT chest/abdomen/pelvis with IV/PO contrast (MRI 
abdomen/pelvis plus noncontrast chest CT is acceptable if patient has a contraindication to 
iodinated dye), and PET/CT to complete staging and confirm absence of metastatic disease. 
 
3. Patient must agree to a baseline EUS for centralized endoscopic staging to confirm the tumor 
is uT1b or uT2 and node negative, at which time a research biopsy endoscopically will also 
be obtained. 
 
4. HER2+ and HER2- patients, and all other known molecular subsets are eligible. 
 
5. Diagnostic laparoscopy is not mandated and can be performed as clinically indicated. 
 
6. Eligible for willing to proceed with surgery with curative intent 
 
7. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding,    and    at     least     one     of     the     following     conditions     applies: a.) 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days after the last dose of study treatment. 
 
8. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial. 
 
9. Measurable or non-measurable disease by RECIST 1.1 will be allowed. 
 
10. Is willing to provide tissue for correlative studies from the primary tumor lesion at baseline 
and at time of surgery. Is willing to provide blood and stool samples for all ordered studies. 
 
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG is to be performed within 7 days prior to the date of allocation. 


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12. Have adequate organ function as defined in the following table (Table 1). 
Table 1 Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
Creatinine OR 
Measured or calculated creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN 
Coagulation 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 
 
6.1.2 Participant Exclusion Criteria 
 
Participants are excluded from the study if any of the following criteria apply: 
 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see 
Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 


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2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137). 
 
3. Previous or concurrent malignancy, except for adequately treated basal cell or squamous 
cell skin cancer, in situ cervical cancer, or any other cancer for which the patient has been 
previously treated and the lifetime recurrence risk is less than 30%. 
 
4. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
 
6. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
7. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
 
8. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
 
9. Has an active infection requiring systemic therapy. 
 
10. Has a known history of Human Immunodeficiency Virus (HIV). 
 
11. Has a known history of active TB (Bacillus Tuberculosis). 
 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator. 
 
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose 
of trial treatment. 


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15. Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study treatment. 
 
6.1.3 Lifestyle Restrictions 
 
6.1.3.1 Meals and Dietary Restrictions 
 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
 
6.1.3.2 Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 3 for approved 
methods of contraception. 
 
For this study, male participants 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). 
 
6.1.4 Pregnancy 
 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). The 
treating 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. If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately and 
the pregnancy must be reported to Merck and followed as described in Section 8.2.2. 
 
6.1.5 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, 
participants who are breast-feeding are not eligible for enrollment. 
 
6.2 
Trial Treatments 
 
The treatment to be used in this trial is outlined below in Table 2 


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Table 2 Trial Treatment 
 
Drug 
Dose/Potenc y 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatmen t 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle x 3 cycles 
Experimenta l 
 
6.2.1 Timing of Dose Administration 
 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 7.0). Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
 
All trial treatments will be administered on an outpatient basis. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks for three 
doses. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
6.2.2 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 AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than on 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. 


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Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
Grade 4 
Permanently 
discontinue 


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feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4 
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-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 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non-selective beta- 
blockers (eg, propranolol) or 
thionamides as appropriate 
• 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 2 
Withhold 
• 
Monitor changes of renal function 


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Nephritis and 
Renal 
dysfunction 
Grade 3 or 4 
Permanently 
discontinue 
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 


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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 


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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 treating 
investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the treating 
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 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 


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Grades 3 or 4 
Stop Infusion. 
No subsequent dosing 
Grade 3: 
Additional appropriate medical therapy may include but is not limited to: 
Prolonged (i.e., not rapidly 
Epinephrine** 
responsive to symptomatic 
IV fluids 
medication and/or brief 
Antihistamines 
interruption of infusion); 
NSAIDs 
recurrence of symptoms 
Acetaminophen 
following initial improvement; 
Narcotics 
hospitalization indicated for 
Oxygen 
other clinical sequelae (e.g., 
Pressors 
renal impairment, pulmonary 
Corticosteroids 
infiltrates) 
Increase monitoring of vital signs as medically indicated until the 
Grade 4: 
participant is deemed medically stable in the opinion of the treating 
investigator. 
Life-threatening; pressor or 
Hospitalization may be indicated. 
ventilatory support indicated 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
treatment. 
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 Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 


 
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 2 weeks of the scheduled interruption, unless 
otherwise discussed with the P.I. The reason for interruption should be documented in the 
patient's study record. If there is any delay in pembrolizumab that would result in patient 
being unable to undergo surgery within 56-77 days of study initiation (day of first 
pembrolizumab dose), then patient will go off trial and go directly to surgery. 
 
6.3 
Randomization or Treatment Allocation 
 
This is an open-label trial; therefore, the P.I., treating investigator and subject will know the 
treatment administered. 
 
6.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination rests 
with the treating investigator and/or the participants’ primary physician. 
 
6.4.1 Acceptable Concomitant Medications 
 
All treatments that the treating investigator considers necessary for a participant’s welfare may 
be administered at the discretion of the investigator in keeping with the community standards 
of medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and Events of Clinical Interest (ECIs) as defined in Section 8.2. 
 
6.4.2 Prohibited Concomitant Medications 
 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (treatment phase refers to the time between the first dose of pembrolizumab 
and the date of surgery) of this trial: 
 
• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 


• Radiation therapy 
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed. 
 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the P.I. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. All 
treatments that the treating investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required. The final decision on any supportive therapy or vaccination rests with the 
treating investigator and/or the participant's primary physician. However, the decision to 
continue the participant on study treatment requires the mutual agreement of the treating 
investigator, the P.I. and the participant. 
 
Antibiotic therapies may be required by some participants during the study, but would avoid 
as safely able as this may affect pembrolizumab response and fecal flora.[41, 42] Antibiotic 
choice: Different classes of antibiotics have been shown to disrupt the microbiome and 
potentially interfere with normal host immune function to varying degrees. If equally indicated 
amoxicillin is the preferred antibiotic as it minimally alters gut flora. Clindamycin is the most 
detrimental antibiotic and should be avoided if possible.[43] Beta-lactams (other than 
amoxicillin) and fluoroquinolones broadly should be avoided if possible as well.[44] 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
6.4.3 Rescue Medications & Supportive Care 
 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.2.2, [Table 3]. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 


guidelines are intended to be applied when the treating investigator determines the 
events to be related to pembrolizumab. 
 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the treating investigator does not need to follow the treatment guidance. Refer to [Table 3] in  
Section 6.2.2 for guidelines regarding dose modification and supportive care. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
 
6.5 
Participant Withdrawal/Discontinuation Criteria 
 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the treating investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the treating 
investigator or the P.I. if study treatment is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 8.1.4 – Other Procedures. 
 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
 
• The participant or participant’s legally acceptable representative requests to 
discontinue study treatment 
 
• Confirmed radiographic disease progression outlined in Section 8.1.2.5.1 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 6.2.2. 
• The participant has a medical condition or personal circumstance which, in the 
opinion of the treating investigator and/or P.I., placed the participant at unnecessary 
risk from continued administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• The participant is lost to follow-up 
• Administrative reasons 


6.6 
Participant Replacement Strategy 
 
Patients that are not treated by intention to treat will be replaced to the total 33 patients 
intended. All patients who receive the first dose of pembrolizumab will be included in analysis 
per intention to treat. Patients who receive at least one dose of pembrolizumab and then do not 
proceed to surgery will be considered grade 3 response. 
 
6.7 
Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete with >10% of data 
unavailable. 
 
2. Poor adherence to protocol and regulatory requirements 
 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants 
 
4. Plans to modify or discontinue the development of the study drug 
 
5. If patient deaths or excessive toxicity attributed to the investigational drug are seen in the 
30 days following surgery. A 30‐day post‐operative death rate of >5% attributed to 
study agent is considered unacceptable. The relationship of the investigational drug to the 
mortality will be determined by the treating medical oncologist and surgeon. 
 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 


 
 
7.0 TRIAL FLOW CHART 
 
7.1 
Study Flow Chart 
 
 
 
Study 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Pre-Surgery 
Surgery 
Post-Op 
Surveillancee 
Off Studyj 
Scheduling Window (Days) 
-28 to -1 
Day 1 
Day 21 ± 3 
Day 42 ± 3 
Day 56 ± 3 
Day 56-77 
42-70 days 
post-op 
Administrative Procedures 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics 
X 
Medical History 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
Clinical Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
Diagnostics and Imaging 
Radiologic Evaluation: CT CAPa 
X 
X 
X 
Xf 
Radiologic Evaluation: PET/CT 
X 
X 
Upper Endoscopym 
X 
X 
Xg 
Endoscopic Ultrasound (EUS) 
X 
X 
Laboratory Procedures/Assessments 
Pregnancy Test – Urine or Serum -HCGb 
X 
X 
X 
X 
X 
CBC with differential 
X 
X 
X 
X 
X 
Basic metabolic panel 
X 
X 
X 
X 
X 
Hepatic function panel 
X 
X 
X 
X 
X 
CEA 
X 
X 
X 
X 
X 
Xh 
X 
CA 19-9 
X 
X 
X 
X 
X 
Xh 
X 
Urinalysis 
X 
X 
X 
X 
X 
TSH, (FT4 and T3)i 
X 
X 
X 
X 
X 
X 
PT/INR and aPTT 
X 
Intervention 
Pembrolizumab administration 
X 
X 
X 
Surgical Assessment and Resection 
X 
Correlative Material Collection 


 
 
 
Pre-treatment research biopsy for pathologist 
review 
X 
Pre-treatment biopsy for biomarker analysisc 
X 
Resected surgical specimen for pathologist 
review 
X 
Resected surgical specimen for biomarker 
analysisc,d 
X 
Foundation One CDx 
X 
Xd 
Guardant 360 ctDNA collection 
and blood bankingl 
X 
X 
X 
Xk 
Stool collection 
X 
X 
X 
Xk 
aCT scan of chest/abdomen/pelvis with IV and PO contrast, OR MRI of abdomen/pelvis plus non-contrast chest CT if contraindication 
to iodinated dye. 
bOnly needed in women of childbearing potential 
cBiomarker analysis includes testing for MSI via immunohistochemistry (IHC), HER2 testing (via IHC and/or fluorescence in situ 
hybridization (FISH)), Epstein-Barr encoding region in situ hybridization (EBER ISH), PD-L1 CPS testing, and whole-exome RNAseq 
expression 
dWill only be able to be performed if there is residual tumor left in surgical specimen 
eSurveillance visits with physician (or nurse practitioner or physician assistant) will occur every 3 months until year 3 post surgery, and 
then every 6 months until year 5 post surgery 
fSurveillance imaging will be performed annually for 2 years post-surgery and then as clinically indicated 
gWill only be performed as needed 
hWill be checked every 3 months until year 3 post surgery, and then every 6 months until year 5 post surgery 
iTSH only be checked, and FT4 and T3 only checked reflexively if TSH is abnormal, per routine care. 
jPatients will come off study 5 years post-surgery, if cancer recurs, or if patient withdraws consent. However, overall survival follow- 
up will continue to year 5 if cancer recurs or if patient withdraws consent from treatment but not follow up. 
kWill only be collected if patient’s gastroesophageal cancer recurs 
lBlood Banking collected and processed per IRB16294A (see Section 8.1.2.6 of this protocol). 
m Endoscopy must be conducted at enrolling institution (see Section 8.1.2.6.2 of this protocol). 
 
 
 


 
 
8.0 TRIAL PROCEDURES 
 
8.1 
Trial Procedures 
 
The Trial Flow Chart - Section 7.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the P.I. and/or Merck 
for reasons related to participant safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
8.1.1 Administrative Procedures 
 
8.1.1.1 Informed Consent 
 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
 
8.1.1.1.1 General Informed Consent 
 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level. 
 
The informed consent will adhere to IRB/ERC requirements and applicable laws and 
regulations. 


 
8.1.1.2 Inclusion/Exclusion Criteria 
 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial. 
 
8.1.1.3 Medical History 
 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease for 
which the participant has enrolled in this study will be recorded separately and not listed as 
medical history. 
 
8.1.1.4 Prior and Concomitant Medications Review 
 
8.1.1.4.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the trial. Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
 
8.1.1.4.2 Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 8.2. 
 
8.1.1.5 Disease Details and Treatments 
 
8.1.1.5.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
 
8.1.1.5.2 Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
8.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment. If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the safety follow-up visit must occur before the first 
dose of the new therapy. Once new anti-cancer therapy has been initiated the participant will 
move into survival follow-up. 


 
8.1.1.6 Assignment of Screening Number 
 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to treatment allocation. Each subject will be 
assigned only one screening number. Screening numbers must not be re-used for different 
subjects. Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Once a screening number is assigned to a subject, it can 
never be re-assigned to another subject. 
 
8.1.1.7 Assignment of Randomization Number 
 
No randomization will be performed and no randomization numbers will be used. 
 
8.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
 
As discussed above, if there is any delay in pembrolizumab that would result in patient being 
unable to undergo surgery within 56-77 days of study initiation (day of first pembrolizumab 
dose), then patient will go off trial and go directly to surgery. 
 
8.1.2 Clinical Procedures/Assessments 
 
8.1.2.1 Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each participant to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 5.0 (see Appendix 2). Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment. 
 
Please refer to Section 8.2 for detailed information regarding the assessment and recording of 
AEs. 
 
8.1.2.2 Full Physical Exam 
 
The investigator or qualified designee will perform a complete physical exam during the 
screening period and at all times as indicated on the study flow chart. Clinically significant 
abnormal findings should be recorded as medical history. A full physical exam should be 
performed during screening, 
 
8.1.2.3 Vital Signs 
 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at all other times points as specified in the 
Trial Flow Chart (Section 7.0). Vital signs should include temperature, pulse, respiratory rate, 
weight and blood pressure. Height will be measured at screening only. 


 
8.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation 
of trial treatment as specified in the Trial Flow Chart. 
8.1.2.5 Tumor Imaging and Assessment of Disease 
 
CT scans of chest, abdomen, and pelvis with IV and PO contrast will be obtained at baseline 
during the screening period, after 3 doses of pembrolizumab (day 56 ± 3 days), post-operatively 
(42-70 days post-operatively) and subsequently according to standard of care surveillance 
(annually for two years post-surgery and then as clinically indicated). Response will be 
assessed by institutional radiologists using RECIST 1.1. If a reason exists precluding use of 
iodinated contrast, MRI abd/pelvis and noncontrast chest CT can be substituted. 
 
 
8.1.2.5.1 Initial Tumor Imaging 
 
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
allocation. CT scans of chest, abdomen, and pelvis with IV/PO contrast will be obtained at 
baseline. If a reason exists precluding use of iodinated contrast, MRI abd/pelvis and 
noncontrast chest CT can be substituted. PET/CT will also be required at baseline. Finally, 
EUS will be required at baseline as per this institution’s standard of care to confirm staging. 
Baseline diagnostic laparoscopy is not mandated and can be performed if clinically indicated. 
 
 
8.1.2.5.2  
Tumor Imaging During the Study 
 
The first on-study imaging assessment (CT chest/abdomen/pelvis with IV/PO contrast) 
should be performed at 8 weeks (56 days ±3 days) from the date of allocation. PET/CT, 
EUS, and upper endoscopy will also be performed at this time. Subsequent tumor imaging 
(CT chest/abdomen/pelvis with IV/PO contrast) should be performed 6-10 weeks post- 
operatively. Thereafter, surveillance imaging will be performed as per standard of care at 
this institution (annually for 2 years post-surgery and then as clinically indicated). Scans will 
be evaluated for progression or new lesions as per RECIST 1.1. If a reason exists precluding 
use of iodinated contrast, MRI abd/pelvis and noncontrast chest CT can be substituted. 
Surveillance EGD will only be performed as clinically indicated. 
 
8.1.2.5.3  
End of Treatment and Follow-up Tumor Imaging 
 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (6-10 weeks after surgery, then 
annually to year 2, and then as needed) to monitor disease status until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the 
end of the study, whichever occurs first. 


 
8.1.2.5.4  
 RECIST 1.1 Assessment of Disease 
 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression/recurrence, and as a basis for all protocol guidelines related to disease 
status (eg, discontinuation of study treatment). 
 
8.1.2.5.5  
iRECIST Assessment of Disease 
 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. When clinically stable, participants should not be 
discontinued until progression is confirmed by the Investigator, working with local 
radiology, according to the rules below. This allowance to continue treatment despite initial 
radiologic PD takes into account the observation that some participants can have a transient 
tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. 
 
A description of the adaptations and iRECIST process is provided in Appendix 4, with 
additional detail in the iRECIST publication. [45] iRECIST will be used by the Investigator 
to assess tumor response and progression/recurrence, and make treatment decisions. 
 
8.1.2.6 Tumor Tissue Collection and Correlative Studies Sampling 
 
Patients will undergo tumor and blood collection as per routine clinical practice and will be 
consented to IRB 16294A prospective protocol for all indicated correlatives. 
 
Tissue specimens collected at diagnosis and at time of surgical resection will be obtained per 
standard-of-care (SOC) practices. As per SOC at this institution, tissue at diagnosis and/or at 
time of surgical resection (if tumor is still present) will undergo testing for MSI via 
immunohistochemistry (IHC), HER2 testing (via IHC and/or fluorescence in situ hybridization 
(FISH)), and Epstein-Barr encoding region in situ hybridization (EBER ISH). These specimens 
will also undergo PD-L1 CPS testing, whole-exome RNAseq expression, as well as NGS 
testing via Foundation One CDxTM (Foundation Medicine, Cambridge, MA). ctDNA using 
Guardant360 (Guardant Health, Redwood, CA) will be evaluated before pembrolizumab 
therapy, after pembrolizumab therapy, after surgery, and at time of recurrence (if applicable) 
as per SOC. 
 
Finally, patient fecal microbiomes will be characterized using fecal 16S RNA sequencing 
before pembrolizumab therapy, after pembrolizumab therapy, after surgery, and at time of 
recurrence (if applicable) as discussed below. 
 
8.1.2.6.1 Fecal 16S RNA Sequencing 
 
At least 3 aliquots of stool will be stored at -80ºC in tubes from the UltraClean® Fecal DNA 
Isolation Kits (MoBio). This technique uses a bead-beating method and removes inhibitors of 
PCR enzymatic reactions. Backup samples will be stored in a 50ml tubes. We will characterize 
the intestinal microbiota by MiSeq deep sequencing of bacterial 16S rRNA. Following 
assessment of genomic DNA quality and concentration, 16S rRNA-based tag sequence 


 
libraries will be generated from an evolutionarily conserved gene marker to obtain deep 
surveys of the microbial communities present using next generation sequencing. The 16S 
rRNA-based Illumina library preparation and data analysis PCR primers to be used are specific 
for the 515-806 base pair V3-V4 region of the 16S rRNA encoding gene (338F: 5’- 
GTGCCAGCMGCCGCGGTAA-3’ and 806R: 5’-GGACTACHVGGGTWTCTAAT-3’) and 
contain Illumina 3' adapter sequences as well as a 12-base pair barcode. This barcode-based 
primer approach allows sequencing of multiple samples in a single sequencing run without the 
need for physical partitioning. Sequencing will be performed by the Next Generation 
Sequencing Core at Argonne National Laboratory using an Illumina MiSeq. Sequences will 
then be trimmed and classified with the QIIME toolkit. Using the QIIME wrappers, OTUs are 
picked at 97% sequence identity using uclust and a representative sequence is then chosen for 
each OTU by selecting the most abundant sequence in that OTU. These representative 
sequences are classified and assigned a taxonomic string using the RDP Classifier. PyNAST- 
aligned sequences are used to build a phylogenetic tree with FastTree for calculation of 
unweighted/weighted UniFrac distances (as well as other measures of diversity) for ecological 
analyses, including visualization via ordination (e.g. principal coordinates analysis). 
Furthermore, the transformation of sequence data into a numerical format (abundance of each 
OTU) allows the application of a variety of ecologic metrics to characterize the samples 
individually (measures of α-diversity) as well as between sample comparisons (measures of β- 
diversity). A comparison of frequencies of specific sequences in patients having a T cell- 
inflamed versus non-T cell-inflamed tumor microenvironment will be performed, and also 
comparisons between clinical responders versus non-responders. Rarefaction curves will be 
used to evaluate and compare OTU richness between libraries. Diversity indices, including the 
Shannon diversity index, and richness estimators (Chao1 and ACE) will be calculated. 
 
8.1.2.6.2 
 Initial Screening Endoscopy  
 
All subjects must receive an initial screening endoscopy at the site enrolling the subject. If the 
subject has received an endoscopy per standard of care prior to joining the study and the 
endoscopy was conducted at the enrolling study site, the subject does not have to repeat the 
procedure. Tissue samples collected from standard of care endoscopies can be accepted at 
screening only if the endoscopy was conducted at the enrolling institution.  
 
If the subject received an endoscopy prior to joining the study at a non-enrolling site, a new 
endoscopy must be conducted at the enrolling site and will be considered part of clinical 
research.  
  
8.1.3 Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5. 


 
 
Table 5 Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Total thriiodothyronine (T3) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
Free thyroxine (T4) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Carcinoembryonic antigen (CEA) 
Absolute Lymphocyte Count 
(CO2 or biocarbonate) 
Urine pregnancy test † 
Carbohydrate antigen 19-9 (CA 19-9) 
Uric Acid 
Blood for correlative studies 
Calcium 
Stool for correlative studies 
Chloride 
PT/INR 
Glucose 
aPTT 
Phosphorus 
Potassium 
Sodium 
Magnesium 
Total Bilirubin 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
Total protein 
Blood Urea Nitrogen 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
‡ If considered standard of care in your region. 


 
8.1.4 Other Procedures 
 
8.1.4.1 Withdrawal/Discontinuation 
 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 8.2 - Assessing and Recording 
Adverse Events. 
 
8.1.4.2 Blinding/Unblinding 
 
Not applicable as this is an open label study. 
 
8.1.5 Visit Requirements 
 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 8.1 - Trial Procedures. 
 
8.1.5.1 Screening 
 
8.1.5.1.1 Screening Period 
 
The screening period is 28 days during which laboratory and imaging studies prior to treatment 
must be completed. See flow chart, Section 7.0 for further details. 
 
8.1.5.2 Treatment Period 
 
8.1.5.3 Post-Treatment Visits 
 
8.1.5.3.1 Safety Follow-Up Visit 
 
Safety assessments will be performed at each physician visit. This includes on day 21 ± 3, day 
42 ± 3, day 56 ± 3, and 42-70 days post-operatively. 
 
The mandatory Safety Follow-Up Visit will be conducted approximately 14 days after the last 
dose of study treatment (on day 56 ± 3). All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded. Participants with an AE of Grade > 1 will be followed until the resolution 
of the AE to Grade 0-1 or until the beginning of a new anti-cancer therapy, whichever occurs 
first. SAEs that occur within 90 days of the end of treatment (end of treatment is the day of last 
dose of pembrolizumab) or before initiation of a new anti-cancer treatment should also be 
followed and recorded. 
 
8.1.5.3.2 Follow-up Visits 
 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should continue surveillance per standard of care. This includes 


 
physician visits with labs (CEA and CA 19-9) every 3 months until year 3 post surgery and 
then every 6 months until year 5 post surgery as well as CT scan of chest/abdomen/pelvis with 
IV/PO contrast (or MRI abdomen/pelvis plus noncontrast chest CT if iodinated dye cannot be 
administered) annually for 2 years and then on an as needed basis. 
 
Every effort should be made to collect information regarding disease status until the start of 
new anti-neoplastic therapy, disease progression, death, or end of the study. Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
 
8.1.5.3.3 Survival Follow-up 
 
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, 
whichever occurs first. 
 
8.2 
Assessing and Recording Adverse Events 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change 
in frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event caused the


participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
 
● All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 
 
● All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier must 
be reported by the investigator. 
 
● All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anticancer therapy 
must be reported by the investigator. 
 
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify Merck. 
 
8.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Principal Investigator 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 P.I. and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215-661-6229) 


 
8.2.2 Reporting of Pregnancy and Lactation to the Principal Investigator and to 
Merck 
 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
they cause the participant to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of P.I.’s product, or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever 
is earlier, must be reported by the investigator. All reported pregnancies must be followed to 
the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the P.I. and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215‐661‐6229) 
8.2.3 Immediate Reporting of Adverse Events to the Principal Investigator and to 
Merck 
 
8.2.3.1 Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event 
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 


 
Refer to Table 6 for additional details regarding each of the above criteria. 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 
hours to the P.I. 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, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the 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 P.I. 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. 
 
8.2.3.2 Serious Adverse Event Reporting to the Coordinating Center  
 
Use the University of Chicago Comprehensive Cancer Center protocol number and the 
protocol-specific patient ID assigned during trial registration on all reports. 
 
All serious adverse events (as defined in Section 8.2.3.1) and all adverse events that 
have been specified to require expedited reporting occurring on this study require 
expedited reporting to the University of Chicago Comprehensive Cancer Center (UC 
CCC). The responsible Research Nurse or other designated individual at the treating site 
should report the SAE to the Study Lead Principal Investigator, the University of 
Chicago CRA and the CCTO by the end of the business day when s/he becomes aware 
of the event.  Events occurring after business hours should be reported to the CCTO by 
12 p.m. (noon) the next business day.  Reports should be made using the ‘Serious Event 
Report’ Form.  Please scan and send via email (preferred) or fax to the following: 
 
University of Chicago Phase II CRA General: 
PhaseIICRA@medicine.bsd.uchicago.edu 
Phone: 773-834-1746 
Fax: 773-702-4889 
 
UC CCC Cancer Clinical Trials Office Quality Assurance: 
qaccto@bsd.uchicago.edu 
   
8.2.3.3 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/randomization, 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, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the 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 8.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the P.I., 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. 
 
8.2.4 Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


 
 
Table 6 Evaluating Adverse Events 
 
An investigator who is a qualified physician (or nurse practitioner or physician assistant), will evaluate all adverse events as to: 
 
V5.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
†Results in death; or 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, lasting >24 hours, even if the hospitalization is a 
precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a serious 
adverse event. A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); 
or 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the P.I. within 24 hours or 1 business day and to Merck 
within 2 working days to meet certain local requirements); or 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the P.I. and to Merck 
within 2 working days... 


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


 
 
 
Relationship 
to Merck 
Product 
(continued) 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the P.I.’s product; or (3) the trial is a single-dose drug trial); or (4) P.I.’s product(s) is/are only used one time.) 
Rechallenge 
Was the participant re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
P.I.’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE P.I. AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product. The temporal sequence of the AE onset relative to the administration of Merck product is reasonable. 
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product. (Also entered for a participant with overdose without an associated 
AE.) 


 
 
 
8.2.5 Principal Investigator Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
 
8.2.6 Additional Safety Considerations 
 
Should a patient’s surgery be delayed beyond the surgical window due to pembrolizumab- 
associated toxicity, the study would be held for a safety review by the lead investigators in 
order to evaluate if this event was attributable to the study intervention. If not, accrual would 
resume. 
 
Safety will be assessed throughout the trial at weekly data safety monitoring meetings (DSM). 
Assessments will be based upon medical review of adverse events reports and the result of 
vital sign measurements, physical examinations, and clinical laboratory tests. The trial will be 
discontinued if any pembrolizumab-related deaths occur or if grade 3-4 toxicity exceeds 
tolerable limits by DSM review. 
 
9.0 STATISTICAL ANALYSIS PLAN 
 
9.1 
Statistical Analysis Plan Summary 
 
9.2 
Statistical Analysis Plan 
 
At our institution, patients with cT1b-2N0M0 GEA typically undergo surgery alone without 
additional therapy. Thus, we expect 100% of resected specimens to have evidence of cancer in 
historical controls. We hypothesize that neoadjuvant pembrolizumab will result in a pCR rate 
(Grade 1a+1b) of 15%. A sample size of 33 patients will provide 90% power with one-sided 
alpha 0.1 to detect this pCR rate using neoadjuvant pembrolizumab. More specifically, we will 
use an optimal, Simon two-stage design to test the null hypothesis that the Grade 1 response 
rate is 1% vs. the alternative that it is 15%. Fifteen patients will be enrolled in the first stage 
and if no complete pathological responses are observed the trial will be terminated for futility. 
If one or more responses are seen, an additional 18 patients will be studied for a total of 33. 
Two or more responses in 33 patients will indicate that the treatment is promising, whereas 
0/15 or 1/33 will be considered a negative result. Patients who receive pembrolizumab but do 
not go to surgery will be counted as not having achieved a pCR. 
 
We will also assess activity in the subset of patients who are PD-L1 positive. Assuming an 
approximate PD-L1 positivity incidence (CPS score >1) of 50% of all patients enrolled, this 
sample size of 16 expected PD-L1 positive patients will provide over 95% power with one- 
sided alpha 0.05 to detect a pCR rate (Grade 1a+1b) of 30% vs. 1% using neoadjuvant 
pembrolizumab in this preplanned subset. Using a higher CPS cutoff of ≥10 we assume 20% 
of patients will be PD-L1 positive based on recent data, and the sample size of 7 expected PD- 


 
L1 positive patients will provide 67% power with one-sided alpha 0.05 to detect a pCR rate 
(Grade 1a+1b) of 30% vs. 1% 
 
Complete responses (R0) will be tabulated along with an exact 90% confidence interval. DFS 
and OS will be estimated using the Kaplan-Meier method. Adverse events will be summarized 
by type, grade, and attribution to the study drug. 
 
Chisquare tests and Spearman or Pearson correlation coefficients will be calculated to assess 
associations among the correlative endpoints. Comparisons of pre-treatment PD-L1 expression 
and other markers between responders and non-responders will be performed using two-sample 
t or Wilcoxon rank-sum tests. Changes in tumor markers will be analyzed using paired t or 
Wilcoxon signed rank tests. If the number of events is sufficient, Cox regression models will 
be fit to determine whether tumor markers are predictive of DFS and OS. 
 
10.0  LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
10.1 Investigational Product 
 
The treating investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Pembrolizumab will be provided by Merck as summarized in Table 7. 
Table 7 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
10.2 Packaging and Labeling Information 
 
Supplies will be labeled in accordance with regulatory requirements. 
 
10.3 Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the participant, the trial site personnel, the P.I. and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 
10.4 Storage and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 


 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
10.5 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the treating investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 


 
11.0 STUDY MANAGEMENT AND REGULATORY AFFAIRS 
 
11.1  Multicenter Guidelines 
 
The specific responsibilities of the Study Lead Principal Investigator and the Coordinating Center are 
presented in Appendix B.  Clinical studies coordinated by The University of Chicago must be conducted in 
accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) and in 
compliance with other applicable regulatory requirements 
 
The Study Lead PI/Coordinating Center is responsible for distributing all official protocols, amendments, 
and IND Action Letters or Safety Reports to all participating institutions for submission to their individual 
IRBs for action as required.   
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
 
Unless otherwise specified, each participating institution must obtain its own IRB approval. It is expected 
that the IRB will have the proper representation and function in accordance with federally mandated 
regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the treating investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles that 
have their origin in the Declaration of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the patient and the treating investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
11.3 Required Documentation 
 
 
Before the study can be initiated at any site, the following documentation must be provided to the Cancer 
Clinical Trials Office (CCTO) at the University of Chicago Comprehensive Cancer Center.  All documents 
must be sent to CCTO prior to study activation.   
 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list 
• 
CVs and medical licensure for the Study Lead Principal Investigator and any sub-investigators who 
will be involved in the study. 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Investigational drug accountability standard operating procedures 
• 
Additionally, before the study can be initiated at any site, the required executed research 
contract/subcontract must be on file with the University of Chicago. 


11.4 
Data and Safety Monitoring  
 
This study will be remotely monitored by the University of Chicago PCCC Monitoring Staff in accordance 
with the University of Chicago, Section of Hematology/Oncology standard operating procedure titled 
Monitoring of Multi-Institutional Investigator Initiated Clinical Trials. 
 
Prior to subject recruitment, and unless otherwise specified, a participating site will undergo a Site Initiation 
Teleconference to be conducted by the designated University of Chicago research team. The site’s Study 
Lead Principal Investigator and his or her study staff must attend the site initiation meeting.  
 
Monitoring will be conducted to verify the following: 
 
• 
Adherence to the protocol 
• 
Completeness and accuracy of study data and samples collected 
• 
Compliance with regulations  
• 
Submission of required source documents  
 
Participating sites will also undergo a site close-out teleconference upon completion, termination or 
cancellation of a study to ensure fulfillment of study obligations during the conduct of the study, and to 
ensure that the site Investigator is aware of his/her ongoing responsibilities. 
 
Unless otherwise specified, this protocol will undergo weekly review at the multi-institutional data and 
safety monitoring teleconference as per procedures specified by the UC CCC NCI-approved Data and Safety 
Monitoring Plan. The conference will review: 
 
• 
Enrollment rate relative to expectations, characteristics of participants 
• 
Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• 
Adherence to protocol (protocol deviations) 
• 
Completeness, validity and integrity of study data 
• 
Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form and sent via email to 
PhaseIICRA@medicine.bsd.uchicago.edu. Deviations that are considered major because they impact 
subject safety or alter the risk/benefit ratio, compromise the integrity of the study data, and/or affect subjects’ 
willingness to participate in the study must be reported within 7 days. Please contact the University of 
Chicago CRA (PhaseIICRA@medicine.bsd.uchicago.edu) if you have questions about how to report 
deviations.  All major protocol deviations should also be reported to the local IRB of record according to 
their policies and procedures. 
 
11.5  Auditing 
 
In addition to the clinical monitoring procedures, the University of Chicago Comprehensive Cancer Center 
will perform routine Quality Assurance Audits of investigator-initiated clinical trials as described in the NCI-
approved UC CCC DSM Plan. Audits provide assurance that trials are conducted and study data are 
collected, documented and reported in compliance with the protocol. Further, quality assurance audits ensure 
that study data are collected, documented and reported in compliance with Good Clinical Practices (GCP) 
Guidelines and regulatory requirements. The audit will review subjects enrolled at the University of Chicago 
in accordance with audit procedures specified in the UC CCC Data and Safety Monitoring plan. For 
institutions who are formal members of the Personalized Cancer Care Consortium (PCCC), the UC CCC will 
conduct on site quality assurance audits on average every two years during the enrollment and treatment 
phase of the study.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its conduct or 
even after its completion. If an inspection has been requested by a regulatory authority, the site investigator 


must immediately inform the University of Chicago Cancer Clinical Trials Office and Regulatory Manager 
that such a request has been made. 
11.6 
Amendments to the Protocol 
 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to the University 
of Chicago IRB for review and approval. A list of the proposed modifications or amendments to the 
protocol and/or an explanation of the need of these modifications will be submitted, along with a revised 
protocol incorporating the modifications. Only the Study Lead PI can authorize any modifications, 
amendments, or termination of the protocol. Once a protocol amendment has been approved by the 
University of Chicago IRB, the UCCCC regulatory contact or their designee will send the amended 
protocol and consent form (if applicable) to the affiliate institutions electronically.  
 
For external sites utilizing a local IRB: 
• 
Upon receipt of the amendment documents the affiliate institution is expected to submit the 
amendment documents to their local IRB for approval as soon as possible.    
 
• 
A copy of the IRB approval letter and approved consent document(s) should be sent to the UCCCC 
regulatory contract as soon as possible.  
o IRB approval should be obtained within 90 calendar days of the document distribution date.  
If approval cannot be obtained within this window, the reason for the delay should be 
provided to the designated UCCCC regulatory contact.   
 
For external sites utilizing the BSD IRB as the IRB of record: 
• 
Upon receipt of the amendment documents the affiliate institution is expected to implement the 
revised documents as soon as possible and no later than 30 calendar days from the document 
distribution date.    
o The date of local implementation should be documented in the local study records and 
provided upon request at time of monitoring and/or auditing.  
• 
No changes to the provided documents may be made at the local site without prior approval 
from the BSD IRB. 
 
11.7 
Annual IRB Renewals, Continuing Review and Final Reports 
 
A continuing review of the protocol will be completed by the University of Chicago IRB and the participating 
institutions’ IRBs at least once a year for the duration of the study. The annual IRB renewal approvals 
for participating institutions should be forwarded promptly to the Regulatory Manager. If the institution’s 
IRB requires a new version of the consent form with the annual renewal, the consent form should be 
included with the renewal letter. 
11.8 
Record Retention 
 
Study documentation includes all CRFs, data correction forms or queries, source documents, Study Lead 
Principal Investigator/treating Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to the conduct 
of a clinical trial must be retained by the study investigator.  In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization (ICH) region.  In all 


other cases, study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.9 
Obligations of Study Site Investigators 
 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  The Study 
Site Principal Investigator is responsible for personally overseeing the treatment of all study patients.  He/she 
must assure that all study site personnel, including sub-investigators and other study staff members, adhere 
to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during 
and after study completion. 
 
The Study Site Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered into the CRFs. Periodically, monitoring visits or audits will be 
conducted and he/she must provide access to original records to permit verification of proper entry of data.  
 
 
12.0 APPENDICES 
 
Appendix 1: ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 


 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quic 
k_Reference_5x7.pdf) 
 
 
 
 
 
 


 
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quic 
k_Reference_5x7.pdf)


 
 
Appendix 3: Contraceptive Guidance and Pregnancy Testing 
 
Woman of Childbearing Potential (WOCBP) 
 
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: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ 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 
○ 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). 
○ 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. 
 
Contraception Requirements 
 
Female Participants: 
 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 8 
during the treatment period and for at least 120 days after the last dose of study treatment 
 
Table 8 
Highly Effective Contraception Methods 
 
 
 
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
Oral 
Intravaginal 
Transdermal 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly. 


 
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ 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.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
Pregnancy Testing 
 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
 
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points 
specified in the Schedule of Activities, and as required locally. 
 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 


 
Appendix 4: Description of the iRECIST Process for Assessment of Disease 
Progression 
 
Assessment at Screening and Prior to RECIST 1.1 Progression 
 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
 
Assessment and Decision at RECIST 1.1 Progression 
 
In participants who show evidence of radiological PD by RECIST 1.1 the treating 
investigator will decide whether to continue a participant on study treatment until repeat 
imaging is obtained (using iRECIST for participant management). This decision by the 
treating investigator should be based on the participant’s overall clinical condition. 
 
Clinical stability is defined as the following: 
 
• Absence of symptoms and signs indicating clinically significant progression of 
disease 
• No decline in ECOG performance status 
• No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST. 
 
If the treating investigator decides to continue treatment, the participant may continue to 
receive study treatment and the tumor assessment should be repeated 4 to 8 weeks later to 
confirm PD by iRECIST, per treating investigator assessment. 
 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of 
measurements”, but “sum of diameters” will be used in this protocol, consistent 
with the original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 


 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target. 
 
Assessment at the Confirmatory Imaging 
 
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
 
Confirmation of Progression 
 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of 
≥ 5 mm, compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point 
 Visible growth of new non-target lesions 
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 
• None of the progression-confirming factors identified above occurs AND 


 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
 
Resolution of iUPD 
 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned. 
 
Management Following the Confirmatory Imaging 
 
If repeat imaging does not confirm PD per iRECIST, as assessed by the treating investigator, 
and the participant continues to be clinically stable, study treatment may continue and follow 
the regular imaging schedule. If PD is confirmed, participants will be discontinued from 
study treatment. 
 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 7. 
 
Detection of Progression at Visits After Pseudo-progression Resolves 
 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 


 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur. 
 
The decision process is identical to the iUPD confirmation process for the initial PD, except 
in one respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
scan the burden of new lesions has increased from its smallest value (for new target lesions, 
their sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD 
or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution 
to iSD or iPR, or until a confirmatory factor causes iCPD. 
 
Additional details about iRECIST are provided in the iRECIST publication.[45] 


 
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