Conditions: Gastric Cardia Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Stage IB Gastric Cancer AJCC v7 Stage II Gastric Cancer AJCC v7 Stage IIA Gastric Cancer AJCC v7 Stage IIB Gastric Cancer AJCC v7 Stage IIIA Gastric Cancer AJCC v7 Stage IIIB Gastric Cancer AJCC v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
This phase Ib/II trial studies the side effects and best way to give pembrolizumab with combination chemotherapy and radiation therapy before surgery and to see how well it works in treating adult patients with gastroesophageal junction or gastric cardia cancer that has spread from where it started to nearby tissue and can be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab, combination chemotherapy, and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel in locally advanced gastroesophageal junction (GEJ)/cardia adenocarcinoma. (Phase Ib) II. To evaluate the pathological complete response (pathCR) rate of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel in locally advanced GEJ/cardia adenocarcinoma. (Phase II)

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS), determine time to relapse (TTR), disease-free survival (DFS), R0 rate, and overall survival (OS) of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel.

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To identify tissue and/or circulating biomarkers that are associated with pathCR, DFS, and other clinical outcomes in patients with locally advanced GEJ/cardia adenocarcinoma treated with neoadjuvant pembrolizumab-based therapy.

II. To determine differences in pre-treatment vs post-treatment tissue expression of immune markers, including PDL1 and tumor infiltrating lymphocytes (CD8+, FOXP3+ Tregs, CD45RO, granzyme B), in patients treated with neoadjuvant pembrolizumab-based therapy.

III. To identify immune markers in pretreatment tissues that correlate with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

IV. To explore whether an EBV-associated tumor molecular profile89 is associated with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

V. To explore whether a microsatellite-unstable (MSI) tumor molecular profile89 is associated with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive pembrolizumab intravenously (IV) over 30 minutes on days -7, 15, and 36 and carboplatin IV and paclitaxel IV over 1-96 hours on days 1, 8, 15, 22 and 29. Patients also undergo radiation therapy once daily (QD) 5 days per week for 4 weeks and 3 days (23 fractions).

Patients with progressive disease receive pembrolizumab IV over 30 minutes, paclitaxel IV over 1-96 hours, and carboplatin IV on day 1. Treatment repeats every 21 days for 2-4 courses in the absence of disease progression or unacceptable toxicity.

NEOADJUVANT TREATMENT (RE-INITIATED): Patients receive pembrolizumab IV over 30 minutes on days 1 and 22 and oxaliplatin IV over 2-6 hours, leucovorin calcium IV over 15 minutes to 2 hours, and fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with progressive disease receive pembrolizumab IV over 30 minutes on days 1 and 22, oxaliplatin IV over 2-6 hours, leucovorin calcium over 15 minutes to 2 hours, and fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 41 days (6 weeks) for 1-3 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Within 5-8 weeks after completion of radiation therapy or 3-6 weeks after completion of chemotherapy for patients receiving chemotherapy alone, patients undergo curative-intent surgery.

ADJUVANT TREATMENT: Patients receive pembrolizumab IV over 30 minutes every 21 days. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 1 year.

Arms:
arm 1: See Detailed Description

Interventions: intervention 1: Carboplatin intervention 2: Computed Tomography intervention 3: Fluorouracil intervention 4: Laboratory Biomarker Analysis intervention 5: Leucovorin Calcium intervention 6: Oxaliplatin intervention 7: Paclitaxel intervention 8: Pembrolizumab intervention 9: Positron Emission Tomography intervention 10: Radiation Therapy intervention 11: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo CT scan intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV intervention 8: Given IV intervention 9: Undergo PET scan intervention 10: Undergo radiation therapy intervention 11: Undergo curative-intent surgery

Protocol document:
Prot_SAP_000.pdf: 




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Table of Contents 
Phase 1b/2 Clinical Trial of Neoadjuvant Pembrolizumab plus Concurrent Chemoradiotherapy with 
Weekly Carboplatin and Paclitaxel in Adult Patients with Resectable, Locally Advanced 
Adenocarcinoma of the Gastroesophageal Junction or Gastric Cardia ............................................ 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema  ......................................................................................................................................................... 4 
1.0 
Background ......................................................................................................................... 5 
2.0 
Goals ................................................................................................................................. 24 
3.0 
Patient Eligibility .............................................................................................................. 24 
4.0 
Test Schedules .................................................................................................................. 30 
5.0 
Grouping Factor ................................................................................................................ 35 
6.0 
Registration/Randomization Procedures ........................................................................... 35 
7.0 
Protocol Treatment ........................................................................................................... 38 
8.0 
Dosage Modification Based on Adverse Events ............................................................... 44 
9.0 
Ancillary Treatment/Supportive Care ............................................................................... 52 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................... 60 
11.0 
Treatment Evaluation ........................................................................................................ 71 
12.0 
Descriptive Factors ........................................................................................................... 75 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................................. 75 
14.0 
Body Fluid Biospecimens ................................................................................................. 78 
15.0 
Drug Information .............................................................................................................. 82 
16.0 
Statistical Considerations and Methodology .................................................................... 98 
17.0 
Pathology Considerations/Tissue Biospecimens ............................................................ 105 
18.0  
Records and Data Collection Procedures ........................................................................ 110 
19.0  
Budget ............................................................................................................................. 111 
20.0 
Reference ........................................................................................................................ 112 
Appendix I 
ECOG Performance Status ............................................................................................. 119 
Appendix II 
Surgical Guidelines for Esophagectomy ......................................................................... 120 
Appendix III 
Radiation Therapy Quality Control Guidelines .............................................................. 122 
Appendix IV 
Guidelines for Histopathological Examination of Esophagogastrectomy Specimens .... 123 
Appendix V 
Pembrolizumab ECI Drug-Induced Liver Injury (DILI) ................................................ 125 
Appendix VI 
Presentation of Dermatologic Event ............................................................................... 127 
 


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Schema 
Phase 1b and 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up information. 
 
1 One induction dose of pembrolizumab will be given on Day 1. Then starting on Day 15, weekly carboplatin plus 
paclitaxel with concurrent daily RT will be administered for approximately 5 weeks, in combination with 1 dose 
of pembrolizumab on Day 22. 
2 Administered once every 3 weeks for up to 6 doses. 
3 Every 3 months for 1 year after registration, then every 4 months for 2nd year and every 6 months for 3rd year. 
Cycle length = 3 weeks during adjuvant therapy only 
 
Generic name 
Pembrolizumab, MK-3475 
Carboplatin 
Paclitaxel 
Brand name 
Keytruda® 
Paraplatin® 
Taxol® 
Mayo abbreviation 
MK-3475 
CBDCA 
TAXOL 
Availability 
Gonda 10 Pharmacy 
Commercial 
Commercial 
 
 
 
Observation3 
(up to 3 years) 
Event Monitoring 
Neoadjuvant: Pembrolizumab + carboplatin + paclitaxel + 
RT1 
↓ 
Surgery 
↓ 
Adjuvant: Pembrolizumab2 
Registration 
PD* at any time 
Unacceptable adverse  
Event 
events 
Monitoring 
Patient refusal 
*unless otherwise specified 
Pre-Registration 


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Background 
1.1 
GEJ/cardia adenocarcinoma poses a worsening public health risk, compared to 
subcardial gastric cancers, and are distinct from esophageal squamous cancers 
In the U.S. and the West, the incidence of esophageal, gastroesophageal junction (GEJ), or 
gastric cardia adenocarcinoma has risen 6-fold since the early 1970s, driven by obesity and 
gastroesophageal reflux1. By contrast, the incidence of subcardial gastric cancer, in which H 
Pylori and cadherin gene inactivation play major etiologic roles, has decreased significantly 
in the US and the West. 
In addition, ample epidemiologic and biologic evidence indicates that adenocarcinomas of the 
GEJ/cardia, as well as of the esophagus, are biologically distinct from esophageal squamous 
cell carcinomas (SCC). 
 
1.2 
Curative-intent treatment for resectable, locally advanced GEJ/cardia cancers 
involves neoadjuvant chemoradiotherapy plus surgery (ie, trimodality therapy) 
Almost half the patients with esophageal/GEJ/cardia cancer present with resectable, locally 
advanced disease. Standard treatment includes weekly carboplatin (AUC 2) with paclitaxel 
(50 mg/m2), combined with concurrent radiation (RT; 41.4 Gy to 50.4 Gy) for 5.5 weeks. 
Within 4-8 weeks of completing chemoradiotherapy (chemoRT), a PET/CT is performed to 
assess for metastatic disease; and once disseminated disease is excluded, surgical resection is 
performed. 
Though a series of small randomized trials supported the addition of chemoRT to surgery in 
esophageal/GEJ cancer, the trimodality approach was established as a worldwide standard of 
care based on the CROSS trial2. In CROSS (N = 366), patients with esophageal/GEJ cancer 
was randomly assigned 1:1 to receive neoadjuvant therapy with weekly carboplatin/paclitaxel 
plus concurrent RT followed by surgery vs surgery alone. By histology, 275 (75%) had 
adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell 
undifferentiated carcinoma. Overall survival (OS), the primary endpoint, was significantly 
improved in the chemoRT arm (HR 0.66; P =.003; median 49 vs 24 months). Other endpoints 
also favored the chemoRT arm: Complete resection with no tumor within 1 mm of the 
resection margins (R0) was achieved in 92% of patients in the chemoRT–surgery group vs 
69% in the surgery group (P <0.001). A pathological complete response (pathCR) was 
achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. 
ChemoRT was well-tolerated. 
Utilizing chemoRT plus surgery for GEJ adenocarcinomas is a favored approach among 
leading cancer centers in the U.S., as demonstrated by the design of most large NCI-
sponsored trials (eg, RTOG-1010, CALGB 9781), and at other cancer centers in the world. 
 
1.3 
Death from GEJ/cardia adenocarcinoma following trimodality therapy usually 
results from disease occurrence in distant anatomic regions outside the original 
radiation field 
Although the OS observed in the CROSS trial was higher than seen in all prior large trials for 
patients with locally advanced esophageal/GEJ adenocarcinoma, cure rates remained low: OS 
rates in the chemoRT arm were 58% at 3 years and 47% at 5 years. These data reflect the 
aggressive biology of this disease and the need for novel therapies2. In one of the largest 
reported GEJ/esophageal adenocarcinoma cohorts (N = 518; 65% had GEJ tumors) that 


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underwent trimodality therapy at a single institution and where site of recurrence data was 
collected, 41% (215/518) of patients experienced disease relapse after a median follow up of 
29 months. Among relapses, 87% (188/215) included a distant site outside the original 
radiation field3. A more recent report from the same institution after longer follow up (median 
37 months) described similar results: 40% of patients (144/356) with esophageal/GEJ cancer 
(85% were GEJ tumors) experienced disease relapse after trimodality therapy, of which 83% 
(119 /144) included distant metastases outside the radiation field4. It is generally accepted 
that occurrence of disease in distant sites results from growth of micrometastases that were 
present, but were by definition undetectable, at the time of trimodality therapy. 
The sites of recurrence among chemoRT-surgery patients in the CROSS trial were most 
commonly hematogeneous (29%), followed by mediastinum (7%), para-aortic (7%), 
supraclavicular (4%), peritoneal (4%), celiac (4%), and anastomosis (3%)3. In the single 
institution series described above of post-trimodality patients, the most common anatomic 
sites of distant metastases, as the first exclusive event, were lung (20%), distant lymph nodes 
(13%), liver (14%), peritoneum (10%), bone (6%), brain (8%) and pleura (7%)4. 
 
1.4 
Pembrolizumab 
Cancer cells are known to have the ability to evade immunosurveillance through a variety of 
mechanisms, including reduced expression of tumor antigens, downregulation of MHC class I 
and II molecules for reduced tumor antigen presentation, secretion of immunosuppressive 
cytokines such TGF-beta, recruitment or induction of immunosuppressive cells such as 
regulatory T cells (Treg) or myeloid derived suppressor cells (MDSC), and overexpression of 
certain ligands (eg, PDL1) that inhibit the host’s existing antitumor immunity5. Recently, 
antibodies targeting the PD-1/PD-L1 or PD-L2 pathway have shown clinical benefit in 
melanoma, with promising activity multiple solid tumors.  
The programmed death 1 (PD-1) pathway is a negative feedback system that represses Th1 
cytotoxic immune responses and that, if unregulated, can damage the host6-8. It is up-
regulated in many tumors and in their surrounding microenvironment. Blockade of this 
pathway with antibodies to PD-1 or its ligands has led to remarkable clinical responses in 
patients with many different types of cancer, including melanomas, non–small-cell lung 
cancer, renal-cell carcinoma, bladder cancer, and Hodgkin’s lymphoma9-15. The expression of 
PD-1 ligands (PD-L1 or PD-L2) on the surface of tumor cells or immune cells is an important 
—but not a definitive— predictive biomarker of response to PD-1 blockade9,11-13,16. 
Immunotherapeutic strategies aimed at overcoming immunotolerance and improving the 
activation of antitumor T cells represent a new promising therapeutic approach. Among them, 
pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD -1 and its 
ligands, PD-L1 and PD-L2. It was recently approved in the U.S. for the treatment of patients 
with unresectable or metastatic melanoma and disease progression following ipilumumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. 
In a phase I study, 655 patients with advanced melanoma were treated with pembrolizumab in 
four treatment cohorts using one of three dose schedules (10 mg/kg every two weeks, 10 
mg/kg every three weeks, or 2 mg/kg every three weeks). Approximately three-fourths of 
patients had received prior systemic therapies for metastatic disease, including 52 percent 
who had received prior ipilimumab. Results from this study were updated at the 2015 
American Society of Clinical Oncology (ASCO) meeting17. The overall objective response 
rate using RECIST criteria and central review was 33%; similar response rates were seen 
using immune-related response criteria. OS at 12 months was 66% and 49% at 24 months. 


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Median PFS was 4.4 months, and 35% of patients remained progression free at 12 months. 
On multivariate analysis, there were no significant differences in outcomes between the three 
dose schedules. In the randomized cohorts, there were no differences in objective response 
rates between those treated with either 2 mg/kg every three weeks or 10 mg/kg every three 
weeks. Preliminary analyses studied PD-L1 expression in the tumor as a predictive marker 
for responsiveness to pembrolizumab. Although these studies suggested that PD-L1 positivity 
correlated with increased responsiveness, absence of PD-L1 expression did not preclude a 
clinical response. Treatment toxicity was manageable; 83 percent of patients experienced one 
or more treatment-related adverse events. The most common toxicities were fatigue, pruritus, 
rash, diarrhea, and arthralgia (36%, 24%, 20%, 16%, and 16%, respectively). Overall 14% of 
patients experienced grade 3 or 4 toxicity, the most common being fatigue (2%), and there 
were no treatment-related deaths. There were similar safety profiles in those previously 
treated with ipilimumab and in those who were ipilimumab naïve. 
Based upon these results, two phase III trials were conducted, one in patients whose disease 
was refractory to ipilimumab, and the other in patients who were treatment naïve. 
In the KEYNOTE-002 trial, 540 patients with ipilimumab-refractory advanced melanoma 
were randomly assigned to pembrolizumab (2 mg/kg every three weeks), pembrolizumab (10 
mg/kg every three weeks) or chemotherapy (carboplatin plus paclitaxel, paclitaxel alone, 
dacarbazine, or temozolomide per institutional standard)18. Treatment continued until 
progressive disease. PFS assessed by central review, the primary endpoint of the trial, was 
significantly improved with both pembrolizumab treatment regimens compared with 
chemotherapy. The 6-month PFS rates 34%, 38%, and 16% for pembrolizumab 2 mg/kg, 
pembrolizumab 10 mg/kg, and chemotherapy, respectively (pembrolizumab 2 mg/kg vs 
chemotherapy HR 0.57, 95% CI 0.45-0.73, and pembrolizumab 10 mg/kg vs chemotherapy 
HR 0.50, 95% CI 0.39-0.64). The ORRs were 21%, 26%, and 4%, respectively. Treatment 
was relatively well tolerated, with grade 3-5 adverse events reported in 11% and 14% of the 
pembrolizumab arms, and 26% of those managed with chemotherapy. The most common 
pembrolizumab-related adverse events were fatigue, pruritus, and rash. Grade 3 immune 
related toxicity was reported in two patients treated with pembrolizumab 2 mg/kg (hepatitis, 
hypophysitis), and in eight patients given pembrolizumab 10 mg/kg (hepatitis, colitis, 
pneumonitis, and iritis or uveitis). The 2 mg/kg and 10 mg/kg doses also had similar efficacy 
and toxicity in the three-armed phase III trial when they were compared with ipilimumab19. 
Pembrolizumab at a dose of 2 mg/kg every three weeks was approved by the US Food and 
Drug Administration (FDA) in September 2014. 
The safety and efficacy of pembrolizumab monotherapy was recently assessed in patients 
with advanced non–small-cell lung cancer (NSCLC)20. In this study, 495 patients received 
pembrolizumab (at a dose of 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks) 
to either a training group (182 patients) or a validation group (313 patients). PD-L1 
expression was assessed in tumor samples by immunohistochemistry (IHC), with results 
reported as the percentage of neoplastic cells with staining for membranous PD-L1 
(proportion score). Response was assessed every 9 weeks by central review. Common side 
effects attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no 
clear difference according to dose or schedule. Among all the patients, the ORR was 19.4%, 
and the median duration of response (DOR) was 12.5 months. Median PFS was 3.7 months, 
and median OS was 12.0 months. PD-L1 expression in at least 50% of tumor cells was 
selected as the cutoff from the training group. Among patients with a proportion score of at 
least 50% in the validation group, the response rate was 45.2%. Among all the patients with a 
proportion score of at least 50%, median PFS was 6.3 months; median OS was not reached. 
Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in 


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patients with advanced NSCLC. PD-L1 expression in at least 50% of tumor cells correlated 
with improved efficacy of pembrolizumab. 
Pembrolizumab is being compared against chemotherapy in NSCLC. Pembrolizumab has 
also been studied in clinical trials in recurrent or metastatic adenocarcinoma of the stomach 
or gastroesophageal junction, classical Hodgkin lymphoma (cHL), urothelial tract carcinoma, 
and head and neck cancer. Though observed response rates are promising, results are 
premature, and trials are single-armed with small numbers. 
 
1.5 
Pembrolizumab in advanced GEJ/gastric adenocarcinoma: proof of concept.  
The safety and efficacy of pembrolizumab in patients with GEJ/gastric cancer was assessed in 
KEYNOTE-012 (NCT01848834) in a cohort of advanced disease21. Archival tumor samples 
from patients from Asia-Pacific and rest of the world with recurrent or metastatic 
adenocarcinoma of the stomach or GEJ were screened for PD-L1 expression using a 
prototype IHC assay with the 22C3 antibody. Only patients with distinctive stromal or ≥1% 
tumor nest cell PD-L1 staining were eligible. Patients received pembrolizumab 10 mg/kg 
every 2 weeks for up to 24 months or until complete response, progression, or unacceptable 
toxicity. Imaging was performed every 8 weeks. Primary efficacy end point was ORR 
assessed per RECIST v1.1 by independent central review. Secondary end points included 
DOR, PFS, and OS.  
 
Of the 162 patients screened, 65 (40%) were PD-L1+. Of these 65 patients, 39 enrolled (19 
from Asia, 20 from rest of the world; median age, 63 years [range 33-78]). The number of 
prior therapies for advanced disease ranged from 0 to 5; 67% received ≥2 prior therapies. 
Median follow-up duration was 8.8 months (range 6.2-12.6); 13 patients (33%) remained on 
therapy at the time of analysis. Four patients experienced 5 total grade 3-5 drug-related 
adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia, and 
pneumonitis (n = 1 each). There was 1 drug-related death (hypoxia). ORR was 22% (95% CI 
10-39) by central review and 33% (95% CI 19-50) by investigator review. Median time to 
response was 8 weeks (range 7-16), with a median DOR of 24 weeks (range 8+ to 33+). PD-
L1 expression level was associated with ORR (1-sided P = 0.10). The 6-month PFS rate was 
24%. The 6-month OS rate was 69%. These early results from a single-arm trial demonstrate 
that pembrolizumab monotherapy has manageable toxicity and promising antitumor activity 
in advanced GEJ/gastric cancer, and support ongoing development of pembrolizumab for 
GEJ/gastric cancer. 
Currently, pembrolizumab is being tested further in advanced GEJ/gastric cancer in the 
following planned or ongoing trials, including in combination with chemotherapy.  
• 
KEYNOTE-059 (phase 2): Combination with cisplatin-5FU chemotherapy and as 
monotherapy in patients with previously untreated GEJ/gastric cancer, and as 
monotherapy in the 3rd-line setting 
• 
KEYNOTE-061 (phase 3): Combination with paclitaxel as compared to paclitaxel 
alone in 2nd-line 
• 
KEYNOTE-062 (phase 3): Pembrolizumab as Monotherapy and in Combination with 
Cisplatin plus 5FU vs Placebo plus Cisplatin plus 5FU in 1st-line 
In these trials, a fixed dose of pembrolizumab 200 mg IV every 3 weeks is being utilized. The 
choice of a fixed dose is based on simulations performed using the population PK model of 
pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide exposures 
that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) 
will maintain individual patient exposures in the exposure range established in melanoma to 


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be associated with maximal efficacy response, and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe. The 
above data indicate that the 200 mg Q3W fixed dose regimen planned to be used in this trial 
is likely similar with regard to efficacy and tolerability to the 10 mg/kg Q2W dose regimen 
used in KEYNOTE-012, and supports its use in this study. A fixed dose regimen will also be 
more convenient for physicians, reduce potential for dosing errors, reduce complexity in the 
logistical chain at treatment facilities, and reduce wastage. 
 
1.6 
Adding pembrolizumab to neoadjuvant chemoradiotherapy may enhance antitumor 
activity in the primary tumor and exert greater control on the growth of distant 
micrometastases, partly through an abscopal effect 
The purpose of neoadjuvant radiotherapy in GEJ adenocarcinoma is to enhance locoregional 
control, and the addition of concurrent chemotherapy to radiotherapy is to enhance 
radiosensitization and to address micrometastatic disease22,23. This combined modality 
approach is the most effective approach, to date, for treating locally advanced disease. 
However, the ability of current cytotoxic chemoagents to eradicate micrometastases is poor, 
yielding a 5-year OS rate of <50%2. Clearly, novel approaches are necessary that can build on 
this combined modality approach. 
It has been hypothesized that radiotherapy acts as an “in situ vaccine” to prime the immune 
response. Despite the known benefit of ionizing radiation (IR) in local tumor control, it also 
enhances the release of cytokines such TGF-beta, a known inducer of tumor invasion and the 
epithelial-mesenchymal transition24-26. On the other hand, IR can also promote immune 
responses through the induction of neoantigens and the stimulation of factors such as IFN-
gamma that can enhance T cell infiltration27. This dual ability to control local tumor 
progression and to influence metastatic spread and immune response constitutes a compelling 
argument for including radiation in combination with the current arsenal of immune 
checkpoint inhibitors. 
The abscopal effect refers to the ability of radiation delivered to a local site to minimize or 
eradicate metastases at distant sites. Although this phenomenon is not often described, it has 
led to complete regression of metastases at several anatomic sites in patients with lung 
adenocarcinoma28 and melanoma29.  
Although radiotherapy causes tumor-cell apoptosis/necrosis, radiation alone is not sufficient 
to trigger antigenic signals, and a second costimulatory signal is required to elicit systemic 
antitumor immune responses, especially in poorly immunogenic cancers30. Moreover, 
radiotherapy alone can suppress the growth of primary breast, colon, and lung cancer tumors 
but not the appearance of lung metastasis in mouse models30-32. Thus, the combination of 
radiotherapy with immune modulators may have the capability to escalate antitumor 
responses to a level that could suppress or eliminate systemic metastasis. 
Although anti–PD-1 and anti–CTLA-4 mAbs may overcome T-cell suppression, T-cell 
activation depends on the engagement of the antigen receptor and the activating costimulation 
molecule CD28 expressed by mature APCs33. In this regard, ionizing radiation can increase 
the production and presentation of tumor antigens, not only by immunogenic cancers like 
melanoma but also by poorly immunogenic tumors; this, in turn, could augment the antitumor 
immune responses elicited by checkpoint immunomodulators anti–PD-1/PD-L1 and anti–
CTLA-430,34,35.  
Preclinical studies have provided insight on how localized radiotherapy can induce the 
abscopal effects and have implicated the immune system as a crucial mediator (reviewed by 


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Frey et al36). Local radiotherapy damages DNA within tumor cells, leading to tumor-cell 
apoptosis/necrosis, increasing cytotoxic T cell activity and the antigenic peptide pool34,37. 
Tumor antigens released from the dying tumor cells potentially can provide antigenic 
stimulation that induces antitumor-specific immune responses. This hypothesis is supported 
by the lack of the abscopal effect of radiotherapy in T cell–deficient (nude) mice or in mice 
with CD8+ T-cell depletion30,38,39. New data from Deng and colleagues40 suggests that the 
combination of radiation and PD-L1 checkpoint blockade can synergistically reduce MDSCs. 
Preclinical studies of murine models have demonstrated that various immunomodulators 
benefit from combinations with radiation through antigen release41. Postow and colleagues29 
and Hiniker and colleagues42 each reported systemic responses in patients with melanoma 
treated with the combined regimen of anti–CTLA-4 mAb ipilimumab and radiation, 
suggesting that coupling radiotherapy with immunotherapy may hold promise for inducing 
powerful, longterm abscopal effects in human patients. 
Demaria et al elegantly found that the abscopal effect could be tumor specific by 
administering the dendritic cell growth factor Flt3-L to mice that were implanted in one flank 
with mammary 67NR tumor cells alone and in the contralateral flank with both 67NR tumor 
cells and A20 lymphoma cells38. They irradiated the flank with only the 67NR tumor cells, 
which led to significant regression in the contralateral flank of the nonirradiated 67NR 
tumors, but did not affect the growth of the antigenically unrelated A20 lymphoma38. By 
contrast, Camphausen et al found that irradiating Lewis lung carcinoma cells restricted the 
growth of nonirradiated T241 (fibrosarcoma) cells that had been inoculated in a second site, 
suggesting that the abscopal effect of radiotherapy can also be mediated through other non–
tumor-specific mechanisms, or that these two tumors are antigenically related43. The systemic 
increase of many proinflammatory cytokines and chemokines after radiation, from both 
immune cells and tumor tissues, could account for the nonspecific eradication of distant 
tumors and metastases44. Alternatively, the release of low-affinity tumor antigens prompted 
by local radiotherapy may also stimulate the release of cross-reactive tumor antigens. 
An abscopal effect was observed in animal models of pancreatic cancer, whereby the addition 
of capecitabine to RT resulted in a synergistic inhibition of growth in lead-shielded distant 
tumors in the contralateral flank, which was associated with a decrease in proliferation45. 
Similarly, in a preclinical colon adenocarcinoma model, marked inhibition of tumor growth at 
the non-irradiated site was observed with the addition of a chemokine ECI301 following 
radiation, as compared to radiation alone or chemokine alone46. 
Effect of RT plus immunomodulation against micro- and macro-metastases. The concept 
that enhancement of the peptide pool via localized RT can suppress micrometastases was 
demonstrated by Chakravarty et al47. A highly metastatic and poorly immunogenic Lewis 
lung carcinoma (3LL/D122) was injected into the footpad of mice, and palpable tumors 
developed. At this time, histologic analysis of lung demonstrated the presence of microscopic 
pulmonary metastases. If the tumor-bearing leg is amputated, all animals are cured from the 
primary tumor, but are known to eventually succumb to massive lung metastases. Palpable 
tumors were given RT (one fraction of 60 Gy, which was previously demonstrated to cure the 
primary), followed by a 10-day course of Flt3L. Flt3L is a cytokine (naturally occurring 
glycoprotein) that stimulates the proliferation and differentiation of a variety of hematopoietic 
cells, including dentritic cells (DCs) in vivo, both in mice and in humans, and that stimulates 
tumor-specific immune responses. DCs can acquire antigen from apoptotic cells and induce 
cytotoxic T lymphocytes (CTL)48. Lung parenchyma of survivors in the RT + Flt3L cohort 
showed no carcinoma cells but had infiltrates of neutrophils, lymphocytes, and mononuclear 
leukocytes. By contrast, all animals who received RT alone or Flt3L alone had diffuse 
metastasis of Lewis lung carcinoma cells. Mean lung weights, measured 21 days after RT (11 


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days after Flt3L therapy), were significantly lower in the animals that received Flt3L + RT, as 
compared to RT alone or Flt3L alone. Contrary to these immunocompetent mice, nude mice 
receiving RT + Flt3L failed to eliminate pulmonary metastatic infiltrates. The combination of 
RT + Flt3L also improved animal survival. Together, these data indicate that the combination 
of improved antigen presentation and RT significantly suppressed micrometastases. 
The concept that anti-CTLA4 blockade plus RT can decrease lung metastases was 
demonstrated by Demaria et al30 in an animal model of mammary carcinoma 4T1. When 
injected subcutaneously in the mammary fatpad, 4T1 cells metastasize primarily by a 
hematogenous route and can be found in the lungs within 7 days. Given the poor 
immunogencity of 4T1 cells, CTLA-4 blockade by the 9H10 mAb alone did not affect the 
tumor growth or survival of the mice. RT at a single dose of 12 Gy significantly delayed the 
growth of the primary irradiated tumor in the presence or absence of 9H10. To directly test 
the effects of treatment on lung metastases, all mice were sacrificed on day 35 post-tumor 
implantation, and the decrease in lung metastases was significant only when RT and 9H10 
were used in combination, consistent with their observation that only this treatment resulted 
in increased survival. To confirm that the inhibition of lung metastases following RT + 9H10 
treatment is mediated by T cells and to identify the population involved, mice were depleted 
of CD4+ or CD8+ T cells starting 3 days before RT treatment: The median number of 
metastases in mice treated with RT + 9H10 and depleted of CD8+ T cells was similar to 
control untreated animals. By contrast, the inhibition of lung metastases observed in mice 
treated with RT + 9H10 was not affected by CD4+ T-cell depletion. These results indicate 
that CD8+ T cells play a crucial role in the antimetastatic effect of the combination treatment. 
Augmented antitumor effect through the combination of anti-PD-1 blockade plus RT. 
Anti–PD-1/-PD-L1 mAbs have drawn much interest for their potential use in lung or colon 
cancer49. The mechanism by which radiation augments the therapeutic effects of the anti–PD-
1/PD-L1 mAbs was elucidated in a preclinical study of triple-negative breast cancer. In this 
study, neither anti–PD-1 mAb nor radiation when given alone was effective in a murine 
model. However, the addition of anti–PD-1 mAbs promoted the rejection of irradiated tumors 
in the physiologically relevant tissue microenvironment of the mammary fat pad.50  
Results of a preclinical study of murine intracranial glioma treated with anti–PD-1 mAbs plus 
radiotherapy showed not only long-term survival of the treated mice, but also robust 
systemic immunologic memory in the surviving mice, as they were able to reject a secondary 
challenge of glioma cells injected in the flank51. Specifically, median survival periods were 
similar for control mice (25 days) and mice given only anti–PD-1 mAbs (27 days) or 
radiation (28 days). However, the combination of radiation plus anti–PD-1 therapy extended 
the median survival to 53 days (P < 0.05), and 15% to 40% of mice survived more than 180 
days after treatment51. The combination therapy increased tumor infiltration by CD8+ CTLs 
and decreased the number of CD4+Tregs. Finally, in a test of immunologic memory, naïve 
and long-term surviving mice were injected in the flanks with GL261-luc cells. All 8 naïve 
mice died from the growth of the challenged glioma cells, whereas mice that received prior 
treatment with the combined regimen rejected the glioma challenge51. 
Increased PD-L1 expression in tumor tissue following ionizing radiation 
While not definitive, the expression of PD-1 ligands (PD-L1 or PD-L2) on the surface of 
tumor cells or immune cells is an important predictive biomarker of response to PD-1 
blockade9,11-13,15,16. PD-L1 expression in the tumor microenvironment has been associated 
with poor outcomes following chemoradiotherapy in cancer patients52,53. In KEYNOTE-012, 
the frequency of PDL1 expression was 40% in human GEJ/gastric cancers, and among PD-
L1-expressing tumors, a higher degree of expression was non-significantly associated with 
improved outcome21. In the largest study evaluating PDL1 expression in gastric cancer, PD-


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L1 expression was evaluated in resected specimens and was defined as ≥5% membrane 
expression on tumor cells with ≥1+ intensity54. In this study, PD-L1 expression was not 
observed in stroma in cases that lacked expression in tumor cells. The PD-L1+ frequency was 
14% (57/398), and PD-L1+ protein expression was correlated with its mRNA expression. 
These data suggest that a minority of untreated gastric tumors express PD-L1 at baseline. 
In an important preclinical report, Deng et al found that ionizing radiation can induce 
expression of PD-L1 in tumor and their microenvironment40. In addition, they found that the 
addition of PD-L1 blockade to radiation controls primary tumor growth in a CD8+-dependent 
and tumor antigen–specific manner, leading to prolonged protective T cell immunity. They 
further found that the PD-L1/radiation combination induces an abscopal effect on non-
irradiated distant tumors40. These data raise the possibility that exposure to radiation could 
induce tumors to develop a dependence on the PD-L1/PD-1 pathway as an immune escape 
mechanism, which could make those tumors more suspectible to PD-1/PD-L1 blockade. 
Fractionated (vs single-dose) radiotherapy has greater synergy with immune therapy 
Dewan et al tested the hypothesis that the type of dose fractionation regimen of RT can 
determine the ability of RT to synergize with anti-CTLA-4 antibody31. In a mouse model 
where colon or breast cancer cells were injected into both flanks, single-dose or fractionated 
RT led to growth delay of the primary tumor, regardless of whether anti-CTLA-4 antibody 
was administered, but had no effect on secondary tumors outside the RT field. However, an 
abscopal effect on the secondary tumor outside the RT field only occurred in mice treated 
with the combination of antibody plus fractionated RT, not single-dose RT. The frequency of 
CD8+ T cells showing tumor-specific IFN-gamma production was proportional to the 
inhibition of the secondary tumor, suggesting that cell-mediated immunity was responsible 
for the abscopal effect. In addition, these investigators found that delaying the initiation of 
anti-CTLA-4 antibody until a few days after the completion of RT reduced the therapeutic 
effect on the primary and secondary tumor, as compared to initiating antibody treatment on 
the first or final day of RT (RT was given in 3 fractions of 6 Gy each). Of note, in Deng et al, 
PD-L1 blockade, administered every 3 days for a total of 4 times, was initiated on the day of 
IR or 1 day before IR40. 
 
1.7 
Safety for combining chemoradiotherapy with pembrolizumab 
In clinical trials completed to date, most immune related adverse events associated with 
pembrolizumab were mild (grade 1–2), some were severe, and a few were lethal. The most 
common toxic effects were considered to be immunologic in origin, and the sites most 
commonly affected were the skin, gastrointestinal system, liver, and lung10,15,55. 
Neoadjuvant carboplatin/paclitaxel chemoradiotherapy in this disease is well tolerated, as 
reported2 and based on our high-volume experience. In the CROSS trial, the most common 
major hematologic toxic effects in the chemoRT–surgery group were leukopenia (6%) and 
neutropenia (2%). The most common major non-hematologic toxic effects were anorexia 
(5%) and fatigue (3%). Postoperative complications were similar in the two treatment groups, 
and in-hospital mortality was 4% in both.  
 
Risk of pneumonitis: Rationale for restrictions on age and pulmonary status  
The known toxicities of neoadjuvant carboplatin/paclitaxel/radiotherapy do not generally 
overlap with pembrolizumab (see below and Section 1.4 and 1.5). One potential exception is 
toxicity involving the thorax or upper abdomen related to organs within the RT field.  


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Radiation pneumonitis is thought to reflect an immune-mediated inflammatory reaction to 
radiation-induced lung damage56,57. Severe forms can be lethal. Similarly, radiation treatment 
in the abdomen that could result in bowel radiation could similarly exacerbate colitis. 
Radiation pneumonitis has been reported in patients who have undergone mediastinal 
radiation therapy for lung cancer, Hodgkin’s lymphoma (HL), breast cancer, and other 
cancers that require radiation therapy to the thorax58. Radiation pneumonitis is reported in 5% 
to 15% of patients receiving definitive external-beam radiation therapy for lung cancer59. 
Clinical factors that may increase the risk of radiation pneumonitis include concomitant 
chemotherapy, previous irradiation, and recent withdrawal of steroids59, although patients 
treated with specific chemotherapeutic drugs, such as platinum, etoposide, taxanes, and 
vinorelbine, and concurrent radiotherapy do not appear to have a higher risk for radiation 
pneumonitis60. A retrospective analysis of 1,911 patients who underwent combined-modality 
therapy for lung cancer demonstrated that the overall risk of radiation pneumonitis was 
7.8%61. In a multivariate analysis, the daily fraction dose, number of daily fractions, and total 
dose were associated with radiation pneumonitis61. Both the V20 (ie, the percentage volume 
of both lungs minus the planning target volume [PTV] receiving 20 Gy) and the mean lung 
dose (MLD) correlate with the risk for radiation pneumonitis62. Although a V20 level of 35% 
to 37% or an MLD value of 20 to 23 Gy (both calculated with a more advanced algorithm) 
have been considered safe, ~10%-15% of patients still may develop severe radiation-induced 
toxicity when they have received much lower doses63. Patient factors, such as lung function, 
age, and sex, do not adequately select patients at high risk for radiation pneumonitis or 
fibrosis64.  
Radiation pneumonitis is typically a delayed acute reaction, usually occurring 1 to 3 months 
after completing mediastinal radiation therapy59. Patients who experience acute radiation 
pneumonitis will often have a self-limited course, with complete resolution of this process. 
However, a minority of patients may develop progressive pulmonary fibrosis, usually 6 to 24 
months after treatment. Late complications of pulmonary fibrosis include cor pulmonale and 
respiratory failure58. Although there is a lack of published data, the EORTC panel for 
radiotherapy use in lung cancer argued that personal experience suggests a high incidence of 
severe and even lethal radiation pneumonitis in patients with idiopathic interstitial 
pneumonitis62.  
In esophageal/GEJ cancer, a careful review of the literature reveals that radiation pneumonitis 
is uncommon in trial settings. In the CROSS trial, during chemoRT, no instance of 
pneumonitis was reported. The most common toxicities of any grade that could conceivably 
involve the thorax or upper abdomen were esophagitis (19%), nausea (53%), vomiting (25%), 
and esophageal perforation (1%). Lung toxicities of any grade were not reported. Grade 3-4 
events involving these regions were uncommon: esophagitis (1%), nausea (1%), vomiting 
(1%), and esophageal perforation (1%). Postoperative events, including death, were not 
increased in the chemoRT plus surgery group, compared to the surgery alone group. In the 
chemoRT group, the most common postoperative events were pulmonary complications 
(46%; pneumonia, serious atelectasis, pneumothorax requiring drainage, pleural effusion 
requiring drainage, pulmonary embolus, or acute respiratory failure defined as partial 
pressure of arterial O2 <60 mm Hg while breathing room air), cardiac complications (21%; 
arrhythmia requiring treatment, MI, left ventricular failure as demonstrated by pulmonary 
edema on radiograph), chlorothorax (10%; elevated levels of triglycerides in intraothoracic 
fluid), mediastinitis (3%), anastomotic leak (22%), death in hospital (4%) and death after 30 
days (2%). 
Other phase 3 trials of patients with esophageal/GEJ cancer, all of which used a cisplatin/5FU 
chemotherapy backbone, which is considered to have an unfavorable toxicity profile than 


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carboplatin/paclitaxel, also report low rates of pneumonitis or pulmonary complications (see 
Table 1). 
Table 1 
Thoracic toxicities in phase 3 trials of patients with esophageal or GEJ cancer 
received concurrent chemoRT (CROSS trial not shown) 
Study (no. 
patients 
receiving 
chemoRT) 
Tumor 
Chemo 
regimen 
RT 
dose 
Grade 1 or 
higher 
Grade 3 or 
higher 
Postop 
Walsh et al. 
1996 (n=58) 
Distal 
esoph AC 
or cardia 
AC 
Cisplatin 
+ 5FU 
40 Gy 
Not reported 
Cardiac NOS n=2 
Respiratory NOS, n=28 
Cardiac NOS, n=14 
Anast. Leak, n=2 
Chlyothorax, n=1 
Burmeister et 
al 2005 
(n=128) 
Distal, 
mid, or 
upper 
esoph AC 
or SCC 
Cisplatin 
+ 5FU 
35 Gy 
Esophagitis 80% 
Pneumonitis 28% 
Esophagitis 16% 
Pneumonitis 2% 
Surg-related death 5%b 
Major pulm 20% 
Cardiac 12% 
Anast. Leak 5% 
Anast. Stricture 19% 
Conroy et al 
2014 
(PRODIGE; 
n=267) 
Esoph 
SCC 
(85%) or 
esoph AC 
(15%) 
FOLFOX 
or 
cisplatin 
+ 5FU 
50 Gy 
Esophagitis 22% 
Cardiac 2% 
Respiratory, none 
reported 
Esophagitis 8% 
Cardiac 1% 
Death due to MI 
or CVA, 2% 
Respiratory, none 
reported 
No surgery arm 
a Herskovic et al 1992 (NEJM) is not shown above, because the trial occurred in an earlier era, and because 84% of patients 
had esophageal SCC; in this trial, severe respiratory toxicities requiring O2 therapy and initiation of glucocorticoid therapy 
was reported in 3% of patients. 
b Causes of death included respiratory (n=2) and MI (n=1). 
 
Among patients treated with agents targeting CTLA-4 and PD-1, rates of severe adverse 
events (Grade 3–4), including pneumonitis, dyspnea, or cough, have ranged from 2% to 
4%10,15,55,65. The agents were believed to contribute to 3 deaths in one study15 and 1 death in 
another study10. In gastric cancer, the only available data for lung toxicity was reported in 
KEYNOTE-012, which enrolled only patients with advanced stage21. Of 39 patients who 
were evaluable for treatment related AEs, Grade 3-5 treatment related AEs were reported in 1 
patient (2.6%) who had Grade 4 pneumonitis and in 1 patient (2.6%) with hypoxia whose 
death was considered to be treatment related. 
In the current trial, as a precaution to reduce risk for thoracic toxicities and/or postoperative 
complications following chemoradiation plus pembrolizumab, the following measures have 
been implemented: 
• 
Patients aged 69 or more will be excluded (see Section 3).  
o The most comprehensive evaluation of the impact of age on the benefit of 
perioperative chemo(radio)therapy was performed in a meta-analysis (14 
randomized controlled trials, N = 2,422)66. In this analysis, which included 
individual patient data in the majority of patients, the OS benefit of perioperative 
therapy was significantly diminished in a stepwise manner as age increased 
(interaction multivariate P =.0168), with a HR of 1 at ages > 65 years, and HRs 
>1 observed at ages 70 or more. This lack of benefit in patients with advanced 
age likely reflects the morbidity associated with trimodality therapy in the setting 
of subclinical frailty. 
• 
Radiation parameters used in the CROSS trial on tumor length and radius, depth, and 
total RT dose (41.4 Gy) will be implemented. Restrictions from RTOG-1010 on the 
size of celiac nodes will be implemented (see section 3).  


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• 
Strict limits on normal tissue doses and other aspects of radiation delivery will be 
mandated per the most updated standard of care and as recommended5 (see section 
7.3). On-study rapid-review quality assurance of radiation planning will be mandated. 
• 
Patients with recent serious pulmonary illness will be excluded (see section 3). 
• 
PFTs will be required pre-chemoRT and pre-surgery (see section 3). PFTs are 
variably utilized but are a standard of care. 
• 
Monitoring will include late lung toxicities, given that pneumonitis often does not 
appear until several months after radiation treatment is completed. 
The combination of pembrolizumab with trimodality therapy is a promising approach in this 
highly fatal disease. Clinical data are needed that evaluates the combination of 
pembrolizumab with concurrent radiation to the esophagogastric region, and with concurrent 
chemotherapy followed by thoracoabdominal surgery. Outcomes for the combination of 
pembrolizumab and (chemo)radiation are being collected in ongoing trials in other tumor 
types.  
• 
Neoadjuvant pembrolizumab plus concurrent chemoRT: In a neoadjuvant 
pancreatic cancer trial, neoadjuvant pembrolizumab 200 mg IV days 1, 22, and 43 
will be given during concurrent radiation (50.4 Gy in 28 fractions) and capecitabine 
(825 mg/m2 BID).  
• 
Adjuvant pembrolizumab following RT: In head and neck cancer, adjuvant 
pembrolizumab will be given once every 3 weeks for a maximum of 6 doses, 
following completion of adjuvant 60 Gy radiation (over 6 weeks) and risk-based 
cisplatin on days 1, 22, and 43.  
Ongoing or planned studies to assess thoracic RT plus pembrolizumab include: 
• 
MK-3475 and Hypofractionated Stereotactic Radiation Therapy in Patients With 
Non-Small Cell Lung Cancer (NSCLC) (NCT02444741) 
• 
Phase I Trial of MK-3475 and Concurrent Chemo/Radiation for the Elimination of 
Small Cell Lung Cancer (NCT02402920) 
• 
Consolidation Pembrolizumab (MK-3475), Following Chemoradiation in Patients 
With Inoperable/Unresectable Stage III NSCLC (NCT02343952) 
In addition, neoadjuvant pembrolizumab with or without chemotherapy (without RT) is 
currently being studied in multiple solid tumors, including: 
• 
Phase Ib/II Study of Neoadjuvant Pembrolizumab With Gemcitabine-Cisplatin 
(Cisplatin-Eligible) or Gemcitabine (Cisplatin-Ineligible) in Subjects With T2-
4aN0M0 Urothelial Cancer (study start May 2015, end March 2018; NCT02365766) 
• 
Neoadjuvant Pembrolizumab for Unresectable Stage III and Unresectable Stage IV 
Melanoma (NeoPembroMel; start Jan 2015; end Feb 2017; NCT02306850) 
• 
A Clinical Trial to Evaluate the Effect of Neoadjuvant MK-3475 (Pembrolizumab) 
Therapy on Intratumoral Immune Infiltrates in Renal Cell Cancer (RCC) Patients 
Undergoing Surgical Resection (start Dec 2014, end Feb 2016; NCT02212730) 
• 
Immunotherapy With MK-3475 in Locoregionally Advanced, Surgically Resectable 
Head and Neck Squamous Cell Carcinoma (start March 2015, end March 2022; 
NCT02296684) 
• 
A Clinical Trial to Evaluate the Effect of Neoadjuvant MK-3475 (Pembrolizumab) 
Therapy on Intratumoral Immune Infiltrates in Renal Cell Cancer (RCC) Patients 
Undergoing Surgical Resection (start Dec 2014, end Feb 2016; NCT02212730) 
 
Reported results from the above studies will be followed to inform potential modifications, if 
appropriate, in the current trial. 


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1.8 
An accepted outcome measure for this trimodality approach is pathCR 
A pathologic complete response (pathCR) is defined as the absence of malignant cells in the 
resected specimen following chemoradiotherapy67. Approximately 15%-29% of patients 
achieve a pathCR, as shown by a large series from Mayo Clinic and randomized clinical 
trials2,67-69. PathCR has become accepted as a primary endpoint in phase 2 trials in the US 
examining the efficacy of neoadjuvant chemoradiation in this disease, including in NCI-
sponsored trials conducted by our group70 and others68,71. This is because the outcome result 
is known soon (~12 weeks after initiation of therapy) and because it is well-accepted as the 
strongest prognostic variable for disease-free survival (DFS) or overall survival (OS)22,23,72. 
Pembrolizumab has been shown in preclinical models to enhance antitumor efficacy on 
primary tumors when added to radiation (see Section 1.6). Together, these considerations 
support the use of pathCR as an endpoint in the current trial. 
 
1.9a 
Disease recurrence is an adequate endpoint of long-term outcome after trimodality 
therapy for GEJ adenocarcinoma 
Utilizing pathCR as the sole primary endpoint has limitations, particularly for a drug such as 
pembrolizumab that may have an abscopal effect on micrometastases that would not be 
expected for cytotoxic chemoagents. The prior data suggesting pathCR is a surrogate 
endpoint of long-term survival is based entirely on the use of cytotoxic therapies, not 
immunotherapies. The benefit from adding pembrolizumab may be demonstrated through its 
ability to eradicate micrometastases (see Section 1.6); it is possible this effect may not be 
adequately reflected in the primary tumor in a small single-arm trial. Therefore, assessing 
disease recurrence is an important endpoint in the current trial.  
Disease recurrence is a reasonable surrogate for OS. As described above, ~40% of patients 
experience disease recurrence after trimodality therapy. The vast majority of recurrences 
occur at a distant anatomic site, and 90% of distant recurrences occur within 24 months of 
completing local therapy. Disease recurrence at a distant anatomic site in esophageal/GEJ 
adenocarcinoma is almost always fatal. The median OS of patients who had distant 
metastases after trimodality therapy is ~10.2 months4.  
In the CROSS trial, after a minimum follow-up of 24 months and a median follow up of 45 
months for surviving patients, 35% of patients in the chemoRT group had disease recurrence. 
Almost all disease recurrences (91% [32%/35%]) included a distant anatomic site. Every 
recurrence occurred within 36 months after randomization. Moreover, the KM curves (which 
include only patients who underwent an R0-R2 resection, of adenoca or SCC histology) 
reveal a DFS rate of 72% at 24 months and 60% at 36 months. The majority (70% 
[28%/40%]) of DFS events occurred within 24 months. In a large series from a single 
institution, 40% of patients (144/356) with esophageal/GEJ cancer (85% were GEJ tumors) 
experienced disease relapse after trimodality therapy after a median follow up of 37 months. 
Among patients who relapsed, 83% (119 /144) included distant metastases outside the 
radiation field4. The distant recurrence rate at 24 months after the completion of local therapy 
was 31% in the overall cohort; among the patient subset who experienced disease recurrence 
at a distant site after trimodality therapy, 91% of distant metastases were diagnosed within 2 
years of local therapy.4 A separate report from the same institution observed a locoregional 
recurrence rate at 24 months of 3.4% (17/518), and these 17 recurrences represented 63% 
(17/27) of all locoregional recurrences from the time of esophagectomy after a median follow 
up 55 months for surviving patients3. Together, these data indicate that 24 months of follow 
up is sufficient to capture the vast majority of DFS events. 
 


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1.9b 
Perioperative chemotherapy alone (without radiotherapy) is an alternative 
approach for the definitive treatment of locally advanced GEJ adenocarcinoma 
While preoperative chemoRT is a preferred approach at leading cancer centers in the U.S. for 
the treatment of locally advanced GEJ adenocarcinoma, perioperative chemotherapy alone 
without radiation is a valid approach. Support for perioperative chemotherapy alone without 
RT for definitive therapy of GEJ adenocarcinoma is based on multiple phase 3 trials utilizing 
platinum/fluoropyrimidine-based combination chemotherapy, which have shown an OS 
benefit for the addition of perioperative chemotherapy to surgery alone for esophagogastric 
cancer73-75.  
Platin/FP doublet is equal to anthracycline/platin/FP triple (OEO5). In the most recently 
reported phase 3 trial examining perioperative chemotherapy alone without RT (MRC OEO5, 
N = 897), patients with adenocarcinoma of the lower esophagus or GEJ were randomized to a 
standard regimen of 2 cycles of preoperative CF (cisplatin 80 mg/m2, 5FU 1000 mg/m2 D1-
4; once every 21 days) vs an intensified regimen of 4 cycles of preoperative ECX76. The R0 
rates were low: 60% in the CF group vs 67% in the ECX group. The trial failed to meet its 
primary endpoint of superior OS in the intensified vs standard regimen (HR 0.92, p=.89), and 
toxicity was increased in the intensified regimen. These data are consistent with cross-trial 
comparisons suggesting that the OS observed with platinum/FP doublets (ACCORD-07)75 are 
comparable to that with platin/FP/anthracycline triplets (MAGIC)73, and provide support for 
the use of a platinum/FP doublet as standard therapy for a perioperative approach that utilizes 
chemotherapy alone without radiation. 
Cisplatin/5-FU doublet regimen (ACCORD-07) A preoperative platin/FP doublet was 
examined in a recent phase 3 trial involving GEJ adenocarcinoma patients (ACCORD-07), 
which randomized patients to perioperative chemotherapy vs surgery alone. In this trial75, 113 
patients were assigned to the chemotherapy arm to receive 2-3 cycles of chemotherapy 
(cisplatin 100 mg/m2 plus 5FU 800 mg/m2/day Days 1-5; every 28 days), followed by 3-4 
cycles of postoperative chemotherapy of the same regimen. While 87% of patients received 2 
or more cycles preoperatively, only 12% received 3 preoperative cycles. The R0 rate was 
84% (95/113) with a 5 year DFS rate of 34% and 5-year OS rate of 38%. Most common 
grade 3-4 toxicities were neutropenia 20%, nausea/vomiting 9%, thrombocytopenia 6%, and 
mucositis 4%. The combination of pembrolizumab 200 mg IV plus cisplatin 80 mg/m2 and 5-
FU 800 mg/m2 D1-5, every 21 days, is being examined in patients with previously untreated 
(KEYNOTE-062) and previously treated (KEYNOTE-059) patients with GEJ/gastric cancer. 
Lack of efficacy benefit from the addition of perioperative cisplatin/5FU to surgery 
alone in US population (INT-0113) However, the combination of cisplatin plus 5-FU is not 
widely used as preoperative regimen in the U.S. This is partly due to the observed toxicity in 
this population. In addition, this regimen (cisplatin 100 mg/m2 day 1 plus 5FU 1000 mg/m2 
days 1-5, every 28 days) demonstrated a lack of efficacy in the largest U.S. randomized trial 
examining perioperative chemotherapy plus surgery vs surgery alone (INT-0113)77,78. In this 
trial (N = 467), R0 rates were observed in 63% in the perioperative chemotherapy group, 
comparable to the R0 rates observed in the CF arm of the recent OEO5 trial, vs 59% in the 
surgery alone group. Only patients with an R0 resection experienced substantial long-term 
survival, which is a well-recognized prognostic factor. After median follow up of 8.8 years, 
median OS was the same between groups (1.3 years in CF-surgery group vs 1.3 years in the 
surgery alone group). 
Combination of oxaliplatin/5FU with PD-L1 inhibitor In immunocompetent mice 
implanted with CT26 colorectal cancer cells, an anti-mouse PD-L1 antibody was recently 
shown to significantly improve survival of mice. The antitumor activity of anti-PD-L1 was 


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enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 
within CT26 tumors81. Pembrolizumab is being tested in combination with mFOLFOX6 in a 
phase 2 trial of advanced CRC (NCT02375672) and in a phase I (dose escalation)/II trial of 
advanced GI malignancies, including gastroesophageal carcinomas (NCT02268825). In the 
former trial, pembrolizumab is administered 200 mg IV (flat dose) every 3 weeks, starting 
with cycle 1, with FOLFOX being given every 2 weeks. In the latter trial, pembrolizumab is 
administered every 2 weeks, starting with cycle 3, with FOLFOX given every 2 weeks (Level 
-1: 50mg IV q 2 weeks Level 1: 75mg IV q 2 weeks Level 2: 200mg IV q 2 weeks).  
Combination of carboplatin/paclitaxel with pembrolizumab The carboplatin/paclitaxel 
doublet has known activity in GEJ cancer in locally advanced disease2 and in advanced 
disease in the first-line82-85 and second-line86,87 settings. Paclitaxel or platinum compounds 
have demonstrated improved antitumor efficacy when combined with anti-PD-1-based 
blockade88. Carboplatin (AUC 6) plus paclitaxel (200 mg/m2) combined with pembrolizumab 
2 mg/kg or 10 mg/kg (all agents given on Day 1 of a 21-day cycle) is currently being tested in 
a phase I/II trial in metastatic NSCLC (KEYNOTE-021; NCT02039674). 
 
1.9c 
Rationale for translational studies 
1.9c1 
Genetic subtypes of GEJ cancer and anti-tumor immunity, including MSI, 
EBV, and PDL1 and PDL2 amplification.  
Recent comprehensive molecular characterization of GEJ/gastric 
adenocarcinomas by the TCGA has revealed 4 molecular subtypes: EBV-
associated (10% of cases, which included PD-L1 and PD-L2 amplifications), 
microsatellite unstable (MSI; 20%), chromosomal instability (50%; characterized 
by intestinal histology, TP53 mutation, and RTK-RAS activation), and genomic 
stability (20%; characterized by diffuse histology, CDH1, RHOA mutations)89.  
These subtypes may have differential response to immune-modulating agents. 
EBV-associated gastric adenocarcinomas display recurrent amplification of PD-
L1 and PD-L289 and are primarily characterized by dysregulation of immune 
response genes90. In addition, EBV ISH-positivity was found to be correlated 
with PDL1 protein expression in a large series of human gastric cancers from 
China54, and EBV infection was strongly associated with intratumoral CD8+ T 
cell infiltration and moderately correlated to stromal CD8+ T cell accumulation 
in a small gastric cancer series91. EBV positivity by ISH was found in 3% of 
gastric cancers from Caucasians (N>400)92. This association has not been studied 
extensively in GEJ adenocarcinomas.  
The association between MSI (mismatch repair [MMR] deficiency) and tumor 
infiltrating lymphocytes (TILs) is well established in multiple epithelial cancers. 
A recent phase 2 study evaluated the clinical activity of pembrolizumab in 41 
patients with progressive metastatic carcinoma with or without deficient MMR. 
Pembrolizumab was administered at a dose of 10 mg/kg every 14 days in patients 
with MMR–deficient colorectal cancer (CRC), patients with MMR–proficient 
CRC, and patients with MMR–deficient non-CRCs. The co-primary end points 
were the immune-related objective response rate (irORR) and the 20-week 
immune-related progression-free survival rate (irPFS). The irORR and irPFS rate 
were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for MMR–
deficient CRCs; and 0% (0 of 18 patients) and 11% (2 of 18 patients) for MMR–
proficient CRCs; and 71% (5 of 7) and 67% (4 of 6) for MMR-deficient non-
CRC cancers. Median PFS and OS were not reached in MMR-deficient CRCs, 


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but were 2.2 and 5.0 months, respectively, in MMR-proficient CRCs (HR for 
disease progression or death, 0.10 [P <.001], and HR for death, 0.22 [P =.05]). 
Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor 
in MMR–deficient tumors, as compared with 73 in MMR–proficient tumors (P 
=.007), and high somatic mutation loads were associated with prolonged PFS93. 
The largest evaluation of MMR in gastric/GEJ cancer (N = 712) revealed that 9% 
of tumors from either a European (25 of 264) or Japan cohort (21 of 230) were 
MMR-deficient94. KRAS mutation (codons 12, 13, and 61) was detected in ~5% 
of tumors, and BRAFV600E mutation was detected in <1% of tumors. KRAS 
mutation status was statistically positively correlated with MMR-deficiency. The 
MMR rate among 446 gastric tumors from Caucasians was reported to be 7%92. 
MSI data are recently available on the Foundation One genomic profile, which 
also provides information on alterations in hundreds of cancer-related genes and 
mutational load (FoundationOne.com). This test is commercially available and 
has been obtained as part of clinical care in Mayo Clinic patients to facilitate 
treatment options. 
 
1.9c2 
Tissue expression of PDL1 and immune markers 
PDL1 expression is an important marker that has potential predictive value for 
pembrolizumab therapy, as described above. Ionizing radiation has been shown 
to induce PDL1 expression in preclinical models, as described above39,40. 
The density of markers of adaptive immunity such as CD3, CD8, FoxP3, and 
CD45RO infiltrating intratumoral/stromal tissue compartments have been 
associated with survival in patients with colorectal cancer, as we95 and others96,97 
have shown. In gastric cancer, the densities of CD3+, CD8+, and CD45RO+ 
TILs were independent favorable prognostic factors98, as were CD8+ and FoxP3+ 
cells in MSI-high gastric cancers99. The percentages of CD8+ T cells that 
produce IL-17 in gastric tumors are associated with survival times of patients and 
promote chemotaxis of MDSCs, which might promote tumor progression100. It is 
possible that adaptive immune markers in TILs, apart from PD-L1 expression, 
can have predictive value for immunomodulating agents101. 
 
1.9c3 
Circulating markers and cells  
Soluble PD-L1. Release of inhibitory coregulatory proteins into the circulation 
may represent one mechanism by which tumors thwart immune responses. A 
collaborator in the current trial (
Laboratory) identified a soluble 
form of PD-L1 that retains immunosuppressive activity and is associated with 
aggressive renal cell carcinoma102. This lab developed an ELISA for 
quantification of PD-L1 in biological fluids. Soluble PD-L1 was detected in the 
cell supernatants of some PD-L1-positive tumor cell lines. Protein sequencing 
established that the measured soluble PD-L1 retained its receptor-binding domain 
and could deliver proapoptotic signals to T cells. Higher preoperative soluble 
PD-L1 levels were associated with larger tumors (P < .001), tumors of advanced 
stage (P =.017) and grade (P =.044), and tumors with necrosis (P =.003). A 
doubling of soluble PD-L1 levels was associated with a 41% increased risk of 
death (P =.010). These observations suggest that soluble PD-L1 may be detected 
in the sera of cancer patients and that it may systemically impair host immunity, 
thereby fostering cancer progression and subsequent poor clinical outcome. 


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Soluble PD-L1 has not been tested in GEJ cancer patients, nor have changes in 
levels in response to neoadjuvant chemoRT been adequately studied. 
Balance of circulating CD8+ effector cell subpopulation. Given that the antigen 
spectrum for a given tumor is usually incomplete, it is possible that neo antigens 
could be generated and released from tumor cells following RT, which would not 
be identified by commercially available tetramers. Since the establishment of 
antigen specificity for the entire T-cell population is not possible, this study will 
ascertain whether the antigen burst and/or inflammatory factors released 
following RT would selectively expand or reduce T cell subpopulation. While 
RT-induced changes are initiated locally at tumor sites, RT can impact the 
systemic immune system as observed in the abscopal effect. We hypothesize that 
tumor antigens and/or inflammatory factors released from RT-induced tumor cell 
necrosis will trigger an efflux of effector or memory T cells in the peripheral 
blood since these subpopulation of T cells are antigen-primed and may have a 
rapid response to altered antigen stimulation in context with inflammatory 
cytokines. It has been reported that RT increases the serum levels of IL-1beta and 
IL-6 and reduces the serum levels of TGF-beta in prostate cancer patients after 1-
2 weeks of RT. Among the cytokines, IL-6 is responsible for expansion of 
effector memory CD8+ T cells and IL-1beta and TGF-beta regulate the 
transmigration or tissue retention of effector and memory CD8+ T cells. In this 
portion of the project, fluctuations in frequencies among naïve 
(CCR7+CD45RA+), central memory (CCR7+CD45RA-), effector/effector 
memory (CCR7-CD45RA-), and terminally differentiated (CCR7-CD45RA+) 
CD8+ T cells will be determined and evaluated together with the development of 
anti-gastric cancer immunity in relation to the timing of RT. PBMCs and plasma 
will be isolated at (baseline), after RT (day 1, 8, 15, pre-surgery), after adjuvant 
therapy, and at tumor recurrence. Cells will be co-stained with antibodies for 
CD3, CD8, CD45RA, CCR7 to identify CD8+ T cells and their phenotype. The 
percentage of each subset will be determined based on the total CD8+ T cells 
when analyzed by flow cytometry. We will compare the frequency of each subset 
of CD8+T cells and their PD-1 expression in relation to the different time points 
following RT. If we identify any significant changes of T cell subset, we will 
measure the cytokine profiles of these patients at that time point using multiplex 
methods.  
Tumor-reactive CD11ahighPD-1high CD8+ T effector population following RT. T 
cell receptor (TCR) tetramers can detect tumor-specific immunity but have 
limitations. Both the down regulation of the TCR induced by persistent tumor 
antigen encounter and the weak affinity of CD8+ T cells for tumor antigens 
contribute to the underestimation of anti-tumor responses measured by tetramers. 
In addition, TCR tetramers are not capable of detecting CD8+ T cell responses to 
subdominant epitopes. Therefore, a novel method of detecting tumor-related T 
cell response is necessary in situations where the identity of tumor antigens are 
unknown or suboptimal to be detected by tetramers. CD11a expression is 
required in the rejection of tumors103. A collaborator laboratory recently 
established that the CD11ahigh PD-1+ CD8+ T cell population represent tumor-
reactive CD8+ T cells104. In addition, work from this lab determined that 
CD11ahighCD8+ T cells inside tumors are tumor-specific functional effector cells 
and that their function is enhanced by stereotactic ablative radiotherapy in PD-1 
knockout mice105. In the current study, we propose to investigate whether the 
CD11ahigh PD-1+ CD8+ T cell population in GEJ cancer patients following the 


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initiation of chemoRT plus pembrolizumab can identify tumor-related T cell 
response. PBMCs and plasma will be isolated at (baseline), after RT (day 1, 8, 
15, pre-surgery), after adjuvant therapy, and at tumor recurrence and will be used 
in the following assays:  
• 
T cell activation marker assay PD-1+ CD11ahigh CD8+ T cells will be 
stained with antibodies for CD69, CD25, CD45RO and CD62L which 
are upregulated upon T cell activation.  
• 
T cell proliferation assay The proliferation of PD-1+ CD11ahigh CD8+ T 
cells will be measured by their larger forward light scatter (FSC) and 
intranuclear expression of Ki67.  
• 
T cell differentiation assay The expression of transcription factors that 
controls T cell differentiation into effector or memory cells will be 
analyzed. We will measure the levels of T-bet (for effector T cells) and 
Eomes (for memory T cells) in PD-1+ CD11ahigh CD8+ T cells.  
• 
T cell function assay. Cytotoxic (CTL) T cell effector functions of 
CD11ahigh PD-1+ CD8+ T cells will be assessed by measuring 
degranulation (CD107a expression) and intracellular production of IFN-
gamma following a 4-hour ex vivo stimulation with PMA/ionomycin or 
with any known prostate antigen peptides. The expression of effector 
molecule of CTL (granzyme B) and its inducer transcription factors 
(Bcl6 and Runx3), will be examined in PD-1+ CD11ahigh CD8+ T cells. 
 
Circulating MDSCs and immune profile  
Recent evidence indicates that circulating myeloid derived suppressor cells 
(MDSCs) may be increased in gastrointestinal tumors and other cancers, and 
these cells may correlate with increased response of melanoma patients to 
ipilumimab. The tumor microenvironment is populated by various types of 
inhibitory immune cells including Tregs, alternatively activated macrophages, 
and myeloid-derived suppression cells (MDSCs), which suppress T cell 
activation and promote tumor outgrowth106. Recent studies indicate that MDSCs 
also play an essential role in chemoresistance and radioresistance107. Therapeutic 
blockade of immune checkpoints has been associated with a reversal in the 
distribution and proportion of MDSCs108,109. In addition, a reduction in 
circulating MDSCs was associated with regression of metastatic tumors in a 
melanoma patient treated with ipilimumab and radiotherapy29. On day 10 after 
ionizing radiation, Deng et al observed that MDSCs, defined by 
CD45+CD11b+Gr1+ expression, were reduced by IR and/or anti–PD-L140. In 
tumors that received anti–PD-L1 or IR treatment alone, the percentage of 
MDSCs in the total CD45+ cell population decreased from 19% in untreated 
tumors to 7% (P =.016) and 5% (P =.0074), respectively. Combination therapy 
with anti–PD-L1 and IR exhibited the greatest effect on MDSCs and further 
reduced the percentage to 0.4% of total CD45+ cells (P <.0001). The extent of 
local reduction in MDSCs was associated with enhanced tumor growth delay and 
tumor regression, and were dependent on CD8+ T cells. These results raise the 
possibility that a local reduction in MDSCs is an essential component in the 
therapeutic efficacy of combination treatment with local IR and anti–PD-L1. 
Other data from this study suggest that CD8+ cells are directly involved in 
controlling MDSC cells by inducing apoptosis of MDSCs, and that RT and anti–
PD-L1 combination therapy restores the function of CD8+ T cells, which, in turn, 
results in the direct elimination of MDSCs. 


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A collaborating laboratory (
) recently developed a method that 
allows the analysis of human leukocyte populations, including MDSCs, by the 
use of eight 10-color flow cytometric protocols in combination with novel 
software analysis110. This method is distinct from, and complementary to, the 
analysis to be completed by the Dong/Kwon Lab described above, by utilizing 
un-manipulated biological sample preparation that allows for comprehensive 
direct quantitation of leukocytes and non-overlapping immunophenotypes. This 
group specifically designed myeloid protocols that enable the identification of 
distinct phenotypes that include mature monocytes, granulocytes, circulating 
dendritic cells, immature myeloid cells, and MDSCs. This method also identified 
CD123 as an additional distinguishing marker for the phenotypic characterization 
of immature LIN-CD33+HLADR-MDSCs. This approach permits the 
comprehensive analysis of all peripheral blood leukocytes and yields data that is 
highly amenable for standardization across inter-laboratory comparisons for 
human studies. 
 
1.9d 
Proposed Trial: Study Overview 
This is a single-arm Phase 1b/2 study. Patients with resectable, locally advanced, 
GEJ/gastric cardia adenocarcinoma will be treated with pembrolizumab plus weekly 
carboplatin and paclitaxel, and concurrent daily radiotherapy for approximately 5 weeks. 
Pembrolizumab will be administered once every 3 weeks for up to 3 preoperative doses. 
Within 4 to 8 weeks following completion of neoadjuvant chemoradiotherapy, a PET/CT 
scan will be performed to rule out distant disease. If distant disease is not confirmed, 
patients will undergo curative-intent surgery to remove the tumor within 4 to 8 weeks 
following completion of neoadjuvant chemoradiotherapy. Following surgery, after all 
acute toxicities in the postoperative period have resolved to grade 1 or less, patients will 
receive adjuvant pembrolizumab once every 3 weeks for up to 6 doses. 
In the phase 1b portion, 15 evaluable patients will be enrolled. Toxicity and safety will be 
actively monitored on an ongoing basis. Enrollment will be halted after the 15th patient to 
assess for safety. If safety parameters fail to be met (see Section 16 for details of safety 
criteria), data will be analyzed to determine the specific nature and etiologies of safety 
concerns.  
We anticipate that safety parameters will be met, in which case the study will move onto 
the Phase 2 portion. In the phase 2 portion, 30 evaluable patients will be enrolled and will 
receive the same neoadjuvant regimen and surgery as in the Phase 1b portion. These 30 
patients will include patients who already received this treatment in the Phase 1b portion. 
It is possible that the neoadjuvant regimen is a modified regimen. 
After pembrolizumab is permanently discontinued, patients will be evaluated with 
history, physical exam, and imaging every 3 months for the 1st year after surgery, then 
every 4 months for the 2nd year. Diagnostic investigations will be performed only when 
recurrence is suspected. Patients will be followed for disease recurrence and overall 
survival up to 2 years after surgery.  
If the primary endpoint is met (ie, pathCR see Section 16), future plans include 
expanding to a larger single-arm or randomized Phase 2, or to a Phase 3 trial, that may 
include a biomarker-selected population. 
 
 
 


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Potential “pseudoprogression” at the time of repeat PET/CT 
In the phase 1b or 2 portion of the trial, repeat PET/CT following the completion of 
neoadjuvant pembrolizumab/chemoRT may detect new lesions at distant anatomic sites, 
or demonstrate that the primary has enlarged or that regional lymph nodes have increased 
in size or number. While these instances are expected to be uncommon, it will be 
challenging to confirm whether these changes are due to worsening disease vs 
pseudoprogression. This is because 10% or more of patients receiving immunotherapy 
are characterized as having PD using traditional (WHO) criteria, but then have 
subsequent evidence of tumor response111. In addition, 4-7% of patients (7 of 180 in 
CROSS2; 16 of 128 in Burmeister et al112) assigned to standard chemoRT without 
immunotherapy experience PD prior to surgery, such that surgery is not possible. 
Symptomatology is often an unreliable indicator of PD due to the confounding effects of 
chemoRT-induced esophagitis which can worsen swallowing and other symptoms.  
Given the complexity and infrequency of these situations, these cases will be addressed 
on an individual basis, and management will depend on the specific clinical scenario with 
final decision-making resting in the clinical judgment of the investigative team. The team 
will undertake multidisciplinary discussions and apply the principles of irRECIST 
adapted to trimodality therapy in GEJ cancers. According to irRECIST113-115 or irRC 
(immune related response criteria)111, new lesions or lesions that show interval 
enlargement must be confirmed on repeat imaging that is completed 4 or more weeks 
later, in order to determine the changes as PD. If new lesions or other radiographic 
changes are observed during or immediately after chemoRT, or at the time of repeat 
PET/CT, in the absence of signs or symptoms of definitive unresectable disease, options 
include: delaying surgery while continuing systemic therapy followed by repeat imaging; 
proceeding directly to surgery which may be preceded by intraoperative confirmation of 
resectability; or obtaining tissue confirmation of a new lesion. Given the unreliability of 
radiographic changes of the primary tumor during or after chemoRT, due to the 
inflammatory effects of chemoRT on tissue, assessment of PD will not routinely include 
changes in the primary tumor or regional nodes, as long as the disease remains resectable.  
If surgery is delayed, the investigators will have the option of continuing pembrolizumab 
with or without chemotherapy (without RT), followed by repeat imaging 4 or more weeks 
later. The recommended chemotherapy backbone will be continuation of carboplatin plus 
paclitaxel (see Section 1.9b for rationale; see Section 7 for details of therapy) . After 
completing at least two cycles, repeat imaging will be performed. 
 
 
 
 


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Amendment 9 
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2.0 
Goals 
2.1 
Primary objectives 
2.11 
Phase 1b 
• 
To determine the safety and tolerability of pembrolizumab when combined 
with radiotherapy plus carboplatin and paclitaxel in locally advanced 
GEJ/cardia adenocarcinoma. 
2.13 
Phase 2 
2.131 To evaluate the pathCR rate of pembrolizumab when combined with 
radiotherapy plus carboplatin and paclitaxel in locally advanced 
GEJ/cardia adenocarcinoma. 
2.2 
Secondary Objectives 
2.21 
To determine progression-free survival (PFS), determine time to relapse (TTR), 
disease-free survival (DFS), R0 rate, and overall survival (OS) of pembrolizumab 
when combined with radiotherapy plus carboplatin and paclitaxel. 
2.3 
Translational Research Objectives 
2.31 
To identify tissue and/or circulating biomarkers that are associated with pathCR, 
DFS, and other clinical outcomes in patients with locally advanced GEJ/cardia 
adenocarcinoma treated with neoadjuvant pembrolizumab-based therapy. 
2.32 
To determine differences in pre-treatment vs post-treatment tissue expression of 
immune markers, including PDL1 and tumor infiltrating lymphocytes (CD8+, 
FOXP3+ Tregs, CD45RO, granzyme B), in patients treated with neoadjuvant 
pembrolizumab-based therapy.  
2.33 
To identify immune markers in pretreatment tissues that correlate with pathCR 
and long-term outcome in patients treated with neoadjuvant pembrolizumab-
based therapy.  
2.34 
To explore whether an EBV-associated tumor molecular profile89 is associated 
with pathCR and long-term outcome in patients treated with neoadjuvant 
pembrolizumab-based therapy. 
2.35 
To explore whether a microsatellite-unstable (MSI) tumor molecular profile89 is 
associated with pathCR and long-term outcome in patients treated with 
neoadjuvant pembrolizumab-based therapy. 
 
3.0 
Patient Eligibility 
Phase 1b only: Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office
 to ensure that a place on the protocol is open to the 
patient. 
3.1 
Pre-Registration Eligibility - Inclusion 
3.11 
≥18 years of age and ≤80 years of age. 
3.12 
Histologically or cytologically confirmed adenocarcinoma involving the 
gastroesophageal junction or gastric cardia. 


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Amendment 9 
Protocol version: 20Dec2019 
3.13 
Central pathology review to determine evaluability of archived EGD/biopsy 
sample 
NOTE: If archived sample was collected >8 weeks prior to Pre-Reg, is not 
available in a timely manner, or was collected outside of Mayo Clinic and 
considered unevaluable, then baseline EGD with primary tumor biopsy at Mayo 
Clinic must be performed unless clinically contraindicated.  Patient is allowed to 
enroll regardless of whether this Mayo Clinic tissue sample is evaluable. (Only 1 
EGD with primary tumor biopsy performed at Mayo Clinic ≤8 weeks prior to 
Pre-Reg is required.) 
NOTE:For both archival or newly obtained tissue, only biopsies are adequate 
(FNA is not adequate). 
3.14 
Willing to provide mandatory tissue samples for research purposes (Section 4.0, 
6.16, and 17.1). 
3.2 
Registration Eligibility 
3.21 
Inclusion Criteria 
3.211 Baseline imaging with an FDG-PET scan negative for distant metastatic 
disease must be obtained ≤28 days prior to registration. 
3.212 Surgically resectable (T2N0, T3N0, Tany with node positivitity, M0), as 
determined by endoscopic ultrasound (EUS) and the following minimum 
diagnostic work-up: 
• 
Whole-body PET/CT (PET/CT of skull base to mid-thigh is 
acceptable) 
• 
EUS ≤35 days prior to registration 
NOTE: Patients may have regional adenopathy including para-
esophageal, gastric, gastrohepatic and celiac nodes. 
NOTE if patient unable to have PET/CT then CT chest/abdomen/pelvis 
with contrast (preferred) or MRI chest/abdomen/pelvis with contrast. 
3.213 Surgical consultation at enrolling site to confirm that patient will be able 
to undergo curative resection after completion of chemoradiation 
≤56 days prior to registration. 
• 
Tumor is amenable to standard resection and reconstruction. 
3.214 Must be considered fit candidate currently by treating provider to 
complete all components of therapy including neoadjuvant 
chemoradiation and surgery.  
NOTE: This assessment must be made ≤7 days prior to registration and 
≤3 days prior to anticipated initiation of treatment.  
3.215 Radiation oncology consultation at enrolling site to confirm that disease 
can be encompassed in a radiotherapy field ≤56 days prior to registration. 
NOTE: Radiotherapy quality assurance rapid review must be performed 
before the first fraction of RT is administered (See Section 7.34). If RT 
constraints cannot be met, the patient will be removed from the protocol 
prior to treatment. 
3.216 Consultation with a medical oncologist at enrolling site ≤56 days prior to 
registration, with determination that treatment with neoadjuvant 


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Amendment 9 
Protocol version: 20Dec2019 
chemoradiotherapy with weekly carboplatin and paclitaxel is considered 
acceptable. 
3.217 ECOG Performance Status 0 or 1 (see Appendix I). 
3.218 Adequate oral intake and nutritional status without current or likely need 
for enteral or parenteral feeding during chemoradiation or the 
preoperative period. 
3.219a Pre-treatment PFTs, collected ≤90 days prior to enrollment, must show 
FEV1 >60% of predicted. 
3.219b Adequate organ function ≤21 days prior to registration: 
• 
Aspartate transaminase (AST) level ≤2.5 x upper limit of normal 
(ULN) and alanine transaminase (ALT) ≤3 × upper limit of normal 
(ULN) 
• 
Total bilirubin level of ≤1.5 x ULN 
• 
Creatinine level ≤1.2 x ULN or creatinine clearance 
>60 mL/min/1.73 m2 for patients with creatinine levels above or 
below the institutional normal (as determined by Cockroft-Gault 
equation*) 
• 
Hemoglobin (Hgb) ≥9 g/dl without transfusion or epoetin 
dependency (≤7 days prior to assessment) 
• 
Absolute neutrophil count ≥1.5 x 109/L 
• 
Platelets ≥100 x 109/L 
• 
Albumin ≥2.5 g/dl 
*Cockcroft-Gault Equations: 
Creatinine clearance for males = (140 - age)(actual body weight in kg) 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females = (140 - age)(actual body weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
3.219c Patients of childbearing potential must be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity 
for the course of the study through 120 days after the last dose of study 
medication.  
NOTE: Patients of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for >1 year. 
3.219d Patients of childbearing potential must have a negative urine or serum 
pregnancy test ≤7 days prior to registration. 
NOTE: If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
3.219e Patients able to father a child must agree to use an adequate method of 
contraception starting with the first dose of study therapy through 120 
days after the last dose of study therapy. 
NOTE; Abstinence is acceptable if this is the established and preferred 
method of contraception for the subject. 
3.219f Provide signed written informed consent. 
3.219g Willing to return to enrolling institution for follow-up. 


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Amendment 9 
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3.219h Willing to provide mandatory tissue and blood samples for research 
purposes.  
NOTE: Patients must be willing to provide at the time surgical resection 
For patients who do not undergo surgery, any on-study tumor biopsy 
obtained for clinical purposes subsequent to the baseline biopsy must 
also be available for analysis. 
3.22 
Exclusion Criteria 
3.221 Tumor characteristics — Any of the following are excluded: 
• 
Evidence of distant metastases 
• 
Tumors whose location is restricted to the tubular esophagus (ie, 
without involvement of the GEJ or cardia) 
• 
Tumors whose proximal end are at the level of the carina or higher 
• 
Invasion of the tracheobronchial tree or presence of 
tracheoesophageal fistula 
• 
Palpable supraclavicular nodes, biopsy-proven involvement of 
supraclavicular nodes, or radiographically involved supraclavicular 
nodes (>1.5 cm in greatest dimension) 
• 
T1N0M0, T4Nany, or in situ carcinoma 
• 
Tumor must not extend 5 or more cm into the stomach 
3.222 Received prior treatment or receiving current treatment for this 
malignancy. 
3.223 Prior radiation to chest or abdomen, or to >30% of the marrow cavity. 
3.224 Inadequate caloric or fluid intake whereby there is a current or likely 
future need for enteral or parenteral feeding during chemoradiation or the 
preoperative period. 
3.225 Major surgery ≤4 weeks prior to registration. 
3.226 Active autoimmune disorders, including patients known to be HIV 
positive, or those requiring chronic steroid administration (excluding 
inhaled steroids). 
3.227 Uncontrolled diabetes (i.e., will interfere with the performance of the 
FDG PET/CT scans). 
3.228 Prior allergic reactions to drugs containing Cremophor, such as 
teniposide or cyclosporine, or study drugs involved in this protocol, or to 
a monoclonal antibody or prior hypersensitivity to platinum-containing 
agents. 
3.229a Heart conditions—Any of the following: 
• 
Any atrial fibrillation ≤3 months prior to registration 
• 
Unstable angina ≤12 months prior to registration 
• 
Prior symptomatic congestive heart failure 
• 
Documented myocardial infarction ≤6 months prior to registration 
(pretreatment ECG evidence of infarct only will not exclude patients) 
• 
Prior significant ventricular arrhythmia requiring medication 
• 
Prior 2nd or 3rd degree heart block or other types of clinically 
significant conduction delay ≤6 months prior to registration 


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Amendment 9 
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• 
Clinically significant pericardial disease (including pericardial 
effusion, pericarditis) or cardiac valvular disease ≤12 months prior to 
registration 
NOTE: As part of history and physical, all patients must be assessed for 
signs or symptoms of cardiac disease, or for prior history of cardiac 
disease. These conditions include but are not limited to diseases related 
to cardiac valves, pericardium, myocardium, atrioventricular delays or 
arrhythmias. It is strongly recommended that signs or symptoms of 
potentially clinically significant disease be evaluated with 
comprehensive cardiac echo. 
3.229b Prior pancreatitis that was symptomatic or required medical intervention 
≤6 months prior to registration (known toxicity of pembrolizumab). 
3.229c Prior enteritis that was symptomatic or required medical intervention 
≤6 months prior to registration (known toxicity of pembrolizumab). 
3.229d Uncontrolled hyper/hypothyroidism or hyper/hypocortism ≤6 months 
prior to registration (known toxicity of pembrolizumab). 
3.229e Pulmonary conditions — any of the following: 
• 
Respiratory condition that required any oxygen supplementation 
≤6 months prior to registration 
• 
Prior or current pneumonitis 
• 
Clinically significant pulmonary hypertension ≤12 months prior to 
registration 
• 
Lung infection requiring treatment ≤3 months prior to registration 
• 
Pulmonary embolism requiring treatment ≤6 months prior to 
registration 
• 
Pleural effusion requiring drainage ≤12 months prior to registration 
3.229f Prior fistula within thorax, including bronchoalveolar or esophageal. 
3.229g Pre-existing motor or sensory neurotoxicity greater than CTCAE 
Grade 1. 
3.229h Acute bacterial, viral, or fungal infection requiring treatment at the time 
of registration. 
3.229i Active infection or other serious underlying medical condition which 
would impair the ability of the patient to receive the planned treatment. 
3.229j Uncontrolled intercurrent illness including, but not limited to, psychiatric 
illness/social situations, or other co-morbid systemic illnesses or severe 
concurrent diseases which, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study or interfere 
significantly with the proper assessment of safety and toxicity of the 
prescribed regimens. 
3.229k Prior malignancy ≤5 years prior to registration if it is believed that 
ongoing treatment or assessments for prior malignancy could 
meaningfully interfere with protocol treatment or assessment.  
NOTE: Ongoing hormonal therapy is allowed. . 
3.229l Dementia or altered mental status that would prohibit the understanding 
and giving of informed consent. 


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Amendment 9 
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3.229m Any of the following because this study involves an agent where the 
genotoxic, mutagenic and teratogenic effects are unknown: 
• 
Pregnant or breastfeeding 
• 
Patient of childbearing potential who is unwilling to employ 
adequate contraception 
3.229n Received live vaccine ≤30 days prior to registration. 
 




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Active Treatment 
 
Post-Treatment 
Observation 
Tests and procedures 
Prior to Registration 
Neoadjuvant during RT 2 
Surgical 
evaluatio
n  
 
 
End of 
Treatment 
Safety 
follow 
up:  
 
≤56 days 
prior to 
pre-
registration 
≤28 days 
prior to 
registra-
tion 
≤21 days 
prior to 
registra-
tion 
D1 D15 D22 D29 D36 D43 
<2 weeks 
prior to 
surgery3,4 
<42 days 
after 
surgery 
During 
adjuvant 
pembro-
lizumab5 
At the time 
of 
discontin-
uation 
30 days 
post-
discontin
-uation 
Follow 
up 
visits6 
Consultation with Medical 
Oncologist (See Section 
6.39c) 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology: CBC/diff 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel 10 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
T3, Free T4, TSH 
 
 
X 
 
 
 
 
 
 
X 
 
X11 
 
X 
 
Urinalysis 12 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test13 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy 14 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PFTs 15  
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
FDG PET/CT 16  
(trunk=“eyes to thighs”) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
CT (chest, abdomen, pelvis) 
 
 
 
 
 
 
 
 
 
 
X 
X17 
X18 
 
X14 
EGD with biopsy 
X 
X19 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                   
10 AST, ALT, alk phos, total bilirubin (direct if TBili is elevated), BUN, creatinine, calcium, albumin, phos, glucose, Na, K, bicarbonate, uric acid, chloride. If 
here is a clinical need for more frequent testing, it may be performed as needed. 
11 Thyroid tests are collected every other treatment cycle of adjuvant pembrolizumab, starting with the first adjuvant dose of pembrolizumab 
12 Urinalysis for protein, glucose, blood 
13 For persons of childbearing potential only. Must be done ≤7 days prior to registration 
14 Bronchoscopy required only if primary tumor is adjacent to the trachea or left main stem bronchus and/or patient is experiencing respiratory symptoms 
(includes transbronchial biopsy) 
15 Including routine spirometry and DLCO 
16 FDG PET/CT imaging is to be used up until the time the patient has had surgery. After surgery, CT imaging must be used. 
17 Starting from the time of surgery, CT scans will be obtained post-surgery as a new baseline, then every 3 months for one year, then every 4 months for 2 years.  
18 During adjuvant pembrolizumab and up to six months after the last dose of adjuvant pembrolizumab: Repeat CT imaging per Section 11. 
19 Only repeat EGD if inadequate tissue is available from pre-registration EGD. 




MC1541 
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Amendment 9 
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Active Treatment 
 
Post-Treatment 
Observation 
Tests and procedures 
Prior to Registration 
Neoadjuvant during RT 2 
Surgical 
evaluatio
n  
 
 
End of 
Treatment 
Safety 
follow 
up:  
 
≤56 days 
prior to 
pre-
registration 
≤28 days 
prior to 
registra-
tion 
≤21 days 
prior to 
registra-
tion 
D1 D15 D22 D29 D36 D43 
<2 weeks 
prior to 
surgery3,4 
<42 days 
after 
surgery 
During 
adjuvant 
pembro-
lizumab5 
At the time 
of 
discontin-
uation 
30 days 
post-
discontin
-uation 
Follow 
up 
visits6 
Optional follow up tissue 
sample27R 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Blood for correlative 
research (to be sent to 
 Lab) 28R 
 
 
X 
 
X 
X 
X 
 
 
X 
 
 
X29 
 
X29 
Blood for correlative 
research (to be sent to 
 
Lab) 30R 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
                                                   
27 An optional newly-obtained core, mucosal (“pinch”), or excisional biopsy (FNA not adequate) is requested at the time of recurrence or progressive disease. 
Endoscopic biopsies or biopsies of metastatic sites are permitted. 
28 Whole blood samples for correlative research to be sent to 
 lab will be collected at the following times points: Baseline, Day 1 (±3 days) of 
chemoradiotherapy, Day 8 (±3 days) of chemoradiotherapy, Day 15 (±3 days) of chemoradiotherapy, surgical evaluation prior to surgery, at the end of 
adjuvant therapy (ie, within 4 weeks after final administered dose of adjuvant therapy), and at the time of tumor recurrence.  The baseline sample may be 
collected ≤56 days prior to Day -7 of therapy.  The Day 1 sample should be collected prior to administration of chemotherapy and RT. 
29 Sample should be collected if there is disease progression (recurrence), whether it occurs during adjuvant pembrolizumab or during post-treatment observation.  
To clarify, if a patient completes adjuvant therapy and has disease progression (recurrence) during observation, this patient will undergo two blood collections 
following definitive therapy (chemoradiation with/without surgery): once at the end of adjuvant therapy and once at the time of disease progression 
(recurrence) during observation. 
30 Whole blood sample for correlative research to be sent to 
Lab (IMPACT Lab) will be collected only at baseline. Collections will only be performed at 
Mayo Rochester. Sample must be hand-delivered to 
 Lab. The baseline sample may be collected ≤56 days prior to Day 1 of therapy. 
R Funded by research 




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5.0 
Grouping Factor 
Phase: 1b vs. 2 
6.0 
Registration/Randomization Procedures 
6.1 
Pre-Registration (Step 1) 
6.11 
Pre-registration 
To pre-register a patient, fax 
a completed eligibility checklist to 
the Mayo Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 
4:30 p.m. central time Monday through Friday. 
6.12 
IRB approval(s) is required for each treating site.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually). If the necessary 
documentation is not submitted in advance of attempting patient registration, the 
registration will not be accepted and the patient may not be enrolled in the 
protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals is no longer necessary. 
6.13 
Prior to accepting the pre-registration, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient pre-registration eligibility  
• 
Existence of a signed consent form   
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.14 
The site has reviewed and understands the process listed in Sections 14 amd 17 
and must account for sufficient time to complete pre-registration and registration 
steps. 
6.15 
Pre-registration tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.16 
Correlative Research 
A mandatory translational research component is part of this study; the patient 
will be automatically registered onto this component (Sections 3.14, 4.0, and 
17.1). 
 
6.2 
Phase 2 (Step 2) 
6.21 
Registration Procedures 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the remote registration/randomization application. The 
registration/randomization application is available 24 hours a day, 7 days a week. 
Back up and/or system support contact information is available on the Web site. 
If unable to access the Web site, call the MCCC Registration Office at 
 between the hours of 8 a.m. and 5:00 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 


MC1541 
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Amendment 9 
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the MCCC web page 
and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office
 If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.3 
Phase 1b and 2 
6.31 
Correlative Research 
6.311 A mandatory translational research component is part of this study; the 
patient will be automatically registered onto this component (Sections 
3.14, 14.0, 17.0). 
6.312 An optional correlative research component is part of this study, there 
will be an option to select if the patient is to be registered onto this 
component (see Section 17.1). 
• 
Patient has/has not given permission to give his/her recurrence tissue 
sample for research testing 
 
6.32 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.33 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
). If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
6.34 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research on cancer at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 


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Amendment 9 
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• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.35 
Treatment on this protocol must commence at Mayo Clinic under the supervision 
of a Mayo Clinic physician.  
 
6.36 
Treatment cannot begin prior to registration and must begin ≤21 days after 
registration.   
Note: It is highly recommended for treatment to be initiated as soon as possible 
after registration. 
 
6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified in the test schedule. 
 
6.38 
All required baseline symptoms (see Section 10.5) must be documented and 
graded. 
 
6.39a 
A radiation oncologist has seen the patient and confirms the patient is a suitable 
candidate for this study ≤56 days prior to registration.  
 
6.39b A surgeon has seen the patient and confirms the patient is a suitable candidate for 
this trial ≤56 days prior to registration. 
 
6.39c 
A medical oncologist has seen this patient and confirms the patient is a suitable 
candidate for this trial ≤56 days prior to registration. 
 
6.39d Study drug is available on site. 
 
6.39e 
Blood draw requisition form availability checked (Arizona only). 






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Amendment 9 
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interval. The reason for withholding dosing of either pembrolizumab or combination 
chemotherapy regimen should be documented in the subject's study record. 
7.21 
Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion. 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). 
See Section 15.1 for specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
7.22 
Paclitaxel 
Administration of paclitaxel should begin following administration of 
pembrolizumab. Please refer to the product label for additional guidance on 
administration procedures (e.g. timing of infusion, premedication) for paclitaxel. 
7.23 
Carboplatin 
Administration of carboplatin should begin following administration of 
pembrolizumab. Please refer to the product label for additional guidance on 
administration procedures (e.g. timing of infusion, premedication) for 
carboplatin. 
Dosed using Calvert Formula with Cockroft & Gault Equation (CBDCA dose 
[mg] = target AUC x [GFR + 25]). For the purposes of this protocol, the GFR is 
considered to be equivalent to the creatinine clearance (CrCl). The CrCl is 
calculated by the method of Cockroft & Gault (CrCl[mL/min] = (140 - age) x 
actual body weight (kg) divided by plasma Cr [mg/dL] x 72 x [0.85 if female or 1 
if male]. 
GFR = Glomerular filtration rate 
7.24 
Alternative regimen with FOLFOX 
FOLFOX chemotherapy may be administered up to 3 days before or after the 
scheduled dosing date for administrative reasons per the Investigator’s judgment. 
7.241 Oxaliplatin 
Administration of oxaliplatin should be initiated with leucovorin. Please 
refer to the product label for additional guidance on administration 
procedures (e.g. timing of infusion, premedication) for oxaliplatin. 
7.242 Leucovorin (folinic acid) 
Administration of leucovorin should be initiated with oxaliplatin. Please 
refer to the product label for additional guidance on administration 
procedures (e.g. timing of infusion, premedication) for leucovorin. 
7.243 Fluourauracil (5FU) bolus 
Administration of 5FU bolus should be initiated after 
oxaliplatin/leucovorin. Please refer to the product label for additional 
guidance on administration procedures (e.g. timing of infusion, 
premedication) for 5FU. 
7.244 Fluourauracil (5FU) IV pump 
Administration of 5FU IV pump should be initiated after 


MC1541 
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Amendment 9 
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pembrolizumab. Please refer to the product label for additional guidance 
on administration procedures (e.g. timing of infusion, premedication) for 
5FU. 
7.3 
Radiation 
7.31 
Dose specifications and technical factors 
Radiation begins on Day 1 of neoadjuvant chemotherapy and continues for 
approximately 4 ½ weeks. The trial administers 1.8 Gy per day without a break 
except for weekends and holidays. The total radiation dose is 41.4 Gy in 
23 fractions. Dose should be prescribed such that ≥95% of the PTV receives the 
prescription dose. 
Dose 
(Gy) 
Number of 
Fractions 
Fraction 
Size 
Rx Length 
Rx Days 
41.4 
23 
1.8 Gy 
4 weeks and 3 days 
M-F 
The energy of the treatment beam will be at least 6 MV and no greater than 
18 MV. 
The use of intensity-modulated radiation therapy (IMRT) or proton beam 
radiation is allowed. The use of intraoperative radiotherapy (IORT) is NOT 
allowed. 
Radiation dose prescriptions will be calculated using heterogeneity corrections to 
take into account tissue inhomogeneities in treatment planning. 
7.32 
Immobilization, simulation, and localization 
Patients should be instructed to be fasting for 2 hours prior to simulation and 
treatment, with the exception of medications and small sips of clear liquids. 
Patients should be positioned head first, supine, with arms up in an 
immobilization device. 
CT simulation should be performed in the treatment position. The planning CT 
should encompass the chest and abdomen (from the mid-cervical spine to the 
iliac crests). This should include all of the lungs and all of both kidneys for 
calculating dose-volume histograms (DVHs) for these organs. 
Use of 4 dimensional CT (4DCT) is strongly recommended to characterize organ 
motion.  
Oral or IV contrast (if no contraindications) should be considered to aid in 
target/normal tissue delineation. 
Breath hold treatment can be considered if the tumor involves the stomach. 
The planning CT will be registered with the diagnostic PET/CT for aiding in 
target delineation. 
Daily verification of the treatment setup will be performed with kilovoltage xray 
images or volumetric imaging (kilovoltage or megavoltage CT) 
 
 




MC1541 
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Amendment 9 
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performance status (see Section 4.0). See Section 7.37 for recommendations for 
supportive care during radiation therapy. 
7.36 
Treatment interruptions 
Treatment interruptions should be minimized through the use of supportive care 
measures (see Section 7.38). Interruptions for life-threatening adverse events 
(CTCAE Grade 4) are allowed. 
7.37 
Supportive care during radiation therapy 
Significant nutritional compromise may occur during radiation and chemotherapy 
for esophageal cancer. Esophagitis, nausea, vomiting, and anorexia can all 
contribute to this issue. Antiemetics such as prochlorpherazine (Compazine®), 
ondansetron, or granisetron should be used, as needed, to manage treatment 
related nausea. The use of concurrent lorazepam (0.5 to 1.0 mg) with 
prochlorperazine can be beneficial. Esophageal pain can be mitigated with liquid 
acetaminophen and narcotic analgesics. Aggressive management of nutritional 
problems during treatment should be considered. Consultation with a 
professional dietitian is appropriate and encouraged. Consideration of a feeding 
tube should be considered in patients who are unable to maintain adequate 
nutrition during treatment with radiation and chemotherapy. Some surgeons 
prefer placement of the feeding tube in the jejunum (PEJ) rather than in the 
stomach (PEG) with regard to issues of surgical reconstruction of the stomach 
after resection of the primary lesion. A nasogastric feeding tube is also 
acceptable. 
7.4 
Surgery 
7.41 
Timing of Surgery 
Surgery to remove the primary cancer should occur no earlier than 24 days after 
the last dose of neoadjuvant pembrolizumab. In addition, although clinical 
judgment is necessary to determine the precise timing of surgery, it is generally 
encouraged for surgery to occur 5 to 8 weeks after the last dose of RT. For 
patients assigned to receive a neoadjuvant regimen that consists of chemotherapy 
alone (ie, no RT), surgery is encouraged to occur 3 to 6 weeks after completion 
of chemotherapy. 
7.42 
Surgeon Experience 
Individual surgeons must have performed a minimum of 50 surgeries of the 
surgery type that is planned:  ie, ≥50 minimally invasive esophagectomy [MIE] if 
MIE is planned; ≥50 Ivor-Lewis if Ivor-Lewis is planned; ≥50 transhiatal if 
transhiatal is planned; ≥50 other [eg, 3-hole or McKweon] if other is planned. 
Any issues regarding surgeon involvement in the study may be reviewed by the 
study team. 
 
 
 


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Amendment 9 
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8.0 
Dosage Modification Based on Adverse Events 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0  
unless otherwise specified   
ALERT: ADR reporting may be required for some adverse events (See Section 10.0) 
 
Standard of care should be followed in considering dose modifications based on adverse events. 
The modifications in this section are considered guidelines. In some cases, a greater or lower 
level of modification may be indicated or necessary.  
 
• 
Omit = Treatment is not given for this cycle (missed days are not made up) 
• 
Hold/Delay = Treatment can be made up as part of this cycle 
• 
Discontinue = Treatment is totally stopped 
8.1 
Dose modification for Radiation Therapy 
Radiation modifications should follow standard of care.   
8.2 
Dosage modifications for pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology. These AEs may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per the Table below. See 
Section 9.0 and Appendix VI for supportive care guidelines, including use of 
corticosteroids. 
 
 


MC1541 
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Amendment 9 
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Table 8.21 
Dose Modification Guidelines for Drug-Related Adverse Events for 
Pembrolizumab 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Gastrointestinal 
disorders 
Diarrhea or 
Colitis 
2-3 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
4 
Permanently discontinue 
Permanently discontinue 
Investigations 
AST, or ALT, or 
Blood bilirubin 
 
2 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose. 
 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Metabolism and 
nutrition disorders 
Glucose 
intolerance (Type 
1 diabetes 
mellitus [if new 
onset]) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
Grade 3-4 
hyperglycemia 
associated with evidence 
of beta cell failure 
Resume pembrolizumab when 
patients are clinically and 
metabolically stable. 
Endocrine disorders 
Endocrine 
disorders – Other, 
specify: 
Hypophysitis 
2-4 
AE resolves to Grade 0-
1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
Endocrine disorders 
Hyperthyroidism 
3 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
4 
Permanently discontinue 
Permanently discontinue 
Endocrine disorders 
Hypothyroidism 
 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted 
General disorders and 
administration site 
conditions 
Infusion related 
reaction 
2b 
AE resolves to Grade 0-
1 
Permanently discontinue if AE 
develops despite adequate 
premedication  
 
 
3-4 
Permanently discontinue 
Permanently discontinue 


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Amendment 9 
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CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
2 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal and urinary 
disorders 
Acute kidney 
injury or Chronic 
kidney disease  
(e g Renal failure 
or Nephritis) 
2 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
3-4 
Permanently discontinue 
Permanently discontinue 
 
All Other Drug-
Related Adverse 
Eventsc 
3 or severe AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients 
should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of 
the original infusion rate   (e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be premedicated  for the next scheduled dose. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion. Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose. 
8.22 
Other instructions for pembrolizumab 
If pembrolizumab-related toxicity does not resolve to Grade 0-1 within 12 weeks 
after last administration of study drug, study therapy discontinuation is 
recommended. With Investigator agreement, patients with a laboratory adverse 
event still at Grade 2 may continue in the study only if asymptomatic and 
controlled. 
In patients who continue on study therapy after experiencing an Adverse Event 
warranting potential dose modification, if considered drug-related by the 
investigator, once the patient has recovered to Grade 0-1 the dosing interval in 
subsequent cycles will be increased by 1 week (e.g., to 3 weeks in patients who 
were on an every 2-week schedule). Following each such dose delay due to 
toxicity, the dosing interval should increase by an additional week. For example, 
patients who began the study on a 3-week dosing schedule, and have stopped 


MC1541 
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Amendment 9 
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drug twice for due to a drug-related toxicity that meets the above criteria, should 
now be dosing every 5 weeks. 
For patients who experience a recurrence of the same severe AEs listed above 
with rechallenge of pembrolizumab, a consultation with the Investigator will 
occur to determine whether the patient should continue in the study. A patient 
who experiences the same SAE of the same NCI CTCAE grade or higher with 
rechallenge of pembrolizumab must discontinue pembrolizumab immediately. 
Reduced dose of pembrolizumab dose (ie, below 200 mg) will not be 
administered. 
8.3 
Dose modifications for carboplatin and paclitaxel 
8.31 
Suggested dose levels for carboplatin and paclitaxel* 
Dose Level 
Carboplatin 
Paclitaxel 
Starting Dose 
AUC2 
50 mg/m2 
-1 
-20% 
-20% 
-2 
-30% 
-30% 
-3 
-50% 
-50% 
*These levels are guidelines only 
NOTE: If carboplatin or paclitaxel is discontinued, or reduced to dose level -3, 
the investigator may choose to replace the chemotherapy with FOLFOX, 
capecitabine (with or without oxaliplatin), or 5FU infusion. 
8.32 
Guidelines for carboplatin and paclitaxel table of events and modifications 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENTa 
ACTION 
Blood and lymphatic 
disorders 
Febrile neutropenia 
(fever without 
clinically or 
microbiologically 
documented 
infection) [ANC <1.0 
X 109 C/L] fever 
≥38.5oC) 
carboplatin 
paclitaxel 
Delay chemotherapy by 1 week until ANC 
recovers to Grade 0-2 and until fever 
resolves. 
Reduce dose by 20% or more for 
subsequent cycles. 
Cardiac Disorders 
Ventricular 
bradycardia 
(asymptomatic) or 
isolated and 
asymptomatic 
ventricular 
extrasystoles 
paclitaxel 
Continue therapy under continuous cardiac 
monitoring 
 
Atrioventricular 
block first degree 
paclitaxel 
Continue therapy under continuous cardiac 
monitoring 
 
Ventricular 
arrhythmia 
(symptomatic) or  
AV block complete 
or other heart blocks. 
paclitaxel 
Discontinue paclitaxel. Manage 
arrhythmia according to standard practice  


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Amendment 9 
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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENTa 
ACTION 
Gastrointestinal 
disorders 
Vomiting 
≥Grade 3 
carboplatin 
paclitaxel 
If not controlled with optimal medication: 
Reduce dose by 20% and use reduced 
level for subsequent cycles 
Immune system 
disorders 
Allergic reaction 
Grade 1 
(eg, mild flushing, 
rash, pruritis) 
paclitaxel 
Complete infusion  
Supervise at bedside 
Immune system 
disorders 
Allergic reaction 
Grade 2-3 
(e.g. moderate rash, 
flushing mild 
dyspnea, chest 
discomfort, mild 
hypotension) 
paclitaxel 
Stop infusion. give IV antihistamine 
(diphenhydramine 50 mg IV and 
dexamethasone 10 mg IV) 
After recovery of symptoms resume 
paclitaxel infusion at a rate of 20 ml/h for 
15 minutes then 50 ml/h for 15 minutes 
then, if no further symptoms, at full dose 
rate until infusion is complete. 
 
Anaphylaxis 
(e.g. one or more of 
the following): 
respiratory distress 
requiring treatment, 
generalized urticaria, 
angioedema, 
hypotension 
requiring therapy) 
paclitaxel 
Stop paclitaxel infusion, give IV 
antihistamine and steroid as above 
Add epinephrine or bronchodilators if 
indicated, report as an adverse event 
Discontinue therapy. 
Investigations 
Neutrophil count 
decreased 
≥Grade 3 (ANC 500 
to <1000/mm3) 
carboplatin 
paclitaxel 
Delay chemotherapy by 1 week until 
recovery to Grade 0-2 
Consider reducing dose by 20% for 
subsequent cycles. 
 
Platelet count 
decreased 
≥Grade 3 (25 to <50 
x 109/L) 
carboplatin 
paclitaxel 
Delay chemotherapy by 1 week until 
recovery to Grade 0-2. Consider reducing 
dose by 20% for subsequent cycles. 
 
Bleeding ≥ Grade 3 
or requiring 
≥2 platelet 
transfusions 
carboplatin 
paclitaxel 
Delay chemotherapy by 1 week until 
bleeding recovers to Grade 0-1 
Permanently discontinue chemotherapy, or 
reduce dose by 20% or more for 
subsequent cycles. 
Nervous system 
disorders 
Peripheral motor 
neuropathy 
Grade 2 
carboplatin 
paclitaxel 
Reduce dose by 20% and use reduced 
level for subsequent cycles. 
 
Peripheral motor 
neuropathy 
Grade 3 or higher 
carboplatin 
paclitaxel 
Discontinue therapy 
All other 
nonhematologic 
≥Grade 3 
carboplatin 
paclitaxel 
Discontinue therapy, or reduce dose by 
20% or more and use reduced dose for 
subsequent cycles. 


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Amendment 9 
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a If a drug is held, omitted, discontinued or dose-reduced, it is the physician’s discretion to apply the 
modification to one or both cytotoxic drugs, and the decision should depend on the nature and 
severity of the particular toxicity and its likely causal relation to the agent. 
8.4 
Dose Modifications for 5-FU and Oxaliplatin 
Table 8.41 
Dose levels for oxaliplatin and 5-FU 
Dose Reduction Steps –Oxaliplatin + 5-fluorouracil/Leucovorin Regimen* 
 
Starting Dose 
Dose Level -1 
Dose Level -2 
Dose Level -3** 
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2 
40 mg/m2 
5-fluorouracil infusion**** 
2400 mg/m2 
1900 mg/m2 
1500 mg/m2 
1200 mg/m2 
* Leucovorin dose remains fixed at 400 mg/m2 (not adjusted). 
**Further dose levels (-4, -5, etc.) will be 20% dose reductions from the previous level. 
****If the 5-FU infusion dose is decreased, the bolus dose of 5-FU should be discontinued for the current 
cycle and for all future cycles. Leucovorin will still be given.  
Table 8.42 
Guidelines for dose modifications for oxaliplatin and 5-F 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
All adverse events 
≤Grade 1 
5-FU 
Oxaliplatin Maintain dose level 
Blood and lymphatic 
system disorders 
Hemolytic uremic 
syndrome1 
≥Grade 3 
Oxaliplatin Discontinue oxaliplatin 
Gastrointestinal 
disorders 
Anal mucositis 
Grade 3 
5-FU 
↓ One 5-FU dose level  
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 
 
Grade 4 
5-FU 
↓ One 5-FU dose level 
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 
 
Diarrhea 
Grade 3 
5-FU 
↓5-FU one dose level 
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 
 
Grade 4 
5-FU 
Oxaliplatin 
↓ both 5-FU and oxaliplatin one dose level  
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 
 
Mucositis oral 
Grade 3 
5-FU 
↓ One 5-FU dose level  
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
 
Grade 4 
5-FU 
↓ One 5-FU dose level 
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 
Gastrointestinal 
disorders 
Vomiting 
≥Grade 3 
Oxaliplatin 
↓ One oxaliplatin dose level 
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 
 
Grade 4 
5-FU 
Oxaliplatin 
↓ both 5-FU and oxaliplatin one dose level  
If Grade ≥2 at start of new cycle hold and 
check weekly 
If Grade ≥2 after 4 weeks, discontinue 
Investigations 
Neutrophil count 
decreased 
≥Grade 3 
(ANC 500 to 
<1000/mm3) 
Oxaliplatin 
↓ One oxaliplatin dose level  
If ANC<1500 at start of new cycle hold and 
check weekly 
If ANC<1500 after 4 weeks, discontinue 
 
Grade 4 
5-FU 
Oxaliplatin 
Omit bolus 5-fluorouracil and ↓ both 
infusional 5-fluorouracil and oxaliplatin 1 
dose level  
If ANC<1500 at start of new cycle hold and 
check weekly 
If ANC<1500 after 4 weeks, discontinue 
Investigations 
Platelet count 
decreased 
≥Grade 3 
(25 to <50 x 109/L) 
Oxaliplatin 
↓ One oxaliplatin dose level 
If PLT <75,000 at start of cycle, hold and 
check weekly then treat based on interval 
adverse event. 
If PLT <75,000 after 4 weeks, discontinue 
therapy 
 
Grade 4 
Oxaliplatin 
↓ Two oxaliplatin dose levels 
If PLT <75,000 at start of cycle, hold and 
check weekly then treat based on interval 
adverse event. 
If PLT <75,000 after 4 weeks, discontinue 
therapy 
Respiratory, thoracic 
and mediastinal 
disorders 
Cough 
≥Grade 3 
Oxaliplatin Hold oxaliplatin until interstitial lung disease 
is ruled out 
 
Dyspnea 
≥Grade 3 
Oxaliplatin Hold oxaliplatin until interstitial lung disease 
is ruled out 
Respiratory, thoracic 
and mediastinal 
disorders 
Hypoxia 
≥Grade 3 
Oxaliplatin Hold oxaliplatin until interstitial lung disease 
is ruled out 
 
Pneumonitis 
≥Grade 3 
Oxaliplatin Hold oxaliplatin until interstitial lung disease 
is ruled out 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
All other 
nonhematologic2 
≥Grade 3 
5-FU 
Oxaliplatin 
↓ One 5-FU dose level  
Note: Dose reduction is not required for 
hypomagnesemia unless symptoms are present 
If Grade ≥2 after 4 weeks, discontinue therapy 
1. Recommended evaluation of suspected HUS: Evaluation should include CBC differential, 
platelets, PT, PTT, fibrinogen, FDP (Fibrin degradation products), Anti thrombin III, Von 
Willebrand factor, anti-nuclear antibody, rheumatoid factor, Compliment Cascade C3, C4, and 
CH50, anti-platelet antibodies, platelet-associated IgG, and circulating immune complexes. Renal 
evaluation should include creatinine, BUN, and urinalysis with microscopic examination. Other 
laboratory and hematological evaluations as appropriate should also be obtained, including 
peripheral blood smear and free hemoglobin. 
2. Exceptions: alopecia, fatigue, anorexia, nausea/vomiting if can be controlled by antiemetics, viral 
infections. 
8.43 
Oxaliplatin Dose Modifications for Non-CTCAE Neurologic Adverse Events 
 
Duration of Adverse Event 
Persistent1 
Adverse Events 
1 - 7 Days 
>7 Days 
Adverse Events 
Paresthesias/Dysesthesias 
 
 
 
Paresthesias/dysesthesias2 of short 
duration that resolve and do not 
interfere with function (Grade 1) 
no change 
no change 
no change 
Paresthesias/dysesthesias2 interfering 
with function, but not activities of daily 
living (ADL) (Grade 2) 
no change 
no change 
↓1 oxaliplatin dose 
level 
Paresthesias/dysesthesias2 with pain or 
with functional impairment that also 
interfere with ADL (Grade 3) 
1st time: ↓1 
oxaliplatin dose 
level 
 
2nd time: ↓1 
oxaliplatin dose 
level 
1st time: ↓1 oxaliplatin 
dose level 
 
2nd time: ↓1 
oxaliplatin dose level 
Stop 
Persistent paresthesias/dysesthesias that 
are disabling or life-threatening 
(Grade 4) 
Stop 
Stop 
Stop 
Laryngeal Dysesthesias 
(investigator discretion used for 
grading): 
 
 
 
Grade 0 = none; Grade 1 = mild 
No change 
↑ duration of infusion 
to 6 hours 
↑ duration of infusion 
to 6 hours 
Grade ≥2 = moderate  
(Also recommended is administration 
of benzodiazepine and patient 
education 
Management of patient if ≥Grade 2 
laryngeal dysesthesias occurs while 
treatment is being administered) 
Stop oxaliplatin infusion 
Administer benzodiazepine and give patient reassurance 
At the discretion of the investigator, the infusion can be restarted at 
1/3 the original rate of infusion. 
Grade 3 = severe 
 


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Duration of Adverse Event 
Persistent1 
Adverse Events 
1 - 7 Days 
>7 Days 
Adverse Events 
1 Not resolved by the beginning of the next cycle. 
2 May be cold-induced. 
 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional anti -
inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to rule 
out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 8.2 
for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
9.2 
Immunotherapy-related toxicities 
Patients should be monitored for signs and symptoms of immunotherapy-related 
toxicities, which include but are not limited to the following: 
• 
Pneumonitis 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
• 
Diarrhea/colitis 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
o All patients who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 


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o For Grade 2 diarrhea/colitis,  administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis [DKA]) 
or ≥Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
For T1DM or Grade 3-4 Hyperglycemia: 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
• 
Hypophysitis 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose 
is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• 
Hepatic 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
 


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• 
Renal failure or nephritis 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
9.3 
Blood products and growth factors  
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 24, No 18 (June 
20), 2006: pp. 2932-2947. 
9.31 
Neutropenia 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor GM-CSF is not allowed in this study. Therapeutic use 
of G-CSF is allowed in patients with Grade 3-4 febrile neutropenia. 
9.32 
Anemia 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications. 
9.33 
Thrombocytopenia 
Transfusion of platelets may be used if clinically indicated. ITP should be ruled 
out before initiation of platelet transfusion. 
9.4 
Anti-infectives 
Patients with a documented infectious complication should receive oral or IV antibiotics 
or other anti-infective agents as considered appropriate by the treating Investigator for a 
given infectious condition, according to standard institutional practice. 
9.5 
Corticosteroids 
Patients requiring chronic steroid administration (excluding inhaled steroids).are 
excluded from the trial. Patients may continue on inhalation therapy. Corticosteroids are 
known immunosuppressive agents that can mitigate the effects of pembrolizumab. 
Steroids should be generally reserved to treat side effects of pembrolizumab. Steroids can 
be used as primary prevention of nausea per institutional guidelines, but steroid doses 
should be reduced in subsequent cycles if nausea/vomiting is absent or very mild (see 
Section 9.5). 
9.6 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. Nausea and 
vomiting should be treated aggressively, and consideration should be given to the 
administration of prophylactic antiemetic therapy according to standard institutional 
practice. Patients should be strongly encouraged to maintain liberal oral fluid intake. 
Volume depletion should be corrected before initiation of study drug. 
If no or minimal nausea/vomiting is reported after first dose of carboplatin/paclitaxel, 
investigators are strongly encouraged to reduce the dose of dexamethasone to 10 mg as 
pre-treatment anti-emetic dosing at time of next dose. In addition, if nausea/vomiting 
continues to be a minimal issue, investigators are strongly encouraged to progressively 
decrease the pre-treatment dose of dexamethasone in subsequent doses (ie, 4 mg or zero). 
If the investigator believes a stronger dose is needed, then s/he may manually increase the 
dexamethasone dose. 


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9.7 
Anti-diarrheals 
Patients should be monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation 
(such as peritoneal signs and ileus). In symptomatic patients, infectious etiologies should 
be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should 
be considered. (See Section 9.7 for management of treatment-related enterocolitis) 
All patients who experience diarrhea should be advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. 
NOTE: Loperamide/diphenoxylate/atropines should NOT be used for diarrhea symptoms 
unless: (1) it is believed that pembrolizumab-related enterocolitis is unlikely to be present 
after detailed evaluation by gastroenterology, including endoscopy; PLUS (2) approval is 
documented by a gastroenterology specialist. 
9.8 
Management of treatment related enterocolitis 
In patients with severe enterocolitis, pembrolizumab will be held and treatment with 
systemic corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month.  
In patients with moderate enterocolitis, pembrolizumab should be withheld and 
antidiarrheal treatment should be started. If symptoms are persistent for more than one 
week, systemic corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or 
equivalent). When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month. 
9.9a 
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 any medication or 
vaccination 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 investigator and/or the patient’s primary physician. 
9.9a1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care. All concomitant medication will be 
recorded in the case report forms (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 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Section 10 and 
Appendix VI. 
9.9a2 
Prohibited Concomitant Medications 
The following medications are not permitted during the screening and treatment 
phase (including retreatment for post-complete response relapse) of this trial: 
• 
Anti-neoplastic systemic chemotherapy or biological therapy 
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 


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• 
Investigational agents other than pembrolizumab 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine. 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology. The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
principal investigator. 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Patients may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
9.9b 
Infusion Reaction 
Table 9.9a Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping treatment infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of study treatment administration. 
9.9c 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm. 
For this trial, male patients will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition). 
Female patients will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male patients of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 120 
days after the last dose of study drug by complying with one of the following: 


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(1) practice abstinence† from heterosexual activity; 
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for patients participating at 
sites in this country/region. 
Patients should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study patients of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days 
prior to the initiation of study medication for oral contraception) throughout the study 
period up to 120 days after the last dose of trial therapy. If there is any question that a 
patient of childbearing potential will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 
9.9d 
Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the 
patient will immediately be removed from the study. The site will contact the patient at 
least monthly and document the patient’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to Mayo Clinic and to 
Merck without delay and within 24 hours to Mayo Clinic and within 2 working days to 
Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn. If a male subject 
impregnates his female partner the study personnel at the site must be informed 


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immediately and the pregnancy reported to Mayo Clinic and to Merck and followed as 
described above. 
9.9e 
Use in Nursing Women 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, patients who are breast-feeding are not eligible for 
enrollment. Specific additional information follows for individual agents used in this 
trial. 
9.9e1 
Pembrolizumab 
It is unknown whether pembrolizumab is excreted in human milk. 
9.9e2 
Cisplatin 
Cisplatin has been reported to be found in human milk; patients receiving 
Cisplatin injection should not breast-feed. 
9.9e3 
Fluorouracil 
It is not known whether 5-fluorouracil is excreted in human milk. Because 5-
fluorouracil inhibits DNA, RNA and protein synthesis, mothers should not nurse 
while receiving this treatment. 
 
 




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Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
First, identify and grade the severity of the event using the CTCAE version 4.0. 
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3). With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.5 and 
18.0). 
10.12 Each CTCAE term in the current version is a unique representation of a specific 
event used for medical documentation and scientific analysis and is a single 
MedDRA Lowest Level Term (LLT). 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE, which is defined in the table in Section 10.4. 
10.2  
Expected vs. Unexpected Events  
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.1, 15.2, 15.3, 15.4, Appendix II, and Appendix III 
of the protocol. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15.1, 15.2, 15.3, 15.4, Appendix II, and Appendix III of the protocol. 
NOTE: “Unexpected adverse experiences” means any adverse experience that is not 
identified in nature, severity, or frequency of risk in the information provided for 
IRB review nor mentioned in the consent form. 
NOTE: The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included 
in the protocol or the investigator brochure. 
10.3 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 


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Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug and the adverse event.  
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) 
on the SAME Arm 
NOTE: The combination of an investigational agent with a commercial agent is 
considered investigational. 
Routine Reporting 
• 
Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial 
agent is stated in the protocol. See Section 10.52. 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, 
biologic, cellular product, or other investigational therapy under an 
IND), the entire combination (arm) is then considered an 
investigational intervention for reporting. 
Expedited Reporting 
• 
An AE that occurs on a combination study must be assessed in 
accordance with the guidelines for CTEP investigational 
agents/interventions in Section 10.4, and where indicated, an expedited 
report must be submitted. 
• 
An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In 
general, only Grade 4 and 5 AEs that are unexpected with at least 
possible attribution to the commercial agent require an expedited report. 
Refer to Section 10.4 for specific AE reporting requirements or 
exceptions. 
• 
Commercial agent expedited reports must be submitted to the FDA via 
MedWatch. 
• 
An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent. Therefore, if an expected AE (for 
the commercial agent) occurs with a higher degree of severity, expedited 
reporting is required. The clinical investigator must determine severity. 
10.32 Special Situations for Expedited Reporting and Submission of Notification 
Forms 
Exceptions to Expedited Reporting and Submission of Notification Forms: 
EXPECTED Serious Adverse Events1 
An expedited report or notification form may not be required for specific Grade 
1, 2, 3 and 4 Serious Adverse Events where the AE is listed in Section 15.0 of the 
protocol or the consent form* as EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supercede the standard 
Expedited Adverse Event Reporting and Notification Form Requirements  
(Note: These adverse events must still be reported through the routine reporting 
mechanism [i.e. Nadir/Adverse Events Form]; see Footnote 1): 


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System Organ 
Class (SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which 
the event will not be 
expeditedly reported1 
General disorders 
and administrations 
site conditions 
Fatigue  
Grade 3 
 
 
Gastrointestinal 
Vomiting 
Grade 3 
Nausea 
Grade 3 
Diarrhea 
Grade 3 
Investigations 
Neutrophil count decreased 
Grade 3 or 4 
White blood cell count 
decreased 
Grade 3 or 4 
Lymphocyte count decreased 
Grade 3 or 4 
Platelet count decreased 
Grade 3 or 4 
Blood and 
lymphatic system 
disorders 
Anemia 
Grade 3 or 4 
1These exceptions only apply if the adverse event does not result in 
hospitalization. If the adverse event results in hospitalization, then the standard 
expedited adverse events reporting requirements must be followed.  
NOTE: Hospitalization related to convenience (e.g. transporttation issues, 
etc.) will not be considered an SAE for purposes of reporting to Merck. 
Specific protocol exceptions to expedited reporting should be reported expedi-
tiously by investigators ONLY if they exceed the expected grade of the event. 
Efficacy endpoints as outlined in this section will not be reported to Merck, 
unless there is evidence suggesting a causal relationship between the drug and the 
event. Any such event will be submitted to the Sponsor (Mayo Clinic) within 24 
hours and to Merck Global Safety within 2 working days either by electronic or 
paper media. 
Specifically, the suspected/actual events covered in this exception include 
any event that is disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and 
safety data to ensure the safety of the subjects in the trial. Any suspected 
endpoint which upon review is not progression of the cancer under study will be 
forwarded to Merck Global Safety as a SAE within 2 working days of 
determination that the event is not progression of the cancer under study. 
10.321 
Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly 
referred to as disabilities), congenital abnormities or birth defects, must 
be reported immediately if they occur at any time following treatment 
with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 
312.64(b). 
10.322 
Death 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 


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• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of 
life that cannot be attributed to a CTCAE term associated with 
Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including 
cysts and polyps) – Other (Progressive Disease)” under the 
system organ class (SOC) of the same name. Evidence that the 
death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: 
clinical deterioration associated with a disease process) should 
be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless 
of attribution to the investigational agent/intervention requires 
expedited reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last does of 
the investigational agent/intervention requires expedited 
reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
10.323 
Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE be reported. Three options are available 
to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
 






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10.52 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.5: 
10.521 
Grade 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
10.522 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.523 
Grade 5 AEs (Deaths) 
10.5231  Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.5232 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.524 
Events of Clinical Interest (ECIs) 
ECIs are selected non-serious and serious adverse experiences that 
must be reported within 24 hours to Mayo Clinic via email 
 and within 2 working days to Merck 
Global Safety (Attn: Worldwide Product Safety Fax 
). 
For the time period beginning when the consent form is signed until 
treatment allocation/randomization, any ECI, or follow up to an ECI, 
that occurs to any subject must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety if it causes 
the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 24 hours to the 
Sponsor and within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined in Section 10.55, 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. 




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agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.55 Reporting of Overdose of Pembrolizumab 
For purposes of this trial, an overdose of pembrolizumab will be defined as any 
dose of 1,000 mg or greater (≥5 times the indicated dose). No specific 
information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product (pembrolizumab), 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 (pembrolizumab) 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 Mayo Clinic
 and within 
2 working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 
). 
10.56 Additional Instructions for AE Reporting to Merck 
A serious adverse event is any adverse event occurring at any dose or during any 
use of Merck’s product that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is an other important medical event  
• 
Note: In addition to the above criteria, adverse events meeting either of the 
below criteria, although not serious per ICH definition, are reportable to the 
Merck in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection 
purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
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 other than progression of the 
cancer under study that occurs to any subject must be reported within 24 hours to 
the Sponsor (Mayo Clinic) and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 
days following cessation of treatment, or 30 days following cessation of 


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treatment if the subject initiates new anticancer therapy, whichever is earlier, any 
serious adverse event, or follow up to a serious adverse event, including death 
due to any cause other than progression of the cancer under study whether or not 
related to the Merck product, must be reported within 24 hours to the Sponsor 
and within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time following consent through the end of the specified 
safety follow-up period specified in the paragraph above, or at any time outside 
of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
All patients with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number:  
. 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA, European Union (EU), Pharmaceutical and Medical Devices 
agency (PMDA) or other local regulators. Investigators will cross reference this 
submission according to local regulations to the Merck Investigational 
Compound Number (IND, CSA, etc.) at the time of submission. Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety;
) at the time of submission to 
FDA. 


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11.0 
Treatment Evaluation 
Response and progression will be evaluated in this study using the Immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST) guidelines.  
11.1  
Schedule of Evaluations:  
Pre-surgery: Two weeks or less prior to surgery, patients will undergo PETCT imaging 
to rule out the appearance of new disease that may preclude surgery (see Sections 11.2 
and 11.3). The purpose of this repeat PETCT is not to assess response. 
At surgery: Patients will be classified with respect to a pathologic tumor response. The 
evaluation for pathologic tumor response will be determined on the basis of surgical 
outcome (see Section 11.4). 
Post-surgery: Subsequent to surgery, patients will undergo periodic imaging to 
determine whether disease has recurred (see 11.5). 
11.2  
Pre-surgery: Evaluation of PET/CT after chemoradiotherapy 
11.21 If repeat PET/CT does not show evidence of the development of unresectable 
disease (eg, metastases in a distant site), the patient will proceed to surgery if 
he/she remains an operable candidate. 
11.22   If the PET/CT shows lesions that indicate the potential development of 
unresectable disease, it is strongly encouraged to obtain 3-dimensional 
imaging within 7 (+/-3) days that includes IV contrast as part of standard 
clinical practice, so as to further characterize abdominopelvic or other 
lesions. Given the unreliability of radiographic changes of the primary tumor 
during or after chemoRT, due to the inflammatory effects of chemoRT on tissue, 
assessment of PD will not routinely include changes in the primary tumor or 
regional nodes, as long as the disease remains resectable. If these images 
demonstrate unresectable disease in the clinical judgment of the investigator, 
they will serve as the First Radiologic Evidence of PD (see Table A). RECIST 
1.1 will be applied to this radiographic assessment. However, applying the 
principles of irRECIST, these radiographic changes in themselves will NOT be 
considered PD in the absence of tissue confirmation of progression or other 
definitive evidence of progression. 
If it is determined that surgery is delayed due to this assessment (see Section 
1.9d), the patient is encouraged to undergo further therapy with: 
• 
pembrolizumab combined with chemotherapy, if the patient remains a 
candidate for chemotherapy or  
• 
pembrolizumab without chemotherapy, if the patient is no longer a candidate 
for chemotherapy 
See Section 1.9b for rationale; see Section 1.9d for study outline; see Section 7 
for details of therapy. 
To confirm already suspected PD, repeat imaging should occur no earlier than 4 
weeks later; repeat imaging is suggested to occur after 6 to 10 weeks of further 
anticancer therapy. Repeat imaging will generally consist of PETCT with or without 
contrast CT chest/abdomen/pelvis, as clinically indicated. If repeat imaging confirms PD, 
then the patient will be designated as having PD and will be taken off protocol treatment.  


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11.3  
Assessment of disease: RECIST 1.1 and irRECIST 
This study will apply the principles of irRECIST that is adapted to the management of 
patients with locally advanced GEJ/cardia cancer undergoing neoadjuvant chemoRT with 
anticipated surgery. Adapted irRECIST is described below. 
RECIST 1.1 will be applied to the First Radiologic Evidence of PD (see Section 11.2). 
For subsequent scans following the First Radiologic Evidence of PD, RECIST 1.1 will 
be adapted to account for the unique tumor response characteristics seen with treatment 
of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses. The 
changes patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an 
apparent initial increase in tumor volume or even the appearance of new lesions. Standard 
RECIST may not provide an accurate response assessment of immunotherapeutic agents 
such as pembrolizumab. Immune-related RECIST (irRECIST) is RECIST 1.1 adapted as 
described below to account for the unique tumor response seen with immuno-
therapeutics. 
irRECIST will be used by Investigators to assess progression after initial 
radiographic progression per RECIST 1.1, and make treatment decisions 
accordingly. In this study, there will be no confirmation from central review for 
irRECIST. Therefore, determination of disease status per irRECIST and 
subsequent decision of treatment continuation/discontinuation is per the treating 
physician. 
In general, in the absence of surgical resection of the primary and nodes, disease 
within the RT field (primary or locoregional nodes) will be considered unreliable 
lesions to be used for designation as radiologic PD. The discussion within this 
section excludes disease within the RT field. 
If radiologic imaging verifies initial disease progression per RECIST 1.1, treatment may 
continue at the discretion of the Investigator until repeat imaging ≥ 4 weeks later (see 
Section 7 for systemic therapy regimens). The Investigator’s decision to continue 
treatment while awaiting repeat imaging should be based on the subject’s overall clinical 
condition guided by the following criteria: 
• 
Absence of signs and symptoms indicating disease progression 
• 
No significant decline in ECOG performance status 
• 
Absence of rapid progression of disease 
• 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
If repeat imaging shows < 20% increase in tumor burden compared to nadir, stable 
previous new lesion (if identified as cause for initial disease progression), and stable non-
target disease (if identified as cause for initial disease progression), treatment may be 
continued / resumed, and subsequent tumor imaging follows protocol schedule. If lesions 
that were identified as cause for initial radiologic disease progression are not deemed to 
be represent unresectable disease, the patient may proceed to surgery. 
If repeat imaging confirms disease progression due to any of the scenarios listed below, 
patients will be discontinued from study therapy. 
• 
Tumor burden remains ≥20% and at least 5 mm absolute increase compared to nadir 
• 
Non-target disease resulting in initial disease progression is worse (qualitative) 


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• 
New lesion resulting in initial disease progression is worse (qualitative) 
• 
Additional new lesion(s) since last evaluation 
In determining whether or not the tumor burden has increased or decreased, Investigators 
should consider all target lesions (with the exception of disease within the RT field) as 
well as non-target lesions. When feasible, study treatment should not be discontinued 
until progression is confirmed. Patients that are deemed clinically unstable are not 
required to have repeat imaging for confirmation of progressive disease. Guidance for 
treatment continuation/discontinuation and repeat imaging per irRECIST is described in 
Table A and Table B. 
Table A. Prior to surgery 
 
Clinically stable 
Clinically unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at 
>4 weeksa to confirm 
PD 
May continue study treatment 
at the Investigator’s discretion 
while awaiting confirmatory 
scan 
Repeat imaging at 
>4 weeksa to confirm PD 
per physician discretion 
only 
Discontinue treatment 
Repeat scan 
confirms PD 
No additional imaging 
required 
Discontinue treatment 
(exception is possible upon 
consultation with PI) 
No additional imaging 
required 
N/A 
Repeat scan 
shows non-PD 
If surgery is not 
performed, continue 
further imaging 
assessments 
If disease is resectable, 
proceeding to surgical 
resection is strongly 
encouraged. Continuation of 
study treatment at the 
Investigator’s discretion 
If surgery is not 
performed, continue 
further imaging 
assessments 
If disease is resectable and 
patient is operable, 
proceeding to surgical 
resection is strongly 
encouraged. May restart 
study treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s discretion. 
PD = progressive disease 
aRepeat imaging is suggested to occur after 6 to 10 weeks of further anticancer therapy. 
NOTE: If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, an exception to continue treatment may be considered 
following consultation with the PI. 
11.4  
At surgery: Measurement of Pathologic Response 
Pathologic response will be evaluated after the patient has had surgery and will be based 
on the pathology review of the submitted surgical specimen according to the following: 
o Pathologic Complete Response (pCR): On review of the resected esophageal 
specimen and accompanying lymph nodes no cancer is recognized by the pathologist 
and margins are free of tumor.  
o Microscopic Cancer: Gross tumor is not seen by the pathologist but tumor remains in 
the microscopic analysis or any part of the entire specimen submitted for pathology 
review.  
o No Response: Gross cancer is found on pathologic examination of the resected 
esophageal cancer and draining lymph nodes. 
 
 


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11.5 
Completeness of Surgical Resection  
All operative and pathology reports from patients in the study must be submitted. 
Reports must contain information about gross and microscopic contamination of 
surgical resection margins.  
11.51 Curative (R0) 
Resections are defined as “curative” (i.e., complete resection; R0 resection) 
when all gross disease has been removed, and microscopic examination 
reveals all surgical margins free of tumor (i.e., pathological stage T1-3, NX, 
MO resected). Resections will still be considered curative if pathologic 
examination reveals positive lymph nodes as long as the nodes were 
completely resected. 
11.52 Incomplete resection (R1) 
“Palliative resection” (i.e., incomplete resection) will be considered to have 
taken place when microscopic examination reveals surgical margins which 
are not free of tumor (R1 resection). Positive margins are defined as tumor 
at or less than 1 mm from the lateral (“deep”), proximal, or distal margins. 
11.53 Incomplete resection (R2) 
“Palliative resection” (i.e., incomplete resection) will be considered to have 
taken place when gross disease has been left behind (R2 resection). Positive 
margins are defined as tumor at or less than 1 mm from the lateral (“deep”), 
proximal, or distal margins. 
11.54 No resection 
The primary tumor could not be removed. 
11.6  
Post-surgery (or after completion of definitive therapy): Evaluation by CT during 
adjuvant pembrolizumab or during event monitoring 
After surgery (or after completion of definitive therapy), CT must be used. If new lesions 
develop during adjuvant pembrolizumab and up to six months after the last dose of 
adjuvant pembrolizumab, the appearance of new lesions must be confirmed by repeat 
imaging performed 4 or more weeks later following the principles outlined in Section 
11.3 (see Table B below). Tissue confirmation should be performed if feasible. If new 
lesions develop subsequent to the period described above, confirmatory imaging is not 
required. 
Table B. Subsequent to surgery 
 
Clinically stable 
Clinically unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at  
>4 weeksa to confirm PD 
May continue study treatment 
at the Investigator’s discretion 
while awaiting confirmatory 
scan 
Repeat imaging at  
>4 weeks a to confirm PD 
per physician discretion 
only 
Discontinue treatment 
Repeat scan 
confirms PD 
No additional imaging 
required 
Discontinue treatment 
(exception is possible upon 
consultation with PI) 
No additional imaging 
required 
N/A 
PD = progressive disease;  
a Repeat imaging to confirm suspected PD needs to occur only during adjuvant pembrolizumab or if 1st radiologic evidence of 
PD occurs within 6 months of completing adjuvant pembrolizumab. The timing of this repeat imaging is suggested to occur 
6-10 weeks later. During this period, pembrolizumab may continue to be administered if the patient is in the adjuvant 
portion of the study. 


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11.7 
Criteria for Discontinuation of Protocol Treatment 
• 
Progression of disease 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
If protocol treatment is discontinued, follow-up and data collection will continue as 
specified in the protocol. 
11.8 
Guidelines for Evaluation of Measurable Disease  
11.81 Measurement Methods:  
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. 
11.82 Acceptable imaging modalities for measurable disease:  
• 
FDG PET/CT scan: The PET component needs to be FDG-PET. FDG 
PET/CT imaging is to be used up until the time the patient has had surgery. 
After surgery, CT imaging must be used. 
• 
CT and MRI: this guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
• 
Ultrasound (US) is not acceptable to measure tumor lesions that are clinically 
not easily accessible. 
 
12.0 
Descriptive Factors 
12.1 
Tumor Location: gastroesophageal junction vs. gastric cardia. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Continuation of treatment 
Patients who are non-PD before surgery will continue treatment per protocol. Patients 
who are recurrence-free after resection will continue treatment per protocol. 
13.2 
Progressive disease (PD) or recurrent disease 
Patients who develop PD while receiving pre-operative therapy will go to the event-
monitoring phase. Patients who develop recurrent disease while receiving adjuvant 


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therapy after resection will go to event-monitoring phase. 
13.3 
Off treatment for reasons other than PD or recurrent disease 
Patients who go off protocol treatment for reasons other than PD or recurrent disease will 
go to the event-monitoring phase per Section 18.0. 
13.4 
Observation 
If the patient has undergone surgery, the patient will be observed every 3 months for 1 
year and then every 4 months for second year post-surgeryplus every 6 months for third 
year for up to 3 years post-registration. 
13.5 
Criteria for Treatment Discontinuation 
Patients may discontinue treatment for the following reasons: 
• 
Patient withdraws consent to continue in the trial 
• 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
• 
The Investigator withdraws the patient in the patient’s best interests 
• 
Patient is lost to follow-up (defined as the inability to contact the patient on 3 
separate occasions) 
• 
Administrative reasons (e.g., the patient is transferred to hospice care) 
• 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation  
Patients should go to event monitoring per section 18.0, unless the patient refuses further 
study participation or is lost to follow-up. 
13.6 
Criteria for Study Discontinuation 
The study may be temporarily or permanently discontinued at any site and at any time. 
Reasons for study discontinuation may include, but are not limited to, the following: 
• 
Safety concerns 
• 
Poor enrollment 
• 
Non-compliance with the protocol, Good Clinical Practice guidance or other 
regulatory requirements by the Investigator(s) 
• 
Request to discontinue the trial by a regulatory or health authority or an IRB 
• 
Manufacturing difficulties/concerns 
All Investigators and the requisite regulatory authorities will be notified if the study is 
suspended or terminated for safety reasons. In the case of such termination, the 
Investigator will notify the IRB. 
13.7 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment at the discretion of the physician as long as there are 
no safety concerns, and the patient was properly registered. 
If the patient discontinues treatment, the patient will go directly to the event-monitoring 
phase of the study (or off study, if applicable): 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. No 
further data submission is necessary. 


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13.8 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
Cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. The patient may continue treatment at the discretion of the physician as 
long as there are no safety concerns, and the patient was properly registered. If the 
physician decides treatment should be discontinued, the patient will go directly to the 
event monitoring phase per Section 18.0 and all data up until the point of confirmation of 
a major violation must be submitted. 
13.9a 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 








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portion of the translational study. Whole blood should be sent to the 
Lab, 
where processing will be completed. 
14.43 Blood for correlative research (
). Two 10 ml EDTA tube whole 
blood specimens will be collected at the following time points:  
• 
Baseline 
• 
Day 1 of radiation therapy (Day 15 of study therapy, ±3 days) 
• 
Day 8 of radiation therapy (Day 22 of study therapy, ±3 days) 
• 
Day 15 of radiation therapy (Day 29 of study therapy, ±3 days) 
• 
Pre-surgery (≤14 days prior to surgery) 
• 
Following completion of adjuvant therapy (≤4 weeks following final dose of 
pembrolizumab) 
• 
At the time tumor recurrence (≤14 days of documented tumor recurrence) 
Whole blood specimens will be shipped to the 
 Lab, where 
specimens will be processed and specimens will be stored. Specimens will be 
analyzed for soluble PD-L1, assays for T cell activation, proliferation, 
differentiation, and function, and for specific effector populations. 
 
14.5 
Return of Genetic Testing Research Results 
Since the results generated by the genetic testing included in this section are not currently 
anticipated to have clinical relevance to the patient or their family members, the genetic 
results will not be disclosed to the patients or their physicians.  
For this study, DNA and RNA specimens are only being banked and no specific genetic 
testing is being performed. If, at any time, genetic results are obtained that may have 
clinical relevance, IRB review and approval will be sought regarding the most 
appropriate manner of disclosure and whether or not validation in a CLIA-certified 
setting will be required. Sharing of research data with individual patients should only 
occur when data have been validated by multiple studies and testing has been done in 
CLIA-approved laboratories. 
 


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15.0 
Drug Information 
15.1 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.11 Background: Pembrolizumab is a potent humanized IgG4 monoclonal antibody 
with high specificity of binding to the PD-1 receptor, thus inhibiting its 
interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
15.12 Formulation  
Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial.  
15.13 Preparation and storage:  
Vials should be stored in the refrigerator at temperatures between 2-8°C.  
Drug concentrate is further diluted with normal saline (or 5% dextrose in 
the concentration range of 1 to 10 mg/mL) in IV containers made of 
polyvinyl chloride (PVC) or non-PVC material. The infusion solution in 
the IV bag should be immediately administered. Pembrolizumab solutions 
may be stored at room temperature for a cumulative period of up to 4 
hours. This includes room temperature storage of reconstituted solution in 
vials, room temperature storage of infusion solution in the IV bag and the 
duration of infusion. 
In addition,IV bags may be stored at 2-8 °C for up to a cumulative time of 
20 hours. If refrigerated, the vials and/or IV bags should be allowed to 
equilibrate to room temperature prior to subsequent use. 
15.14 Administration: Pembrolizumab is administered by intravenous infusion over 
30 minutes via a 0.22 micron in-line filter. The final infusion volume must be 
between 1 and 10 mg/mL. Maximum rate of infusion should not exceed 6.7 
mL/minute through a peripheral or indwelling catheter. Flush the line with 0.9% 
NaCL following the completion of the infusion. 
15.15 Pharmacokinetic information: 
a) Absorption – Because pembrolizumab is administered intravenously, it 
is immediately and completely bioavailable.  Steady-state 
concentrations of pembrolizumab are reached by 16 weeks of repeated 
dosing with a Q3W regimen and the systemic accumulation is 2.1-fold. 
The peak concentration, trough concentration, and area under the 
plasma concentration versus time curve at steady state of 
pembrolizumab increased dose proportionally in the dose range of 2 to 
10 mg/kg Q3W. 
b) Distribution – Pembrolizumab has a limited volume of distribution.  
c) Excretion - CL is approximately 23% lower after achieving maximal 
change at steady state compared with the first dose.  The terminal 
elimination half-life (t½) is estimated to be 22 days at steady state. 
d) Metabolism - Pembrolizumab is catabolized through non-specific pathways; 
metabolism does not contribute to its CL. 
15.16 Potential Drug Interactions: There are no known significant drug 
interactions. 
15.17 Known potential adverse events 
Very common known potential toxicities, ≥10%: 


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Gastrointestinal disorders: diarrhea, nausea 
Skin and subcutaneous tissue disorders: rash, pruritis 
General disorders and administration site conditions: fatigue 
Common known potential toxicities, ≥1% to < 10%: 
Respiratory, thoracic, and mediastinal disorders: pneumonitis, dyspnea, 
cough 
Gastrointestinal disorders: colitis, vomiting, abdominal pain, constipation, 
dry mouth 
Skin and subcutaneous tissue disorders: severe skin reactions,  
vitiligo, dry skin, erythema 
Musculoskeletal and connective tissue disorders: arthralgia,  
myositis, musculoskeletal pain, arthritis, pain in extremity 
General disorders and administration site conditions: asthenia,  
edema, pyrexia, influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate  
aminotransferase increased, blood alkaline phosphatase increased, blood 
creatinine increased 
Uncommon known potential toxicities, ≥0.1% to <1%: 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
Endocrine disorders: hypophysitis, adrenal insufficiency,  
thyroiditis 
Metabolism and nutrition disorders: type I diabetes mellitus,  
hyponatremia, hypokalemia, hypocalcemia 
Psychiatric disorders: insomnia 
Nervous system disorders: epilepsy, lethargy, peripheral  
Neuropathy 
Eye disorders: uveitis, dry eye 
Cardiac disorders: myocarditis 
Vascular disorders: hypertension 
Gastrointestinal disorders: pancreatitis 
Hepatobiliary disorders: hepatitis 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, 
alopecia, dermatitis, dermatitis acneiform, eczema, hair color changes, 
papule 
Musculoskeletal and connective tissue disorders: tenosynovitis 
Renal and urinary disorders: nephritis 
Investigations: blood bilirubin increased, amylase increased, 
hypercalcemia 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
Blood and lymphatic system disorders: immune thrombocytopenic  
purpura, hemolytic anemia 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome 
Gastrointestinal disorders: small intestinal perforation 
Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-
Johnson syndrome, erythema nodosum 
The risk profile for pembrolizumab also includes two important potential 


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risks: a) myasthenic syndrome, and b) an increased risk of severe 
complications (such as early severe graft versus host disease and 
venoocclusive disease) of allogeneic transplant in patients with 
hematologic malignancies who have previously been treated with PD-1 
inhibitors.  
Patients with multiple myeloma who were treated with pembrolizumab in 
combination with either pomalidomide or lenalidomide and 
dexamethasone, had an increased number of serious side effects and deaths 
as compared to patients who received only dexamethasone and either 
pomalidomide or lenalidomide. The benefit-risk profile is unfavorable for 
the combination of pembrolizumab, pomalidomide, and dexamethasone in 
relapsed refractory multiple myeloma, and the combination of 
pembrolizumab, lenalidomide, and dexamethasone in newly diagnosed 
treatment-naive multiple myeloma. 
15.18 Drug procurement: Pembrolizumab will be provided free of charge to study 
participants by Merck. 
15.19 Nursing Guidelines: 
15.191 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.192 
Diarrhea can be seen however, is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.193 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the 
study team. Treat per Section 9.0 and monitor for effectiveness.  
15.194 
Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 
15.195 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.196 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 
feeling well.” Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
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15.197 
Patients who are started on steroid therapy for any side effects of 
pembrolizimab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper.  
15.198 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.199a   Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines.  
15.199b  Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and venoocclusive disease, if they have previously been treated with 
pembrolizumab 
15.199c Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
15.199d   Autoimmune hematologic disorders including ITP and hemolytic 
anemia  have been reported. Monitor blood counts closely and report 
any abnormalities to the study team. 
15.199e Rare neurologic disorders including Guillian-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, parasthesias or numbness, 
tingling to the study team immedicately. 
 
 
 
 


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15.2 
Carboplatin (Paraplatin®, CBDCA) 
15.21 Background 
Carboplatin is an alkylating agent which covalently binds to DNA;interferes with 
the function of DNA by producing intrerstrand DNA cross-links. 
15.22 Formulation 
Commercially available for injection as:  
Solution Reconstituted: 150 mg. 
Solution: 10 mg/mL (5 mL, 15 mL, 45 mL, 60 mL) 
15.23 Preparation, storage, and stability 
Refer to package insert for complete preparation and dispensing 
instructions. Store intact vials at room temperature at 25ºC (77F); 
excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Protect from light. 
Further dilution to a concentration as low as 0.5 mg/mL is stable at room 
temperature (25ºC) for 8 hours in 0.9% NaCl or D5W; Stability has also 
been demonstrated for dilutions in D5W in PVC bags at room temperature 
for 8 days; however the manufacturer states to use within 8 hours due to 
lack of preservative.  
15.24 Administration 
Refer to the treatment section for specific administration instructions. When 
administered as a part of a combination chemotherapy regimen, sequence of 
administration may vary by regimen; refer to specific protocol for sequence 
recommendation. Needles or IV administration sets that contain aluminum 
should not be used in the preparation or administration of carboplatin; aluminum 
can react with carboplatin resulting in precipitate formation and loss of potency. 
15.25 Pharmacokinetic information: 
Distribution: Vd: 16 L/kg; into liver, kidney, skin, and tumor tissue. 
Protein binding: 0%; however the platinum from carboplatin becomes 
irreversibly bound to plasma proteins. 
Metabolism: Minimally hepatic to aquated and hydroxylated compounds. 
Half-life elimination: CrCl >60 mL/min: Carboplatin: 2.6-5.9 hours 
(based on dose of 300-500 mg/m2); Platinum (from carboplatin): >5 days. 
Excretion: Urine (~70% as carboplatin within 24 hours; 3% to 5% as 
platinum within 1-4 days). 
15.26 Potential Drug Interactions:  
Increased Effect/Toxicity: Aminoglycosides increase risk of ototoxicity 
and/or nephrotoxicity. When administered as sequential infusions, 
observational studies indicate a potential for increased toxicity when 
platinum derivatives (carboplatin, cisplatin) are administered before taxane 
derivatives (docetaxel, paclitaxel). 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in 
estrogen-dependent tumors.  
15.27 Known potential adverse events 
Consult the package insert for the most current and complete information. 
Percentages reported with single-agent therapy. Note: Myelosuppression is 
dose related, schedule related, and infusion-rate dependent (increased 


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incidences with higher doses, more frequent doses, and longer infusion 
times) and, in general, rapidly reversible upon discontinuation. 
Common known potential toxicities, >10%:  
Central nervous system: Pain 
Endocrine & metabolic: Hyponatremia, hypomagnesemia, hypocalcemia, 
hypokalemia 
Gastrointestinal: Vomiting, abdominal pain, nausea 
Hematologic: Myelosuppression (dose related and dose limiting; nadir at 
~21 days; recovery by ~28 days), leukopenia, anemia, neutropenia, 
thrombocytopenia 
Hepatic: Alkaline phosphatase increased, AST increased 
Hypersensitivity: Hypersensitivity 
Neuromuscular & skeletal: Weakness 
Renal: Creatinine clearance decreased, BUN increased 
Less common known potential toxicities, 1% - 10%:  
Central nervous system: Peripheral neuropathy, neurotoxicity 
Dermatologic: Alopecia 
Gastrointestinal: Constipation, diarrhea, stomatitis/mucositis, taste 
dysgeusia 
Hematologic: Hemorrhagic/bleeding complications 
Hepatic: Bilirubin increased 
Infection: Infection 
Local: Pain at the injection site 
Neuromuscular & skeletal: Peripheral neuropathy 
Ocular: Visual disturbance 
Otic: Ototoxicity 
Renal: Creatinine increased 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular 
accident, dehydration, embolism, erythema, febrile neutropenia, hemolytic 
anemia (acute), hemolytic uremic syndrome, hyper-/hypotension, injection 
site reaction (pain, redness, swelling), limb ischemia (acute), malaise, 
metastases, pruritus, skin rash, tissue necrosis (associated with 
extravasation), urticaria, vision loss 
15.28 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
15.29 Nursing Guidelines 
15.291 
Monitor CBC and PLTs. Watch for profound neutropenia and give low 
count precautions and instructions as necessary. Nadir occurs at 
approximately day 21 with recovery at day 28-30. Thrombo-neutro-
leukopenia may be cumulative. Thrombocytopenia can be dose-
limiting and is more pronounced than with cisplatin. It can be more 
severe in patients with previous chemotherapy, concurrent radiation 
therapy, or patients with impaired renal function. Instruct patient to 
immediately report any unusual bruising or bleeding. Anemia (70-90% 
of patients) may be symptomatic with asthenia being the most common 
complaint. Instruct patient in energy saving lifestyle. 


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15.292 
Assess baseline renal function (creatinine clearance). Reduced renal 
function can contribute to an increased risk of thrombocytopenia.  
15.293 
Monitor fluid status - encourage hydration. 
15.294 
Advise patient of probable taste alterations. Frequent oral hygiene is 
helpful. Instruct patient in appropriate interventions to achieve and 
maintain optimal nutritional status. 
15.295 
Older patients (>65) may experience some peripheral neuropathy with 
paresthesias. Instruct patients to report any tingling, burning, loss of 
sensation. 
15.296  
Mild nausea and vomiting occur in up to 94% of patients, 6-12 hours 
after treatment and may persist for 24 hours or longer. 
Diarrhea/cramping/constipation has been experienced by 
approximately 17%. Premedicate with antiemetics/antidiarrheals—
evaluate effectiveness. 
15.197 
Administer following paclitaxel (in regimens that contain both drugs) 
to maximize cell kill. 
15.196 
Patients have experienced allergic reactions while receiving 
carboplatin. Watch for signs and symptoms of hypersensitivity 
reactions. If these occur, stop drug immediately, notify MD, and treat 
appropriately. 
 
15.3 
Paclitaxel (Taxol) 
15.31 Background 
Antineoplastic Agent, Antimicrotubular, Taxane derivative. Paclitaxel promotes 
microtubule assembly by enhancing the action of tubulin dimers, stabilizing 
existing microtubules, and inhibiting their disassembly, interfering with the late 
G2 mitotic phase, and inhibiting cell replication. In addition, the drug can distort 
mitotic spindles, resulting in the breakage of chromosomes. Paclitaxel may also 
suppress cell proliferation and modulate immune response. 
15.32 Formulation 
Commercially available for injection 6 mg/mL (5 mL, 16.7 mL, 25 mL, and 
50 mL) [contains alcohol and purified Cremophor EL (polyoxyethylated castor 
oil)]. 
15.33 Preparation, storage, and stability 
Refer to package insert for complete preparation and dispensing instructions. 
Store intact vials at room temperature and protect from light. Dilute in 250-1000 
mL D5W or 0.9% NaCL to a concentration of 0.3 – 1.2 mg/mL. Solutions in 
D5W and 0.9% NaCl are stable for up to 3 days at room temperature. 
Chemotherapy dispensing devices (e.g., Chemo Dispensing Pin) should not be 
used to withdraw paclitaxel from the vial. 
Paclitaxel should be dispensed in either glass or non-PVC containers (e.g., 
Excel/PAB). Use nonpolyvinyl (non-PVC) tubing (e.g., polyethylene) to 
minimize leaching.  
15.34 Administration 
Infuse IV over 1-96 hours. When administered as sequential infusions, taxane 
derivatives should be administered before platinum derivatives (cisplatin, 
carboplatin) to limit myelosuppression and to enhance efficacy. Infuse through a 
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15.35 Pharmacokinetic information: 
Distribution: Vd: Widely distributed into body fluids and tissues; affected 
by dose and duration of infusion 
Vdss: 1- to 6-hour infusion: 67.1 L/m2 
Vdss: 24-hour infusion: 227-688 L/m2 
Metabolism: Hepatic via CYP2C8 and 3A4; forms metabolites (primarily 
6α-hydroxypaclitaxel). 
Half-life elimination: 1- to 6-hour infusion: Mean (beta): 6.4 hours, 
3-hour infusion: Mean (terminal): 13.1-20.2 hours 
24-hour infusion: Mean (terminal): 15.7-52.7 hours 
Excretion: Feces (~70%, 5% as unchanged drug); Urine (14%) 
Clearance: Mean: Total body: After 1- and 6-hour infusions: 5.8-16.3 
L/hour/m2; after 24-hour infusions: 14.2-17.2 L/hour/m2 
15.36 Potential Drug Interactions:  
Cytochrome P450 Effect: Substrate (major) of CYP2C8, CYP3A4; 
Induces CYP3A4 (weak).  
Increased Effect/Toxicity: CYP2C8 inhibitors may increase the 
levels/effects of paclitaxel. Refer to the package insert or LexiComp1 for 
example inhibitors. 
Decreased Effect: CYP2C8 inducers may decrease the levels/effects of 
paclitaxel. Refer to the package insert or LexiComp1 for example inducers. 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in 
estrogen-dependent tumors. Avoid valerian, St John’s wort (may decrease 
paclitaxel levels), kava kava, gotu kola (may increase CNS depression). 
15.37 Known potential adverse events 
 Consult the package insert for the most current and complete information. 
Percentages reported with single-agent therapy.  
U.S. Boxed Warning: Bone marrow suppression is the dose-limiting toxicity; do 
not administer if baseline absolute neutrophil count (ANC) is <1500 cells/mm3 
(1000 cells/mm3 for patients with AIDS-related KS); reduce future doses by 20% 
for severe neutropenia.  
U.S. Boxed Warning: Severe hypersensitivity reactions have been reported. 
Common known potential toxicities, >10%:  
Cardiovascular: Flushing, ECG abnormal, edema, hypotension. 
Dermatologic: Alopecia, rash. 
Gastrointestinal: Nausea/vomiting, diarrhea, mucositis, stomatitis, abdominal 
pain (with intraperitoneal paclitaxel)  
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, bleeding. 
Hepatic: Alkaline phosphatase increased, AST increased. 
Local: Injection site reaction (Erythema, tenderness, skin discoloration, 
swelling). 
Neuromuscular & skeletal: Peripheral neuropathy, arthralgia, myalgia, weakness. 
Renal: Creatinine increased. 
Miscellaneous: Hypersensitivity reaction, infection. 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Bradycardia, tachycardia, hypertension, rhythm abnormalities, 
syncope, venous thrombosis. 
Dermatologic: Nail changes. 


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Hematologic: Febrile neutropenia. 
Hepatic: Bilirubin increased. 
Respiratory: Dyspnea. 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Anaphylaxis, ataxia, atrial fibrillation, AV block, back pain, cardiac conduction 
abnormalities, cellulitis, CHF, chills, conjunctivitis, dehydration, enterocolitis, 
extravasation recall, hepatic encephalopathy, hepatic necrosis, induration, 
intestinal obstruction, intestinal perforation, interstitial pneumonia, ischemic 
colitis, lacrimation increased, maculopapular rash, malaise, MI, necrotic changes 
and ulceration following extravasation, neuroencephalopathy, neutropenic 
enterocolitis, ototoxicity, pancreatitis, paralytic ileus, phlebitis, pruritus, 
pulmonary embolism, pulmonary fibrosis, radiation recall, radiation pneumonitis, 
pruritus, renal insufficiency, seizure, skin exfoliation, skin fibrosis, skin necrosis, 
Stevens-Johnson syndrome, supraventricular tachycardia, toxic epidermal 
necrolysis, ventricular tachycardia (asymptomatic), visual disturbances. 
15.38 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
15.39 Nursing Guidelines:  
15.391 
Premedicate with steroids, antihistamines, and H2 blockers as per 
institutional guidelines. 
15.392 
Mix the infusion bag well. Thorough admixture of this drug often 
prevents a hypersensitivity reaction. An inline filter of <0.22 micron 
must be used distal to the infusion pump. Filter may need to be 
changed if infusion is to be prolonged >12 hours. Inspect solution for 
excessive particulate matter, if present do not use. 
15.393 
Caution patients that the alcohol contained in the infusion may cause 
impairment in operating heavy equipment or in driving a vehicle and to 
assess their ability before trying either. Advise avoidance of any 
alcohol or depressants such as sedatives and opiates if not necessary. 
15.394 
Assess the patient frequently for the first 30 minutes. Taxol® 
hypersensitivity reactions, which may include chest pain, back pain, 
flushing, diaphoresis, dyspnea, pruritus, hypotension, hypertension, 
bronchospasm and/or urticaria, usually occur early in the infusion. 
Have the anaphylaxis tray available. 
15.395 
If a reaction occurs, stop the infusion immediately. Epinephrine, IV 
fluids, diphenhydramine, and methylprednisolone may be used as per 
MD’s order. 
15.396 
Approximately 60% of patients experience peripheral sensory 
neuropathy (numbness, tingling, burning pain, fine motor skills 
impairment, paresthesias, distal sensory loss). Patients receiving higher 
doses at shorter infusion times are at greater risk. Most cases have been 
reported at doses >170 mg/m2/day and with cumulative doses over 
multiple courses of therapy. The nerve damage may take months to 
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been effective in treating neuropathic pain. Consult MD about trying 
tricyclic antidepressants or possibly Neurontin.  
15.397 
Increased risk of cardiotoxicity when given in combination with 
doxorubicin, with a sharp increase in risk of CHF once cumulative 
dose of doxorubicin is > 380 mg/m2. At this point taxol should be 
continued as a single agent only. Monitor for sign/symptoms of CHF. 
Instruct patient to report any swelling in the hands, arms, feet, or legs, 
and any chest pain. 
15.398 
Mucositis can usually be managed with a salt and soda mouthwash (1 
tsp. Salt, 1 tsp. Soda and 1 quart boiled water) or try OTC oral Lysine 
or Vitamin E. 
15.399a Narcotics and nonsteroidal anti-inflammatory drugs may be used to 
manage the myalgias. 
15.399b Monitor CBC closely. Neutropenia is most severe in patients who have 
had previous chemotherapy. Instruct patient to report signs or 
symptoms of infection, unusual bruising or bleeding to the health care 
team. 
15.399c There is an increased risk of neutropenia and stomatitis when given 
prior to doxorubicin. Therefore Taxol should always be given after 
doxorubicin administration. 
15.399d Monitor IV site closely and establish patency before administration. 
Paclitaxel is an irritant, however rarely rash, radiation recall, and 
ulceration have occurred with infiltration of drug. 
15.399e Monitor liver function tests 
15.399f Inform patient about total alopecia. 
15.399g If given on the same day as a platinum agent, paclitaxel should be 
administered first to limit myelosuppression and enhance efficacy of 
agent. 
 
 
 


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15.4 
Regimen if carboplatin with paclitaxel not tolerated 
15.41 Oxaliplatin (Eloxatin®, OXAL) 
15.411 Background 
Oxaliplatin, a platinum derivative, is an alkylating agent. Following 
intracellular hydrolysis, the platinum compound binds to DNA forming 
cross-links which inhibit DNA replication and transcription, resulting in 
cell death. Cytotoxicity is cell-cycle nonspecific. 
15.412 Formulation 
Commercially available for injection as:  
Solution [preservative free]: 5 mg/mL (10 mL, 20 mL, 40 mL) 
15.413 Preparation, storage, and stability 
Refer to package insert for complete preparation and dispensing 
instructions. Store intact vials in original outer carton at room 
temperature and; do not freeze. According to the manufacturer, solutions 
diluted for infusion are stable up to 6 hours at room temperature or up to 
24 hours under refrigeration. Oxaliplatin solution diluted with D5W to a 
final concentration of 0.7 mg/mL (polyolefin container) has been shown 
to retain >90% of it’s original concentration for up to 30 days when 
stored at room temperature or refrigerated; artificial light did not affect 
the concentration (Andre, 2007). As this study did not examine sterility, 
refrigeration would be preferred to limit microbial growth. Do not 
prepare using a chloride-containing solution (e.g., NaCl). Dilution with 
D5W (250 or 500 mL) is required prior to administration. Infusion 
solutions do not require protection from light.  
15.414 Administration 
Refer to the treatment section for specific administration instructions. 
Administer as I.V. infusion over 2-6 hours. Flush infusion line with D5W 
prior to administration of any concomitant medication. Patients should 
receive an antiemetic premedication regimen. Cold temperature may 
exacerbate acute neuropathy. Avoid mucositis prophylaxis with ice chips 
during Oxaliplatin infusion. 
15.415 Pharmacokinetic information 
Distribution: Vd: 440 L 
Protein binding: >90% primarily albumin and gamma globulin 
(irreversible binding to platinum) 
Metabolism: Nonenzymatic (rapid and extensive), forms active and 
inactive derivatives 
Half-life elimination: Terminal: 391 hours; Distribution: Alpha phase: 
0.4 hours, Beta phase: 16.8 hours 
Excretion: Primarily urine (~54%); feces (~2%) 
15.416 Potential Drug Interactions 
Increased Effect/Toxicity: Nephrotoxic agents may increase Oxaliplatin 
toxicity. When administered as sequential infusions, observational 
studies indicate a potential for increased toxicity when platinum 
derivatives (carboplatin, cisplatin, oxaliplatin) are administered before 
taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Oxaliplatin may decrease plasma levels of digoxin. 


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15.417 Known potential adverse events 
Consult the package insert for the most current and complete 
information. Percentages reported with monotherapy. 
Common known potential toxicities, > 10%:   
Central nervous system: Fatigue, fever, pain, headache, insomnia 
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, 
constipation, anorexia, stomatitis  
Hematologic: Anemia, thrombocytopenia, leukopenia 
Hepatic: Liver enzymes increased 
Neuromuscular & skeletal: Back pain, peripheral neuropathy (may be 
dose limiting). The most commonly observed oxaliplatin toxicity is acute 
and cumulative neurotoxicity, observed in patients treated at doses above 
100 mg/m2/cycle.  This neurotoxicity has included paresthesias and 
dysesthesias of the hands, feet, and perioral region as well as unusual 
laryngopharyngeal dysesthesias characterized by a loss of sensation of 
breathing without any objective evidence of respiratory distress 
(hypoxia, laryngospasm, or bronchospasm).  OXAL neurotoxicity 
appears to be exacerbated by exposure to cold.  Patients on this study 
will be counseled to avoid cold drinks and exposure to cold water or air.  
Should a patient develop laryngopharyngeal dysesthesia, their oxygen 
saturation should be evaluated via a pulse oximeter; if normal, an 
anxiolytic agent should be given and the patient observed in the clinic 
until the episode has resolved.  Because this syndrome may be associated 
with the rapidity of OXAL infusion, subsequent doses of OXAL should 
be administered as a 6-hour infusion (instead of the normal 2-hour 
infusion). 
Acute and cumulative neurotoxicities are dose limiting for OXAL.  The 
acute neurotoxicity is characterized by paresthesias and dysesthesias that 
may be triggered or exacerbated by exposure to cold.  These symptoms 
occur within hours of exposure and are usually reversible over the 
following hours or days.  Cumulative doses of OXAL above 680 mg/m2 
may produce functional impairment characterized by difficulty 
performing activities requiring fine sensory-motor coordination; 
impairment is caused by sensory rather than motor changes.  
The likelihood of experiencing neurotoxicity is directly related to the 
total cumulative dose of OXAL administered.  The relative risk of 
developing neurotoxicity was 10%, 50%, and 75% in patients who 
received total cumulative OXAL doses of 780 mg/m2, 1,170 mg/m2, and 
1,560 mg/m2, respectively.  Both acute and cumulative neurotoxicities 
due to OXAL have lessened in 82% of patients within 4 to 6 months, and 
have completely disappeared by 6 to 8 months in 41% of patients.  In 
addition, the likelihood that neurologic symptoms will regress has been 
shown to correlate inversely with cumulative dose.  
Respiratory: Dyspnea, cough 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Edema, chest pain, peripheral edema, flushing, 
thromboembolism 
Central nervous system: Dizziness 
Dermatologic: Rash, alopecia, hand-foot syndrome 


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Endocrine & metabolic: Dehydration, hypokalemia 
Gastrointestinal: Dyspepsia, taste perversion, flatulence, mucositis, 
gastroesophageal reflux, dysphagia 
Genitourinary: Dysuria 
Hematologic: Neutropenia 
Local: Injection site reaction 
Neuromuscular & skeletal: Rigors, arthralgia 
Ocular: Abnormal lacrimation 
Renal: Serum creatinine increased 
Respiratory: URI, rhinitis, epistaxis, pharyngitis, pharyngolaryngeal 
dysesthesia 
Miscellaneous: Allergic reactions, hypersensitivity (includes urticaria, 
pruritus, facial flushing, shortness of breath, bronchospasm, diaphoresis, 
hypotension, syncope, hiccup 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Gastrointestinal: Life threatening enteric sepsis secondary to neutropenia 
and diarrhea. 
Hepatic: Veno-occlusive disease of the liver is a rare serious adverse 
event that has occurred in association with administration of oxaliplatin 
and fluorouracil.  
Otic: Clinical ototoxicity occurs in less than 1% of patients following 
oxaliplatin administration, and sever ototoxicity has not been reported. 
15.418 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
15.42 Leucovorin Calcium (CF) 
15.421 Background 
A reduced form of folic acid, leucovorin supplies the necessary cofactor 
blocked by methotrexate, enters the cells via the same active transport 
system as methotrexate. Stabilizes the binding of 5-dUMP and 
thymidylate synthetase, enhancing the activity of fluorouracil. 
15.422 Formulation 
Commercially available as: 
Injection, powder for reconstitution: 50 mg, 100 mg, 200 mg, 350 mg 
Injection, solution: 10 mg/mL (50 mL) 
15.423 Preparation, storage, and stability 
Powder for injection: Store at room temperature, protect from light. 
Reconstitute with sterile water for injection or bacteriostatic water for 
injection; dilute in 100-1000 mL 0.9% NaCl or D5W. When doses > 10 
mg/m2 are required, reconstitute using sterile water for injection, not a 
solution containing benzyl alcohol. Solutions reconstituted with 
bacteriostatic water for injection must be used within 7 days. Solutions 
reconstituted with sterile water for injection must be used immediately. 
Parenteral admixture is stable for 24 hours stored at room temperature 
and for 4 days when stored under refrigeration. 
Solution for injection: Prior to dilution, store vials under refrigeration, 
protect from light. 


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15.424 Administration 
Due to calcium content, do not administer I.V. solutions at a rate > 160 
mg/minute. Refer to individual protocols for specific administration 
instructions. 
Leucovorin should be administered I.V. push or I.V. infusion (15 
minutes to 2 hours). Leucovorin should not be administered concurrently 
with methotrexate. It is commonly initiated 24 hours after the start of 
methotrexate. Toxicity to normal tissues may be irreversible of 
leucovorin is not initiated by ~40 hours after the start of methotrexate. 
In combination with fluorouracil: The fluorouracil is usually given after 
the leucovorin infusion. Leucovorin is usually administered by I.V. bolus 
injection or short (10-120 minutes) I.V. infusion. Other administration 
schedules have been used; refer to the treatment section of the protocol 
for specific directions. 
In combination with oxaliplatin: Leucovorin is compatible with 
oxaliplatin and may be administered concurrently via Y-connector at 
normal doses. Oxaliplatin is incompatible with 0.9% NaCl. Leucovorin 
must be diluted in D5W when administered with oxaliplatin. 
In combination with irinotecan: Leucovorin is compatible with irinotecan 
via Y-site injection.3 
15.425 Pharmacokinetic information: 
Metabolism: Intestinal mucosa and hepatically to 5-methyl-
tetrahydrofolate (5MTHF; active) 
Half-life elimination: ~4-8 hours 
Time to peak: I.V.: Total folates: 10 minutes; 5MTHF: ~1 hour 
Excretion: Urine (primarily); feces 
15.426 Potential Drug Interactions: 
Decreased Effect: May decrease efficacy of trimethoprim/ 
sulfamethoxazole against Pneumocystis carinii pneumonia.  
15.427 Known potential adverse events 
Consult the package insert for the most current and complete 
information. 
Common known potential toxicities, >10%: 
None  
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Rash, pruritus, erythema, urticaria 
Gastrointestinal: Nausea, vomiting 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Allergic reactions, anaphylactoid reactions, dyspnea, thrombocytosis 
15.428 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
 
 


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15.43 Fluorouracil (Adrucil, Efudex, [5FU]) 
15.431 Background 
Antineoplastic Agent, Antimetabolite (Pyrimidine Analog). Fluorouracil 
is a fluorinated Pyrimidine Antimetabolite that inhibits thymidylate 
synthetase, blocking the methylation of deoxyuridylic acid to thymidylic 
acid, interfering with DNA, and to a lesser degree, RNA synthesis. 
Fluorouracil appears to be phase specific for the G1 and S phases of the 
cell cycle. 
15.432 Formulation 
Commercially available for injection 50 mg/mL (10 mL, 20 mL, 50 mL, 
and 100 mL). 
15.433 Preparation, storage, and stability 
Store intact vials at room temperature and protect from light. A slight 
discoloration may occur with storage but usually does not denote 
decomposition. Dilute in 50 – 1000 mL of 0.9% NaCl or D5W. If 
exposed to cold, a precipitate may form; gentle heating to 60ºC will 
dissolve the precipitate without impairing the potency. Solutions in 50 – 
1000 mL 0.9% NaCl or D5W or undiluted solutions in syringes are 
stable for 72 hours at room temperature. Fluorouracil should not be 
coadministered with either diazepam, doxorubicin, daunorubicin, 
idarubicin, cisplatin, or cytarabine. However, fluorouracil and leucovorin 
are compatible for 14 days at room temperature. Fluorouracil is 
compatible with vincristine, methotrexate, and cyclophosphamide. 
15.434 Administration 
Fluorouracil may be given IV push, IV infusion.  
Refer to Section 7.0 (treatment) administration instructions specific to 
the protocol.  
15.435 Pharmacokinetic information: 
Distribution: Vd ~ 22% of total body water; penetrates extracellular 
fluid, CSF, and third space fluids (e.g., pleural effusions and ascitic fluid) 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; Fluorouracil 
must be metabolized to be active. 
Half-life elimination: Biphasic: Initial: 6-20 minutes; two metabolites, 
FdUMP and FUTP, have prolonged half-lives depending on the type of 
tissue. 
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) 
in 6 hours. 
15.436 Potential Drug Interactions 
Fluorouracil may increase effects of warfarin. Avoid ethanol (due to GI 
irritation). Avoid black cohosh. 
15.437 Known potential adverse events 
Consult the package insert for the most current and complete 
information. 
Common known potential toxicities, >10%:   
Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia. 
Gastrointestinal (route and schedule dependent): Heartburn, nausea, 


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vomiting, anorexia, stomatitis, esophagitis, anorexia, diarrhea. GI 
toxicity (anorexia, nausea, and vomiting) is generally more severe with 
continuous-infusion schedules. 
Emetic potential: <1000 mg: Moderately low (10% to 30%) ≥ 1000 mg: 
Moderate (30% to 60%) 
Hematologic: Leukopenia; Myelosuppressive (tends to be more 
pronounced in patients receiving bolus dosing of FU). Decreased white 
blood cell count with increased risk of infection; decreased platelet count 
with increased risk of bleeding. 
Local: Irritant chemotherapy.  
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Dry skin 
Gastrointestinal: GI ulceration 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Cardiac enzyme abnormalities, chest pain, coagulopathy, dyspnea, ECG 
changes similar to ischemic changes, hepatotoxicity; hyperpigmentation 
of nail beds, face, hands, and veins used in infusion; hypotension, 
palmar-plantar syndrome (hand-foot syndrome), photosensitization. 
Cerebellar ataxia, headache, somnolence, ataxia are seen primarily in 
intracarotid arterial infusions for head and neck tumors.  
15.438 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
 
 


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16.0 
Statistical Considerations and Methodology  
16.1 
Study Overview / Rationale 
This single-arm Phase 1b/2 study is designed to evaluate the safety and anti-tumor effect 
of patients with resectable, locally advanced, GEJ/gastric cardia adenocarcinoma, who 
are treated with pembrolizumab plus weekly carboplatin and paclitaxel, and concurrent 
daily radiotherapy for approximately 5 weeks, followed by surgery and post-operative 
pembrolizumab. Fifteen patients will be enrolled for phase 1b portion of the study to 
conduct a thorough review of adverse event data of pre-operative pembrolizumab. The 
phase II portion of the study implements a single-arm design based on the primary 
endpoint of pathological complete response (pathCR) rate. Other endpoints include 
toxicity profile of pre-operative and post-operative treatment and surgical complications, 
progression-free survival (PFS), disease free survival (DFS), R0 rate, time-to-relapse 
(TTR), and overall survival (OS).  
16.2 
Sample size and accrual time: 
A maximum of 34 patients (17-phase I, 17-phase II) will be enrolled to yield a total of 30 
evaluable patients (15-phase I, 15-phase II), assuming 10% of patients who are deemed 
ineligible after registration, withdraw consent before any treatment or are lost-to-follow 
up prior to resection. If more than the targeted evaluable patients are accrued, the 
additional patients will not be used in any decision making process; however, they will be 
included in final estimations of rates and associated confidence interval of primary and 
secondary endpoints. We estimate that we will need to accrue an additional 11 patients 
during the pre-registration phase to end up with 34 patients for the registration phase of 
the trial (17-phase I, 17-phase II). So in summary, we anticipate pre-registering 45 
patients to register a total of 34 patients necessary for the study design and allotted over 
accrual. 
16.3 
Statistical design for phase 1b portion 
16.31 Definition of dose limiting toxicities (DLTs)  
We anticipate neoadjuvant carboplatin/paclitaxel/radiotherapy will be well-
tolerated when combined with pembrolizumab. However, theoretically, toxicities 
may arise from an interaction between radiotherapy and pembrolizumab, so as a 
precaution, safety will be assessed in the phase 1b portion of the study. When the 
first 15 patients who become evaluable for phase 1b dose limiting toxicities 
(DLTs), accrual will be halted. A patient is evaluable for phase 1b safety 
assessment if the patient initiates pre-operative treatment per protocol. We 
anticipate accruing 17 eligible patients to yield 15 evaluable patients, based on 
93% rate of undergoing surgery reported for the chemoRT arm in the CROSS 
trial. The DLTs during the phase 1b portion are defined as the following: 
1. Type 1 DLT:  
Grade 4 (life-threatening) non-hematologic adverse event (AE) during pre-
operative chemoradiotherapy that is possibly, probably, or definitely related 
to pembrolizumab-based chemo(radio)therapy; OR  
A delay in the initiation of neoadjuvant chemotherapy or neoadjuvant 
radiation by >14 days that is at least possibly due to pembrolizumab toxicity 
during the neoadjuvant portion of the study; OR 
A delay in surgery such that surgery occurs >12 weeks after the last dose of 
RT due to toxicities that are at least possibly related to pembrolizumab will 


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be considered a DLT during the neoadjuvant portion of the study; OR 
Any Grade 5 adverse event during neoadjuvant therapy. 
NOTE: Patients will be followed for up to 90 days after last dose of 
neoadjuvant therapy or until surgery, whichever occurs first. 
2. Type 2 DLT:  
Grade 5 event within 30 days after surgery; OR Grade 4 non-hematologic AE 
within 30 days after surgery at least possibly related to pembrolizumab, 
excluding AEs that resolve to Grade 2 or less within 7 days. 
3. Type 3 DLT:  
Grade 4 non-hematologic adverse event during adjuvant pembrolizumab that 
is possibly, probably, or definitely related to pembrolizumab; OR 
Any Grade 5 adverse event during adjuvant pembrolizumab 
NOTE: Patients who received at least one dose of pembrolizumab after 
surgery will be considered evaluable for a Type 3 DLT. 
NOTE: Patients will be followed for a Type 3 DLT for up to 90 days after 
last dose of adjuvant pembrolizumab. 
16.32 Decision rules for continuation of accrual for phase 2 portion 
With 15 evaluable patients, the analyses of DLTs will be conducted. 
Consideration will be made to proceed to the Phase 2 portion if all of the 
following criteria are met (see above for definition of DLT): 
1. ≤4 patients (out of 15 evaluable patients) have a Type 1 DLT 
2. ≤2 patients (out of 15 evaluable patients) have a Grade 5 Type 2 DLT  
3. ≤6 patients (out of 15 evaluable patients) have a Grade 4 non-hematologic 
Type 2 DLT 
4. ≤3 patients (out of 15 evaluable patients) have a Grade 4 non-hematologic 
Type 3 DLT  
5. ≤1 patients (out of 15 evaluable patients) have a Grade 5 Type 3 DLT  
In addition, dose delays and interruptions of chemotherapy and radiation that are 
at least possibly related to toxicity of the treatment regimen will be considered in 
the evaluation of safety. 
After this evaluation, we will consider resuming accrual, for the phase 2 portion. 
Patients enrolled for the phase 1b portion who are evaluable for phase 2 primary 
endpoint evaluation will be included in the phase 2 efficacy decision-making 
processes, and final endpoint rates estimations. 
If the results from safety analysis indicate that safety parameters were not met, 
data will be analyzed to determine the specific nature and etiologies of safety 
concerns. After consideration by the study team (study chair[s], statistician, etc.) 
and the primary IRB, a decision will be made as to whether accrual can be 
resumed, or modifications to the protocol should be adapted. 
We acknowledge that the final decision to move to the Phase 2 portion of the 
study will rest in the clinical judgment of the investigative team and that 
mitigating factors such as a patient’s decision not to undergo surgery, or the 
occurrence of severe unexpected complications during neoadjuvant therapy may 
potentially factor into the decision-making process. 
If more than 2 patients experience a Grade 5 event that is at least possibly related 
to study treatment, the study will not proceed to Phase 2. 
16.33 Phase 1b portion study operating characteristics:  


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Assuming that the occurrence of two types of DLTs are independently distributed 
with binomial distribution, the probabilities of failing to meet the phase 1b 
decision rules can be tabulated according to various true rate of the DLTs. See 
table below:  
True rate of type 1 
DLT 
True rate of type 2 
DLT 
Probability of failing to meet the 
phase 1b safety criteria 
0.1 
0.05 
0.0485 
0.2 
0.05 
0.1945 
0.3 
0.05 
0.5032 
0.1 
0.1 
0.1944 
0.2 
0.1 
0.3181 
0.3 
0.1 
0.5794 
0.1 
0.2 
0.6070 
0.2 
0.2 
0.6673 
0.3 
0.2 
0.7948 
0.1 
0.3 
0.8748 
0.2 
0.3 
0.8940 
0.3 
0.3 
0.9346 
 
 
16.4 
Statistical design for phase 2 portion 
16.41  Overview 
A single-arm design will be implemented for the phase 2 portion. Phase 2 portion 
patients will receive the same neoadjuvant regimen and surgery as in the Phase 
1b portion (pembrolizumab plus weekly carboplatin and paclitaxel, and 
concurrent daily radiotherapy for approximately 5 weeks, followed by surgery 
and post-operative pembrolizumab). 
The CROSS trial was the largest trial, to date, examining neoadjuvant 
carboplatin/paclitaxel/RT therapy in esophageal/GEJ adenocarcinoma patients2. 
This trial established this regimen as a new standard of care in this indication. In 
CROSS, of 180 patients assigned to chemoRT/surgery, 161 patients underwent 
resection, and 148 patients had an R0 resection. Primary analysis included only 
those patients who were assigned to the chemoRT arm and who did not withdraw 
consent. A total of 178 patients were included primary analysis (2 patients of the 
180 patients total withdrew consent prior to initiating chemoRT), among which 
134 patients had adenocarcinoma histology. Among the 134 adenocarcinoma 
patients assigned to the chemoRT/surgery arm included in primary analysis, 21% 
(28/134) had a pathCR. (It is important to distinguish histologic subtypes, since 
the pathCR rate among SCC patients was significantly higher [~49%].) The 
number of adenocarcinoma patients who initiated chemoRT, underwent surgery, 
or underwent resection, was not reported. As a second reference, in Burmeister et 
al (see below), 80 eligible patients with esophageal/GEJ adenocarcinoma were 
assigned to cisplatin/5FU-based chemoRT (35 Gy), of whom 6 patients had a 
pathCR, yielding a pathCR rate of 7.5% (6/80) with the denominator being all 
eligible patients assigned to chemoRT regardless of whether treatment was 
initiated. 
Based on these data from CROSS, we conservatively selected a pathCR rate of 
21% as our historical control, with the denominator being eligible patients who 


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do not withdraw consent, as it is the most reliable available estimate of the 
reference pathCR rate in this patient population. The addition of neoadjuvant 
pembrolizumab is expected to improve the pathCR rate by 27% or more in this 
population, to yield a pathCR rate of 48% or more.  
16.42  Primary endpoint 
Pathological complete responses (pathCR): is defined as number of patients with 
pathologic complete responses (see definition in section 11.6) divided by total 
evaluable patients.  
All phase II patients meeting the eligibility criteria that have signed a consent 
form and have begun protocol treatment will be considered evaluable for pathCR. 
16.43  Study design and decision rules 
The phase 2 portion is powered to detect an improvement in the pathCR rate of 
27% (i.e. achieving pathCR rate of at least 48% for the alternative hypothesis) 
compared to historical control of 21%, which is the null hypothesis. A total of 15 
evaluable patients provides a power of 81% to claim the proposed regimen 
warrants further study at one-sided significance level of 0.08, if at least 6 patients 
achieve pathCR (40% observed pathCR rate). We acknowledge the limitations of 
pathCR in reflecting the anti-tumor efficacy of pembrolizumab. If fewer than 6 
patients achieve pathCR, the decision for further study will be discussed by the 
study team, after analysis of safety and toxicity data, PFS and other endpoints.  
16.44  Power and significance level 
Assuming the number of patients with pathCR is binomially distributed, the 
operating characteristics of current design can be tabulated according to various 
true rates of pathCR (see table below). 
True pathCR 
rate 
Probability of declaring that the proposed 
regimen warrants further study is… 
0.21 
0.08 
0.30 
0.28 
0.40 
0.60 
0.45 
0.74 
0.48 
0.81 
16.45  Analysis plan 
Pathological complete responses (pathCR) rate: The pathCR rate will be 
estimated by the number of patients who achieve pathCR divided by the total 
evaluable number of patients. Ninety percent two-sided confidence interval will 
be calculated according to the exact binomial method. 
16.5 
Analyses plan for secondary endpoints: 
16.51 Progression-free survival (PFS)  
Progression-free survival is defined as the time from the date of study registration 
to the date of death due to all causes, recurrences if R0 resections are achieved, 
progression disease before undergoing surgery, or R1/R2 resection at surgery, 
whichever occurs first, among evaluable patients. The distribution of PFS will be 
estimated using the method of Kaplan-Meier. Two-year PFS rate and confidence 
interval will be estimated based on Kaplan-Meier curve.  


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16.52 Overall survival (OS) 
Overall survival is defined as the time from the date of study registration to the 
date of death due to all causes, among evaluable patients. The distribution of OS 
will be estimated using the method of Kaplan-Meier. Two-year OS rate and 
confidence interval will be estimated based on Kaplan-Meier curve. 
16.53 Disease free survival (DFS) 
DFS is defined as the time from the date of study registration to the date of death 
due to all causes or recurrence, whichever occurs first, among patients who 
achieved an R0 resection.  The distribution of DFS will be estimated using the 
method of Kaplan-Meier. Two-year DFS rate and confidence interval will be 
estimated based on Kaplan-Meier curve. 
16.54 Time-to-relapse (TTR)  
TTR is defined as the time from the date of study registration to the date of 1st 
documented relapse/recurrence among patients who achieve R0 resection. The 
distribution of TTR will be estimated using the method of Kaplan-Meier. Two-
year relapse-free rate and confidence interval will be estimated based on Kaplan-
Meier curve. 
16.55 R0 rate 
R0 rate is defined as the number of patients who achieve R0 resection divided by 
total number of evaluable patients.  
16.56 Adverse events 
The maximum grade for each type of adverse events that are possibly, probably 
or definitely related to study treatments will be recorded for each patient. The 
frequency tables will be reviewed to determine the patterns. 
16.6 
Data & Safety Monitoring 
16.61 Review 
The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The trial is monitored continually by the study team 
who are notified of every Grade 4 and 5 event in real time. The Mayo Clinic 
Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, based on 
reports provided by the MCCC Statistical Office. 
16.62 Adverse Event Stopping Rules 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the intervention(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. CTCAE v4.0 will be used 
to determine grading for these stopping rules. 
Accrual will be temporarily suspended to this study if at any time we observe 
adverse events that satisfy any of the following during the Phase II portion of the 
trial: 


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• 
If at any time 33% or more of patients, including the patients from the 
phase 1b, experience a Grade 4 or 5 non-hematologic adverse event (AE) 
during neoadjuvant therapy that is possibly, probably, or definitely 
related to pembrolizumab-based chemo(radio)therapy. (Type 1 DLT, 
where patients will be followed for a Type 1 DLT (ie, during 
neoadjuvant therapy) for up to 90 days after last dose of neoadjuvant 
therapy or until surgery, whichever occurs first) 
• 
If at any time 14% or more of patients, including the patients from the 
phase 1b, experience a Grade 5 event within 30 days after surgery that is 
possibly, probably, or definitely related pembrolizumab-based 
chemo(radio)therapy. (Type 2 DLT) 
• 
If at any time 54% or more of patients, including the patients from the 
phase 1b, experience a grade 4 non-hematologic AE within 30 days after 
surgery at least possibly related to pembrolizumab, excluding AEs that 
resolve to grade 2 or less within 7 days.  (Type 2 DLT) 
• 
If at any time 25% or more of patients, including the patients from the 
phase 1b, experience a Grade 4 non-hematologic adverse event during 
adjuvant pembrolizumab that is possibly, probably, or definitely related 
pembrolizumab. (Grade 4 non-hematologic Type 3 DLT) 
• 
If at any time 10% or more of patients, including the patients from the 
phase 1b, experience a Grade 5 adverse event during adjuvant 
pembrolizumab that is possibly, probably, or definitely related 
pembrolizumab. (Grade 5 Type 3 DLT) 
We note that we will review all Grade 5 adverse events on a case-by-case basis 
as well (regardless of attribution), and may suspend accrual after just one Grade 5 
event, if we feel it is necessary for patient safety. 
16.7 
Inclusion of Women and Minorities 
16.71 Study availability 
This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.72 Statistical analysis by subset 
There is no information currently available regarding differential effects of study 
regimens in subsets defined by race, gender, or ethnicity, and there is no reason 
to expect such differences to exist. Therefore, although the planned analysis will, 
as always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses.  
 
 


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16.73 Regional population 
Based on prior studies involving similar disease sites, we expect about 10% 
patients will be classified as minorities by race and about 12% of patients to be 
women. Expected size of racial by gender subsets are shown in the following 
table:  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
3 
0 
3 
Not Hispanic or Latino 
4 
27 
0 
31 
Ethnic Category: Total of all subjects 
4 
30 
0 
34 
Racial Category 
 
American Indian or Alaskan Native 
0 
2 
0 
2 
Asian 
0 
0 
0 
0 
Black or African American 
0 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
4 
27 
0 
31 
Racial Category: Total of all subjects 
4 
30 
0 
34 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: 
Individuals from the Philippine Islands have been recorded as Pacific Islanders in 
previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups 
of Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or 
African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


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17.0 
Pathology Considerations/Tissue Biospecimens  
17.1 
Tissue Biospecimen Submission 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
Type of tissue 
biospecimen to submit 
Mandatory 
or optional When to submit 
Reason for submission 
(background/methodology 
section) 
Where to find 
specific details 
for biospecimen 
submission 
ALL prior to treatment 
diagnostic slides from 
original biopsy or cytologic 
tissue 
Mandatory 
As soon as 
possible after 
biopsy, prior to 
enrollment 
Confirmation of tissue 
evaluability through central 
review (Section 17.21) 
Section 17.21 
FFPE tissue blocks with 
corresponding H&E, OR 
unstained slides with 
corresponding H&E, from 
original biopsy 
Mandatory* 
As soon as 
possible after 
biopsy, prior to 
enrollment 
Correlative studies  
(Section 17.5) 
Section 17.321 
ALL diagnostic slides from 
surgically resected tissue 
post-treatment 
Mandatory 
≤42 days after 
surgical 
resection 
Confirmation of 
determination of pathCR 
through central review and 
(Section 17.21) 
Section 17.23 
FFPE tissue blocks with 
corresponding H&E, OR 
unstained slides with 
corresponding H&E, from 
surgical resection 
Mandatory 
≤42 days after 
surgical 
resection 
Correlative studies  
(Section 17.5) 
Section 17.322 
Recurrence/PD –any type 
of tissue available (See 
Section 17.31) 
Optional 
≤30 days after 
biopsy 
Correlative studies  
(Section 17.5) 
Section 17.32 
*If an outside institution is not able to provide the mandatory tissue, it is mandatory that a new attempt be 
made to collect adequate tissue at Mayo Clinic (see Section 3). However, if adequate tissue is not obtained 
after an additional attempt, then the patient will be allowed to enroll. (Only one EGD with primary tumor 
biopsy performed at Mayo Clinic ≤8 weeks prior to pre-registration is required). 
FFPE = Formalin-fixed paraffin-embedded 
17.2 
Required materials for confirmation of eligibility (Section 17.21) AND from surgical 
resection (Section 17.22). 
17.21 Original biopsy or cytological specimen - ALL diagnostic slides used to make 
the diagnosis of adenocarcinoma of the gastroesophageal junction, or gastric 
cardia should be clearly labeled and forwarded as soon as possible after surgery 
for pre-registrationcentral review. If the original slides cannot be released, slides 
from the same tumor biopsy block used to make the diagnosis are acceptable. 
The following materials below are mandatory (unless indicated otherwise) and 
required for shipment: 
• 
All diagnostic slides from original biopsy or cytologic specimen 
• 
Pathology Reporting Form 
• 
Tissue Submission Form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 




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date sections were cut, and thickness of section. The H&E stain should be 
labeled as such and will count as Slide 1. This H&E slide will be reviewed 
centrally under the research base’s protocol for assessing tissue quality. The 
remaining unstained slides will be processed as described in Section 17.5. 
For samples containing less than 7 square millimeters of tumor tissue, multiple 
sections should be mounted onto each slide to ensure that the appropriate amount 
of tumor tissue is available. Ideally, each slide must have a minimum of 75% 
tumor tissue on the slide to be deemed adequate for study. Do not bake or place 
cover slips on the slides. 
Note: For the biopsy specimen, the participating institution may provide fewer 
sections from the biopsy block but only if insufficient tissue will remain for 
clinical purposes. A minimum of eighteen (18) unstained slides of 5-micron 
thickness. 
17.32 The following materials at the indicated time points below are mandatory (unless 
indicated otherwise) and required for shipment. 
17.321 Baseline Biopsy Tissue (mandatory): 
• 
Paraffin embedded tissue blocks with corresponding H&E slide (OR 
unstained sections with corresponding H&E as outlined in Section 
17.31) 
• 
Research Tissue Submission Form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 
Note: Please include the patient study ID number on all materials 
listed above. 
17.322 Surgical Resection Tissue (mandatory): 
• 
Paraffin embedded tissue block with corresponding H&E slide (OR 
unstained slides with corresponding H&E as outlined in Section 
17.31) 
• 
Research Tissue Submission Form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 
Note: Please include the patient study ID number on all materials 
listed above. 
17.323 Recurrence Biopsy Tissue (optional): 
• 
Paraffin embedded tissue blocks with corresponding H&E slide (OR 
unstained sections with corresponding H&E as outlined in Section 
17.31) 
• 
Research Tissue Submission Form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 
Note: Please include the patient study ID number on all materials 
listed above. 
17.33 The block/slides must be appropriately packed to prevent damage (e.g., slides 
should be placed in appropriate slide container) and placed in an individual 
plastic bag. Label the bag with the protocol number, patient study ID number, 
and patient initials. 




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2) BIM/PD-1 expression in tumor infiltrating T cells using double-stained IHC 
(1 unstained slide +1 slide for H&E).  Testing will be performed in 
 lab. 
3) CD3, CD8, CD45, granzyme B by IHC (4 unstained slide + 1 H&E) - 
Testing will be performed in 
 lab. 
17.53  Recurrent tissue (if collected; total 12 sections: Slides 1-12): 
1) PDL1 IHC (4 unstained slides +1 slide for H&E) – Testing will be performed 
in PRC or Merck-associated lab 
2) BIM/PD-1 expression in tumor infiltrating T cells using double-stained IHC 
(1 unstained slide +1 slide for H&E).  Testing will be performed in 
 lab. 
3) CD3, CD8, CD45, granzyme B by IHC (4 unstained slide + 1 H&E) - 
Testing will be performed in 
lab. 
17.54 The institutional pathologist will be notified by the Operations Office (Pathology 
Coordinator) if the block may be depleted. 
17.55 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
17.6 
Return of Genetic Testing Research Results 
No genetic specimens will be collected from tissue biospecimens for this study. If future 
genetic testing is being requested for stored tissue, patient reconsent is required. 
 


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18.0  
Records and Data Collection Procedures  
18.1 
Submission Timetables 
18.11 Pre-Registration Material(s) 
Case Report Form (CRF) 
Pre-Screen Phase 
(No active testing) 
Pre-Registration Screening Failure 
Complete only if patient is NOT registered 
after he/she is pre-registered 
Pathology Materials – (See Section 17.0) 
X 
18.12 Initial Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study 
≤2 weeks after registration 
Adverse Event - Baseline 
Reports 
Research Blood Submission – Baseline (see Section 14.0) 
Research Tissue Submission (see Section 17.0) 
Laboratory - Chemistry 
Laboratory – Thyroid Function 
End of Active Treatment/Cancel Notification 
Submit ≤2 weeks after registration if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
 
18.13 Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule 
Section 4.0) 
Observation 
At each evaluation 
during treatment 
At end of 
treatment 
Follow-up 
visits 
Evaluation/Treatment Phase 1b/Phase 21 
(Neoadjuvant) 
X 
X 
 
Evaluation/Treatment Phase 1b/Phase 22 
(Adjuvant) 
X 
X 
 
Adverse Event 
X 
X 
X 
Pre-Surgery Measurement 
X 
X 
 
Pre-Surgery Confirmation Measurement  
X 
X 
 
Laboratory - Chemistry 
X 
X 
X 
Laboratory – Thyroid Function2 
X 
X 
X 
Measurement 
X 
X 
X 
Surgical 
X 
 
 
Pathology Materials (See Section 17) 
X 
 
 
RT Material 
X 
 
 


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CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule 
Section 4.0) 
Observation 
At each evaluation 
during treatment 
At end of 
treatment 
Follow-up 
visits 
Evaluation/Observation3 
 
 
X 
Reports 
X4 
X4 
 
Research Blood Submission  
(see Section 14.0) 
X5 
X5 
 
Research Tissue Submission Mandatory 
 (see Section 17.0) 
X5 
 
 
Research Tissue Submission - Optional - At PD 
(see Section 17.0) 
X5 
X5 
 
End of Active Treatment/Cancel Notification 
 
X 
 
ADR/AER (see Section 10.0) 
At each occurrence 
 
 
1. Complete at each evaluation during Neoadjuvant Active Treatment (see Section 4.0). 
2. Complete at each evaluation during Adjuvant Active Treatment (see Section 4.0). 
3. Complete at each evaluation during Observation (see Section 4.0). 
4. Submission of these reports is only required for documentation of recurrence. For documentation 
of recurrence, submit one report for one of the measures where recurrence was seen. Attention: 
QAS for MC1541. 
5. Only when required by the Test Schedule (see Section 4.0). 
18.14 Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
q. 6 months 
until PD or 
subsequent 
treatment2 
At PD or 
subsequent 
treatment 
q. 6 months 
after PD or 
subsequent 
treatment 
Death 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each 
occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Submit copy of documentation of progression to Attention: 
 
 Rochester, MN 55905; Fax 
 
 
19.0  
Budget 
19.1 
Costs charged to patient 
Routine clinical care costs will be the responsibility of the patient and/or the patient’s 
insurance company. This responsibility includes costs associated with surgery and with 
the administration of standard chemotherapy (carboplatin/paclitaxel or FOLFOX), and 
radiotherapy. These drugs are commercially available and will be the responsibility of the 
patient and/or the patient’s insurance company. 
19.2 
Costs to be research funded 
• 
Correlative studies  
• 
Pembrolizumab, including its administration 
• 
Collection, processing and storage of blood and tissue samples for future, unspecified 
research. 


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20.0 
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79. 
Cunningham D, Okines AF, Ashley S. Capecitabine and oxaliplatin for advanced 
esophagogastric cancer. N Engl J Med 2010;362:858-9. 
80. 
Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus 
fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final 
results of a randomised, phase 2/3 trial. The Lancet Oncology 2014;15:305-14. 
81. 
Stewart R, Morrow M, Hammond SA, et al. Identification and Pre-clinical Characterization of 
MEDI4736, an Antagonistic anti-PD-L1 Monoclonal Antibody. Cancer Immunol Res 2015. 
82. 
El-Rayes BF, Shields A, Zalupski M, et al. A phase II study of carboplatin and paclitaxel in 
esophageal cancer. Annals of oncology : official journal of the European Society for Medical 
Oncology / ESMO 2004;15:960-5. 
83. 
Polee MB, Sparreboom A, Eskens FA, et al. A phase I and pharmacokinetic study of weekly 
paclitaxel and carboplatin in patients with metastatic esophageal cancer. Clinical cancer 
research : an official journal of the American Association for Cancer Research 2004;10:1928-
34. 
84. 
Gadgeel SM, Shields AF, Heilbrun LK, et al. Phase II study of paclitaxel and carboplatin in 
patients with advanced gastric cancer. Am J Clin Oncol 2003;26:37-41. 
85. 
Philip PA, Zalupski MM, Gadgeel S, Hussain M, Shields A. A phase II study of carboplatin 
and paclitaxel in the treatment of patients with advanced esophageal and gastric cancer. Semin 
Oncol 1997;24:S19-86-S19-88. 
86. 
Stathopoulos GP, Rigatos SK, Fountzilas G, Polyzos A, Stathopoulos JG. Paclitaxel and 
carboplatin in pretreated advanced gastric cancer: a phase II study. Oncol Rep 2002;9:89-92. 
87. 
Chang HM, Kim TW, Ryu BY, et al. Phase II study of paclitaxel and carboplatin in advanced 
gastric cancer previously treated with 5-fluorouracil and platinum. Jpn J Clin Oncol 
2005;35:251-5. 
88. 
Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X. Combined PD-1 blockade and GITR triggering 
induce a potent antitumor immunity in murine cancer models and synergizes with 
chemotherapeutic drugs. J Transl Med 2014;12:36. 
89. 
Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-9. 
90. 
Kim SY, Park C, Kim HJ, et al. Deregulation of immune response genes in patients with 
Epstein-Barr virus-associated gastric cancer and outcomes. Gastroenterology 2015;148:137-47 
e9. 
91. 
Haas M, Buttner M, Rau TT, Fietkau R, Grabenbauer GG, Distel LV. Inflammation in gastric 
adenocarcinoma of the cardia: how do EBV infection, Her2 amplification and cancer 
progression influence tumor-infiltrating lymphocytes? Virchows Archiv : an international 
journal of pathology 2011;458:403-11. 
92. 
Lin SJ, Gagnon-Bartsch JA, Tan IB, et al. Signatures of tumour immunity distinguish Asian 
and non-Asian gastric adenocarcinomas. Gut 2014. 
93. 
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. 
The New England journal of medicine 2015;372:2509-20. 


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94. 
van Grieken NC, Aoyama T, Chambers PA, et al. KRAS and BRAF mutations are rare and 
related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results 
from a large international multicentre study. Br J Cancer 2013;108:1495-501. 
95. 
Yoon HH, Orrock JM, Foster NR, Sargent DJ, Smyrk TC, Sinicrope FA. Prognostic impact of 
FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte density in human colon 
carcinomas. PLoS One 2012;7:e42274. 
96. 
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within 
human colorectal tumors predict clinical outcome. Science 2006;313:1960-4. 
97. 
Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in 
colorectal cancer. N Engl J Med 2005;353:2654-66. 
98. 
Lee HE, Chae SW, Lee YJ, et al. Prognostic implications of type and density of tumour-
infiltrating lymphocytes in gastric cancer. Br J Cancer 2008;99:1704-11. 
99. 
Kim KJ, Lee KS, Cho HJ, et al. Prognostic implications of tumor-infiltrating FoxP3+ 
regulatory T cells and CD8+ cytotoxic T cells in microsatellite-unstable gastric cancers. Hum 
Pathol 2014;45:285-93. 
100. Zhuang Y, Peng LS, Zhao YL, et al. CD8(+) T cells that produce interleukin-17 regulate 
myeloid-derived suppressor cells and are associated with survival time of patients with gastric 
cancer. Gastroenterology 2012;143:951-62 e8. 
101. Kluger HM, Zito CR, Barr ML, et al. Characterization of PD-L1 Expression and Associated T-
cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites. Clinical cancer 
research : an official journal of the American Association for Cancer Research 2015;21:3052-
60. 
102. Frigola X, Inman BA, Lohse CM, et al. Identification of a soluble form of B7-H1 that retains 
immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clinical 
cancer research : an official journal of the American Association for Cancer Research 
2011;17:1915-23. 
103. Schmits R, Kundig TM, Baker DM, et al. LFA-1-deficient mice show normal CTL responses to 
virus but fail to reject immunogenic tumor. The Journal of experimental medicine 
1996;183:1415-26. 
104. Liu X, Gibbons RM, Harrington SM, et al. Endogenous tumor-reactive CD8 T cells are 
differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control 
tumor growth. Oncoimmunology 2013;2:e23972. 
105. Park SS, Dong H, Liu X, et al. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer 
Immunol Res 2015;3:610-9. 
106. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: 
impact on clinical outcome. Nat Rev Cancer 2012;12:298-306. 
107. Acharyya S, Oskarsson T, Vanharanta S, et al. A CXCL1 paracrine network links cancer 
chemoresistance and metastasis. Cell 2012;150:165-78. 
108. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proc Natl Acad Sci U S A 2010;107:4275-80. 
109. Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with 
other modalities of immunotherapy T-cell function to prevent immune decline in ovarian 
cancer. Cancer Res 2013;73:6900-12. 
110. Gustafson MP, Lin Y, Maas ML, et al. A method for identification and analysis of non-
overlapping myeloid immunophenotypes in humans. PLoS One 2015;10:e0121546. 
111. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clinical cancer research : an official journal 
of the American Association for Cancer Research 2009;15:7412-20. 
112. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy 
followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III 


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trial. The lancet oncology 2005;6:659-68. 
113. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements. Clinical cancer research : an official journal of the 
American Association for Cancer Research 2013;19:3936-43. 
114. Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-related tumor 
response assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab? J Immunother Cancer 2014;2:17. 
115. Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response criteria: 
irRECIST. ESMO 2014:Abstr 4958; Accessed on 7/10/2015: 
https://www.parexel.com/files/9214/1449/9078/Adaptation of the Immune Related Response
Criteria irRECIST.pdf. 
 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. 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 ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 
 


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Appendix II 
Surgical Guidelines for Esophagectomy 
Procedure Type: Esophageal malignancies located in the upper esophagus (above azygous vein) will be 
removed by either an “Extended Ivor Lewis” approach utilizing a combined abdominal, right chest, and 
neck incision; or transhiatal resection. For lower mid-esophageal and gastroesophageal malignancies, 
either an “Ivor-Lewis” procedure (abdominal incision and right thoracotomy) or transhiatal resection 
should be performed. Gastroesophageal tumors also may be removed via a left thoracoabdominal 
incision. Lesions located with the cervical esophagus thus requiring concurrent laryngectomy should not 
be included. Minimally invasive resections involving either a laparoscopic or combined laparoscopic/ 
thoracoscopic resection are permissible provided lymph node dissection guidelines are followed. Robotic 
dissections in either the chest, or abdomen, or both are also permissible under the same criteria. Any 
questions regarding eligibility of surgical technique can be referred to the surgical PI for review. 
 
It is strongly recommended that the mediastinal pleura overlying the esophageal cancer and the 
periesophageal fat 5-cm proximal and distal to the primary lesion be removed en bloc with the tumor 
during the esophagectomy. Ligation of the thoracic duct is encouraged if this structure is seen at the time 
of surgery or that if injury to the duct may have occurred to prevent postoperative chylothorax. Also any 
indeterminate lesions with in the lung should be removed to determine if metastatic disease is present. 
 
Surgical Margins: Lateral surgical margins between the primary tumor and mediastinal structures should 
be marked by both the surgeon (metal clips) and pathologist (inked). Microscopic or deep margins <1mm 
will be considered positive for malignancy and will be dually noted. 
 
All margins should be at least 5 cm beyond gross tumor if possible after removal of the esophagus. It is 
recommended that the length of the margin be measured with the specimen stretched out by the 
pathologist before surgical closure. Frozen sections should be obtained to ensure negative surgical 
margins for cancer as well as Barrett’s esophagus. 
 
Lymph Node Dissections: All patients should undergo complete mediastinal lymph node and perigastric 
(lesser curvature and left gastric artery) dissection regardless of whether the nodes appeared positive or 
negative during clinical staging. If a patient had positive lymph nodes on clinical staging, the stations that 
had been positive should be removed at the time of surgery to confirm nodal status. At the time of 
esophagectomy, lymph node stations should be should be individually sampled and sent as separate 
specimens to the pathologist. However, lymph nodes densely adherent to the tumor should not be 
removed separately, but sent en bloc with the specimen. All lymph nodes that are technically accessible 
should be removed. After careful labeling, the status of these nodes should be conveyed to the central 
review site. Simple sampling of representative nodes should be discouraged. 
 
Lymph nodes from levels 2R, 3p, 4R, 7,8,9,15,16,17,18,19,20 should be submitted for review if feasible. 
All submitted nodes should be resected and labeled for each individual station. Lesser curve nodes and 
celiac axis nodes should be marked by the surgeon and evaluated for levels 15,16,17,20. If one of the 
levels sited above is not sampled, an explanation should be submitted to the Central Office. 
 
Exceptions: Exceptions to any of the above are acceptable if documentation of rationale is provided. If the 
patient is found to have evidence of metastatic disease intraoperatively, a palliative resection may be 
pursued. 
 
 
 
 


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Known potential adverse events from esophageal/gastric surgery or postoperative period (usually 
up to 60 days, but can be longer) 
Common potential toxicities, >10%:  
• 
Central nervous system: Pain. Pain at the wound site may be chronic. 
• 
Endocrine & metabolic: Hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia, abnormal 
glucose levels 
• 
Gastrointestinal: Flatulence; cramping; bloating; nausea; vomiting; diarrhea; constipation; 
abdominal pain; trouble and/or pain with swallowing; delayed gastric emptying or other digestive 
dysfunction (e.g., dumping); reflux; decreased movement of the bowels (ileus) that could lead to 
complications that include but are not limited to small bowel dilatation, delay in conduit 
emptying, distension, pain, delay in reaching enteral nutrition goals, prolonged nasogastric tube 
requirement, wound complications, bacteremia (gut translocation), and abscess formation.  
Symptoms of dumping syndrome include nausea, diarrhea, weakness, sweating, dizziness or 
feeling faint. 
• 
Hematologic: High white count, anemia, thrombocytopenia; deep venous thrombosis 
• 
Cardiovascular:  Abnormal heart rhythm which can cause irregular and/or forceful beating of the 
heart (palpitations, tachycardia), lightheadedness, fainting, and/or decreased blood pressure and 
be associated with EKG, cardiac imaging (including depressed ejection fraction), and/or 
biochemical abnormalities; edema of the extremities  
• 
Respiratory, thoracic, or mediastinal:  : Incomplete expansion of the lungs (atelectasis) with 
retention of secretions and shortness of breath that may require procedural intervention; 
pulmonary embolism; edema, effusion, shortness of breath, injury to diaphragm, lung damage, 
ventilator dependence or prolonged ventilation, respiratory failure, coughing, aspiration; 
laryngopharyngeal dysfunction including but not limited to issues with swallowing, airway 
protection, and speech. 
• 
Nutrition:  Poor nutritional status requiring enteral or parenteral feeding; poor appetite; weight 
loss 
• 
Infection: pneumonia or thoracic, wound, urinary, intra-abdominal, bowel (e.g., c dif) 
• 
Constitutional: Fatigue, fever 
 
Less common potential toxicities, rare to 10%:  
• 
Blood and lymphatic:  Bleeding during or after the operation, which may require a blood 
transfusion; thrombosis with/without embolic event 
• 
Respiratory, thoracic, or mediastinal:  Laryngopharyngeal dysfunction including but not limited 
to issues with recurrent laryngeal nerve injury, voice/pharyngeal fatigue, vocal cord paralysis, 
sensory or motor dysfunction; thoracic dissection including but not limited to dissection of 
lymphatic, vascular, or other tissues and blood loss 
• 
Cardiac: Myocardial infarction 
• 
Other: A leak from the thoracic duct (a lymph vessel) that can be damaged during surgery, which 
could result in fluid around the lungs, shortness of breath, and loss of protein leading to 
malnutrition.  Anastomotic leak which could result in fever, increased white cell count, and low 
blood pressure.  Leaks could lead to increased fluid in the abdominal cavity.  Fistula formation 
including but not limited to esophagus and tracheobronchial tree, or between bowel and other 
organs 
• 
Gastrointestinal: esophageal/anastomotic stricture, fibrosis, or perforation; serious ileus or small 
bowel dilatation can lead to bacteremia, sepsis, perforation, peritoneal infection, abscess; bowel 
necrosis or ischemia 
• 
Death 
Any of the above postoperative complications can lead to prolonged hospitalization, permanent injury, or 
other complications including death 


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Appendix III 
Radiation Therapy Quality Control Guidelines 
 
1) Prescription dose and fractionation: 
Total administered prescription dose: 41.4 Gy 
Total number of fractions: 23 
 
2) Target coverage 
PTV4140: V100 ≥ 95% and max dose (0.03 cc) ≤ 110% 
 
3) Normal tissue constraints 
Spinal cord: Max dose (0.03 cc) ≤45 Gy 
Lung: mean ≤15 Gy and V20 ≤20% 
Heart: mean ≤30 Gy and V40 ≤50% 
Bowel (small bowel and large bowel): Max dose (0.03 cc) ≤45 Gy  
Liver: mean ≤25 Gy and V30 ≤40% 
Kidneys: V20 ≤40% 
 
4) Treatment duration/interruptions 
Elapsed days from first fraction to last fraction: ≤38 days 
Treatment plans/administration meeting all of the above criteria will be considered “per protocol.” 
Treatment plans/administration failing to meet one or more of the above criteria will be considered an 
“unacceptable deviation.” 
 
Known Potential Adverse Events of Radiation Therapy  
Common (>20%) 
• 
Inflammation of the esophagus  
• 
Narrowing or scarring of the esophagus, which can cause problems with swallowing  
• 
Fatigue  
• 
Decrease in blood counts, which can cause infection, bleeding, and bruising  
• 
Tanning and redness of the skin in the treatment area  
• 
Nausea/vomiting  
 
Occasional (4-20%) 
• 
Growth of fibrous tissues underneath your skin  
• 
Diarrhea  
• 
Weight loss  
 
Rare (1-3%) 
• 
Inflammation of the muscle tissue of the heart  
• 
Inflammation and/or scarring of the lung tissue or the lining around the lung 
• 
Inflammation of the spinal cord 
• 
Bleeding from the esophagus and stomach  
 
 


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Appendix IV Guidelines for Histopathological Examination of Esophagogastrectomy Specimens 
Gross examination 
 
The esophagogastrectomy specimen should be opened along the longest side of stomach after inking the 
esophageal adventitia. 
 
Example of Gross Description: 
 
1. A segment of (distal, proximal, mid) esophagus, __ cm in length and __ cm in circumference, with 
portion of proximal stomach, __ cm in length.  
 
2. An ulcerated/fungating tan friable/firm tumor, __x__x__ cm, has its epicenter in the distal esophagus, 
__ cm proximal to the EGJ/in the esophagogastric junction and focally extends to the adventitial 
margin. The tumor is __ cm from the proximal and __ cm from the distal resection margins.  
OR 
2. A shallow ulcer/smooth depressed area, __x_x_ cm, overlying fibrotic wall is present, has its 
epicenter in the distal esophagus, __ cm proximal to the EGJ/in the esophagogastric junction and 
focally extends to the adventitial margin. The ulcer is __ cm from the proximal and __ cm from the 
distal resection margins.  
(Note: Post treatment resection specimens may have little grossly evident tumor. The location of the 
tumor should be verified by referring to previous path reports and/or clinic notes. The entire abnormal 
area must be submitted.) 
 
3. The uninvolved esophagus is unremarkable/dull, granular/a segment of Barrett's mucosa, __ cm in 
length is evident proximal/distal/surrounding the tumor. (Describe any nodular area within the 
Barrett's mucosa.)  
 
The stomach is unremarkable, (OR comment on any gross abnormalities) 
 
Sampling for esophagogastrectomy specimen 
 
Typically, esophageal carcinomas show extensive ulceration after pre-operative chemoradiation.  
 
1. If residual tumors are grossly identifiable, tumor and ulcerated area (this includes the whole 
circumference of esophagus if ulceration is focal or patchy) should be sampled for histological 
evaluation at 2-3 mm intervals. Each section should include whole thickness of esophageal wall 
including inked adventitia for evaluation of radial margin. At least 1 cm of normal appearing 
esophagus or stomach should be sampled proximal and distal to tumor and ulcerated area. 
 
2. If no residual tumors are grossly identified, areas with ulceration (this includes the whole 
circumference of esophagus if ulceration is focal or patchy) indicating of treatment field should be 
completely sample at 2-3 mm intervals and submitted for histological examinations. Each section 
should include whole thickness of esophageal wall including inked adventitia for evaluation of radial 
margin. At least 1 cm of normal appearing esophagus or stomach should be sampled proximal and 
distal to tumor and ulcerated area. 
 
3. If no ulceration indicating of treatment field is identified. The entire esophagus including 
gastroesophageal junction should be completely sampled at 2-3 mm intervals and submitted for 


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histological examinations. Each section should include whole thickness of esophageal wall including 
inked adventitia for evaluation of radial margin. 
 
4. Proximal esophageal resection margin and distal gastric resection margin should be completely 
submitted for histological evaluation. 
 
5. All grossly identifiable lymph nodes should be completely submitted for histological evaluation. If 
less than 10 lymph nodes are identified, the whole periesophageal and perigastric soft tissue should be 
completely submitted for histological evaluation for the presence of lymph nodes. 
 
6. Representative sections of normal esophagus and normal stomach sections should also be sampled. 
 
 
Sections: 
 
• 
proximal margin en face (frequently submitted for frozen section)- open the specimen first 
before submitting blocks for frozen section 
• 
distal margin en face (frequently submitted for frozen section)- open the specimen first before 
submitting blocks for frozen section 
• 
tumor with deepest extent and adventitial margin  
• 
tumor with adjacent non-neoplastic tissue 
• 
Barrett’s, if any 
• 
When tumor is not grossly evident as in post-chemoradiated esophagus, the entire abnormal 
segment must be submitted. 
• 
Lymph nodes should be clearly labeled as paraesophageal and paragastric lymph nodes 
indicating location (greater or lesser curvature, etc.) 
• 
Representative GE junction, normal esophagus and normal stomach 
 
 
Histological examination for esophagogastrectomy specimen  
Immunohistochemical stain for Cytokeratin (AE1/AE3) should be performed if microscopic foci of 
suspicious residual tumor are identified on routine H&E sections (tumor, lymph node, or margin sections) 
to accurately stage the tumor. This stain will not be performed routinely if no histological evidence of 
residual tumor is seen on H&E sections. 
 


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Appendix V 
Pembrolizumab ECI Drug-Induced Liver Injury (DILI) 
Hepatotoxicity is injury or damage to the liver that may be associated with impaired liver function 
(Navarro and Senior 2006). Drug-induced hepatotoxicity is one of the most common causes of 
termination of drug development, a major reason for refusal of market authorization and for restricted use, 
and the single most important cause of the withdrawal of market authorization for products (Björnsson 
2006). Thus, drug-induced hepatotoxicity is a major concern during the discovery, development to 
postauthorization phases of the product life cycle (excerpted from Draft Guidance Document, 
Hepatotoxicity of Health Products, Ministry of Public Health, Canada, December 2010). 
As stated in the United States Food and Drug Administration (FDA) Guidance for Industry - Drug-
Induced Liver Injury: Premarketing Clinical Evaluation; hepatocellular injury (usually detected by serum 
aminotransferase elevations [AT]) can be caused by drugs that rarely, if ever, cause severe DILI (e.g. 
aspirin, tacrine, statins, and heparin) as well as by drugs that do cause such injury. The frequency of 
serum AT elevations also is not a good indicator of a potential for severe DILI, because drugs such as 
tacrine (not a cause of severe DILI) can cause AT elevations in as many as 50 percent of patients. Very 
high levels of observed ATs may be a somewhat better indicator of potential for severe DILI, but the most 
specific indicator is evidence of altered liver function accompanying or promptly following evidence of 
hepatocellular injury. 
The single clearest (most specific) predictor found to date of a drug’s potential for severe hepatotoxicity, 
is the occurrence of hepatocellular injury (AT elevation) accompanied by increased serum total bilirubin 
(TBL), not explained by any other cause, such as viral hepatitis or exposure to other hepatotoxins, and 
without evidence of cholestasis, together with an increased incidence of AT elevations in the overall trial 
population compared to control. Increased plasma prothrombin time, or its international normalized ratio 
(INR), a consequence of reduced hepatic production of Vitamin K dependent clotting factors, is another 
potentially useful measure of liver function that might suggest the potential for severe liver injury. 
Recognition of the importance of altered liver function, in addition to liver injury, began with Hyman 
Zimmerman’s observation that drug-induced hepatocellular injury (i.e. AT elevation) accompanied by 
jaundice (i.e. TBL elevation) had a poor prognosis, with a 10 to 50 percent mortality from acute liver 
failure (in pretransplantation days) (Zimmerman 1978, 1999). This became known as "Hy's Law". This 
document describes the recommended process for monitoring and evaluation of subjects meeting the 
laboratory criteria for potential DILI defined as: 
• 
an elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater 
than or equal to three times (3X) the upper limit of normal (ULN)  
and 
• 
an elevated total bilirubin (TBL) lab value that is greater than or equal to two times (2X) ULN 
and 
• 
at the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
as a result of within-protocol-specific testing or unscheduled testing. 
The protocol identifies these laboratory criteria for potential DILI as ECIs. ECIs are selected adverse 
experiences that must be reported within 24 hours. 
Initiate close observation as defined below and continue follow-up until resolution. 
• 
Repeat liver enzyme and serum bilirubin tests two (2) or three (3) times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or study drug has been 
discontinued and the subject is asymptomatic. 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases. 


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• 
Obtain a history of concomitant medication use (including prescription and nonprescription 
medications, herbal and other dietary supplements), alcohol use, recreational drug use and special 
diets. (See Section 5 for details.) 
• 
Obtain a history of exposure to chemical agents or other environmental toxins. 
• 
Obtain additional history and complete Stage 1 workup to attempt to rule out other potential 
causes of the transaminase elevation, including but not limited to the following: acute viral 
hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis 
(NASH); hypoxic/ischemic hepatopathy; and biliary tract disease 
• 
Consider gastroenterology or hepatology consultation 
 


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Appendix VI Presentation of Dermatologic Event 
Collect information on clinical presentation and potential contributing factors. Key information should be 
summarized and entered on the Adverse Experience CRF. Any treatments administered should be entered 
on the Concomitant Medication CRF. Scan and forward this form to Principal Investigator. 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
____________________________________________________________________________ 
2. Has the subject contacted any known allergens? □ Yes □ No 
If so what kind?  _______________________________________ 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, 
personal care product, poison ivy, etc.)? □ Yes □ No 
If so what kind?  _______________________________________ 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)? 
□ Yes □ No 
If so what kind?  _______________________________________ 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
If so what kind?  _______________________________________ 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
If so what kind?  _______________________________________ 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No 
If so what kind?  _______________________________________ 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. 
Molluscum Contagiosum)? □ Yes □ No 
9. Has the subject had recent sun exposure? □ Yes □ No 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 
If so what kind?  _______________________________________ 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No  
iii. Signs of dyspnea? □ Yes □ No 


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iv. Fever, night sweats, chills? □ Yes □ No 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine 
therapy? □ Yes □ No 
If so what kind?  _______________________________________ 
 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No 
List medication(s) and dose(s):  _______________________________________ 
13. Is the rash pruritic (itchy)? □ Yes □ No 
Focused Skin Examination 
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience CRF. 
 
Primary Skin Lesions Description 
Color: _______________________________________ 
 
General description: 
_________________________________________________________________ 
_________________________________________________________________ 
 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
_________________________________________________________________ 
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
_________________________________________________________________ 
 
Any associated signs on physical examination? 
_________________________________________________________________ 
 
 
Scan this form and forward by email to the Principal Investigator listed on the cover page of the protocol. 

ICF_001.pdf: 
 
 
 
 
 
MC1541 / 15-005311 
 
 
Phase 1b/2 Clinical Trial of Neoadjuvant Pembrolizumab Plus 
Concurrent Chemoradiotherapy With Weekly Carboplatin and 
Paclitaxel in Adult Patients With Resectable, Locally Advanced 
Adenocarcinoma of the Gastroesophageal Junction or Gastric 
Cardia 
 
 
NCT02730546 
 
 
Document Date: 04/23/2021 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
 
RESEARCH PARTICIPANT CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Study Title: MC1541 Phase 1b/2 Clinical Trial of Neoadjuvant Pembrolizumab plus 
Concurrent Chemoradiotherapy with Weekly Carboplatin and Paclitaxel in Adult 
Patients with Resectable, Locally Advanced Adenocarcinoma of the 
Gastroesophageal Junction or Gastric Cardia 
 
IRB#:  
15-005311 
 
Principal Investigator:  Harry H. Yoon M.D. and Colleagues 
 
Please read this information carefully. It tells you important things about this research study. A 
member of our research team will talk to you about taking part in this research study.  If you 
have questions at any time, please ask us. 
 
Take your time to decide.  Feel free to discuss the study with your family, friends, and healthcare 
provider before you make your decision.   
 
To help you decide if you want to take part in this study, you should know: 
• Taking part in this study is completely voluntary.  
• You can choose not to participate.  
• You are free to change your mind at any time if you choose to participate. 
• Your decision won’t cause any penalties or loss of benefits to which you’re otherwise 
entitled. 
• Your decision won’t change the access to medical care you get at Mayo Clinic now or in 
the future if you choose not to participate or discontinue your participation.   
 
For purposes of this form, Mayo Clinic refers to Mayo Clinic in Arizona, Florida and Rochester, 
Minnesota; Mayo Clinic Health System; and all owned and affiliated clinics, hospitals, and 
entities. 
 
If you decide to take part in this research study, you will sign this consent form to show that you 
want to take part. We will give you a copy of this form to keep. A copy of this form will be put 
in your medical record. 
 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
 
 
CONTACT INFORMATION 
 
 
You can contact … 
At … 
If you have questions about … 
Principal Investigator: 
Dr. Harry H Yoon  
 
 
 
 
 
 
Arizona PI: 
Dr. Daniel H. Ahn 
Phone: 
(507) 284-2511 
 
Address: 
Mayo Clinic 
200 First St SW 
Rochester MN 55905 
 
Phone: 
(480) 301-8000 
 
Address: 
Mayo Clinic Hospital 
5777 E Mayo Blvd 
Phoenix AZ 85054 
 Study tests and procedures 
 Research-related injuries or 
emergencies 
 Any research-related concerns or 
complaints 
 Withdrawing from the research 
study 
 Materials you receive 
 Research-related appointments 
Mayo Clinic Institutional 
Review Board (IRB) 
Phone: 
(507) 266-4000 
Toll-Free: 
(866) 273-4681 
 Rights of a research participant 
 
Research Subject 
Advocate 
(The RSA is independent 
of the Study Team) 
Phone: 
(507) 266-9372 
Toll-Free: 
(866) 273-4681 
E-mail: 
researchsubjectadvocate@mayo.edu 
 
 Rights of a research participant 
 Any research-related concerns or 
complaints 
 Use of your Protected Health 
Information 
 Stopping your authorization to 
use your Protected Health 
Information 
Patient Account Services 
 Toll Free:   
(844) 217-9591 
 Billing or insurance related to this 
research study 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
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Other Information: 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Website will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Website at any time. 
 
 
1. 
Why are you being asked to take part in this research study? 
 
 
You are being asked to take part in this research study because you have been diagnosed with 
cancer of the gastro-esophageal junction or the gastric cardia. 
 
One standard treatment for your disease includes chemotherapy plus radiation followed by 
surgery. Another standard treatment includes chemotherapy without radiation followed by 
surgery. The treatment used in this study is chemotherapy with radiation followed by surgery. 
 
The plan is have about 34 people take part in this study at Mayo Clinic. 
 
 
2. 
Why is this research study being done? 
 
 
In this study, we want to find out more about how effectively a new drug for cancer, called 
pembrolizumab, fights against your tumor when combined with chemotherapy and radiation. We 
also want to find out how safe and tolerable this combination is. Everyone in this study will 
receive pembrolizumab, which is experimental in the treatment of this cancer. This drug is 
approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with 
melanoma or lung cancer. It is not approved by the FDA for other cancers. However, the FDA 
has allowed the use of this drug in this research study. 
 
 
3. 
Information you should know 
 
 
Who is Funding the Study? 
 
Merck & Co. and Mayo Clinic are funding the study. Merck will pay Mayo Clinic to cover costs 
related to running the study. 


 
 
Approval Date:  
April 23, 2021 
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4. 
How long will you be in this research study? 
 
 
This study will last approximately three years. You will be in the study for as long as your cancer 
is responding to the treatment and you are not having side effects that cannot be managed. 
 
 
5. 
What will happen to you while you are in this research study? 
 
 
Before starting the study drug, you will participate in a screening period. The screening period 
will help the study doctor find out if you are eligible to enter the study. You will need to have the 
following exams, tests or procedures as part of your standard clinical care to find out if you can 
be in the study: 
 
Prior to Registration 
• Physical exam including complete medical history, height, weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood and urine tests 
• Pregnancy test if you are a woman who is able to become pregnant 
• Consultation with a radiation oncologist 
• Consultation with surgeons 
• Bronchoscopy 
• Pulmonary function testing (PFT) to see how your lungs are working 
• FDG-PET/CT of whole body 
• CT scan of chest, abdomen and pelvis 
• EGD with biopsy 
• Endoscopic esophageal ultrasound 
• Electrocardiogram (ECG) and Troponin T blood test to see how your heart is working 
 
These exams, tests or procedures are part of regular clinical care and may be done even if you do 
not join the study. If you have had some of them recently, they may not need to be repeated. This 
decision will be up to the Principal Investigator. 
 
You will also have the following required tests, which are part of the research study: 
• Research blood tests (36 ml or about 2.5 tablespoons) 
• Research tissue samples (taken during the biopsy) 


 
 
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Neoadjuvant treatment 
If you are eligible for the study, you will start chemotherapy and radiation, plus pembrolizumab. 
 
The side effects of pembrolizumab may cause delays and/or inability to receive standard 
treatment with radiation, chemotherapy, and/or surgery. 
 
You will receive neoadjuvant treatment on this trial, which means part of your treatment is given 
before surgery to remove the cancer. 
 
Most patients will receive chemotherapy with carboplatin and paclitaxel. All these drugs are 
given intravenously (IV) through a needle into a vein in your arm or through a port. For 
carboplatin and paclitaxel, you will need to come to the clinic once a week for infusions of these 
drugs for five weeks (Days 15, 22, 29, 36 and 43).  
 
All patients will receive pembrolizumab. Pembrolizumab is also given by IV, but only on Days 1 
and 22 during neoadjuvant treatment with carboplatin and paclitaxel. 
 
You will also be receiving treatment with radiation during the neoadjuvant phase. Radiation is 
given every day, generally Monday-Friday, for a total of about five weeks. 
 
During your neoadjuvant treatment, you will have the following tests and procedures. These 
exams are part of regular care for your cancer: 
• Physical exam including weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood tests 
• Electrocardiogram (ECG) and Troponin T blood test to see how your heart is working 
 
You will also have the following, which are part of the research study: 
• Research blood tests (20 ml or about 1.5 tablespoons) 
 
Surgery 
Once you complete neoadjuvant treatment and radiation, you will have a surgical evaluation as 
part of regular care for your cancer. If you are able to have surgery, it will be scheduled. You 
will have the following tests and procedures prior to surgery. These exams are part of regular 
care for your cancer: 
• Physical exam including weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood tests 
• Pregnancy test if you are a woman who is able to become pregnant 


 
 
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• Pulmonary function testing (PFT) to see how your lungs are working 
• FDG-PET/CT of whole body 
• Electrocardiogram (ECG) and Troponin T blood test to see how your heart is working 
 
We will also draw some blood for research testing (20 ml or about 1.5 tablespoons). 
 
At the time of your surgery, we will take a portion of your tumor tissue for research testing. (This 
testing is required for participation in this study.) 
 
After your surgery, you will recover for a few weeks. Then, about four to seven weeks after your 
surgery, you will have the following tests and procedures (as part of regular care for your 
cancer): 
• Physical exam including weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood tests 
• CT scan of chest, abdomen and pelvis 
• Electrocardiogram (ECG) and Troponin T blood test to see how your heart is working 
 
Adjuvant Treatment 
Once you have completed neoadjuvant treatment and surgery, you will be evaluated for whether 
your body is strong enough to start adjuvant treatment with pembrolizumab. During this stage, 
pembrolizumab is given once every three weeks. These three weeks are called a “cycle.” You 
will receive up to six (6) cycles of adjuvant pembrolizumab. You will have the following tests 
and procedures once each cycle. These exams are part of regular care for your cancer: 
• Physical exam including weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood tests 
• CT scan of chest, abdomen and pelvis once every three months 
• Electrocardiogram (ECG) and Troponin T blood test to see how your heart is working 
 
Treatment discontinuation 
When you stop treatment on this study, you will have the following tests and procedures if they 
have not been done recently. Your doctor will determine which ones are needed. These exams 
are part of regular care for your cancer: 
• Physical exam including weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood tests 
• CT scan of chest, abdomen and pelvis 
 


 
 
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We will also draw some blood for research testing (20 ml or about 1.5 tablespoons) at the time of 
treatment discontinuation or if the tumor comes back. 
 
Safety Follow-up  
About 30 days after your last treatment with pembrolizumab, you will have the following tests 
and procedures if they have not been done recently. Your doctor will determine which ones are 
needed. These exams are part of regular care for your cancer: 
• Physical exam including weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood tests 
• CT scan of chest, abdomen and pelvis 
 
Follow-up visits 
After you have finished all your treatment, you will have the following tests and procedures once 
every three months for the first year and then once every four months for two more years: 
• Physical exam including weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood tests 
• CT scan of chest, abdomen and pelvis once every three months starting from post-surgery 
scan for the first year; then once every four months for two more years 
 
Optional Research Laboratory Tests: 
If your cancer returns, and a biopsy of the recurrent tumor is collected, we would like to obtain a 
portion of the biopsy tissue for research testing. These tests will be done in order to understand 
how your cancer responds to treatment. It is hoped that this will help investigators better 
understand how to make this therapy more effective. The results of these tests will not be sent to 
you or your study doctor and will not be used in planning your care. These tests are for research 
purposes only, and you will not have to pay for them. 
 
You can take part in the treatment portion of this study without taking part in these research 
laboratory tests. 
 
If my cancer comes back and a biopsy is done, I agree to provide tissue sample(s) from my 
biopsy to Mayo Clinic for research testing planned as part of this study. 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
 
QST-NSTD1Y
QST-NSTD1N


 
 
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6. 
What are the possible risks or discomforts from being in this research 
study? 
 
 
Risks and side effects of pembrolizumab (MK-3475) 
The study doctors believe that the side effects listed below were caused by pembrolizumab. 
 
Very common side effects (>10%) seen in people taking pembrolizumab include the 
following: 
• Feeling tired  
• Itching of the skin  
• Rash 
• Frequent or excessive bowel movements or diarrhea 
• Fever 
• Shortness of breath 
• Decreased appetite 
• Cough 
• Nausea and vomiting 
• Decreased in red blood cells that may result in feeling tired or short of breath  
• Pain in joints 
• Headache 
• Back pain 
• Swelling of the legs 
• Muscle weakness or lack of energy 
• Bowel movements occurring less often than usual (constipation) 
 
Common side effects (1-10%) seen in people taking pembrolizumab include the following: 
• Pain or cramping in a muscle or group of muscles 
• Decreased release of thyroid hormone that may appear as feeling tired, weight gain, 
feeling cold easily, or bowel movements occurring less often than usual 
• Abnormal laboratory result of liver test by blood that occasionally indicates liver failure, 
may have yellowing of the skin or whites of the eyes, fatigue, or leg swelling 
• Feeling cold or sick 
• Loss of skin color 
• Pain or uncomfortable feeling in the belly 
• Momentary feeling of whole body warmth possibly accompanied by sweating 


 
 
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• Sweating extensively while sleeping such that clothes and sheets are wet 
• Feeling dizzy or unsteady when walking or standing 
• Loss of weight 
• Pain in the back, arms, or legs 
• Weakness 
• Decreased platelets that may cause a tendency to bruise easily or bleed easily 
• Dry eyes 
• Blurred or changed vision 
• Dry mouth 
• Feeling of pain, pins & needles, or burning, usually in the fingers or toes 
• Inflammation of the lungs (pneumonitis) 
• Change of blood cholesterol or triglyceride level 
• Change of blood sugar or albumin level 
• Change of blood electrolytes, e.g. sodium, potassium, or magnesium 
• Loss of body fluid, may feel tired, confused, have a dry mouth, or feel thirsty 
• Lung infection 
• Fluid around the lung 
• Blood clot developed in lung 
• Inflammation of the large intestine (colon) that may lead to frequent or excessive watery 
bowel movements 
 
Serious Adverse Events (No event occurred in >2% of everyone treated) 
Please note that some of these events have been previously stated above, so some have occurred 
more frequently but with less severity. Serious adverse events seen in people taking 
pembrolizumab include: 
• Trouble thinking clearly or confused easily 
• Decreased white blood cells, red blood cells, and platelets - may have fever, feeling cold, 
infections, shortness of breath, feeling tired, a tendency to bruise easily, or a tendency to 
bleed easily 
• Increased release of thyroid hormone which may cause anxiety, irritability, or trouble 
sleeping, weakness, trembling, sweating, feeling uncomfortable in warm weather, fast or 
uneven heartbeats, feeling tired, weight loss, and frequent or excessive bowel 
movements. 
• Infection throughout the body by a fungus or bacteria or others that may result in fever, 
feeling tired, feeling cold, and not responding to most antibiotics. This is serious and can 
be life threatening. 
• Inflammation of the lining around the heart which may cause sharp chest pain and/or a 
fever 


 
 
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• Inflammation of the pancreas 
• Inflammation of the muscles that may result in weakness or pain in the muscles 
• Inflammation of the kidneys causing them not to work as well, you may have swelling of 
the legs and possibly need dialysis 
• Inflammation of the pituitary gland, which may manifest as headache, nausea, a sensation 
of the room spinning around you, changes in behavior, double vision, or weakness 
• Change of blood pressure or body fluid level as a result of inflammation of the body 
status 
• Failure of liver or lung function 
• Damage of the peripheral nerves to cause weakness of muscle 
• Cancer of the skin 
• Severe infusion reaction, which may be life-threatening 
• Severe skin reactions including Stevens-Johnson Syndrome (SJS) and toxic epidermal 
necrolysis (TEN) 
• Inflammation of the heart muscle which can cause shortness of breath or heart rhythm 
problems 
• Myasthenic Syndrome (muscle weakness)  
• Guillain-Barre Syndrome (damage to the nervous system (causing numbness and/or 
paralysis)) 
• Vogt-Koyanagi-Harada syndrome – an autoimmune disorder that affects tissues 
containing melanin such as eyes and skin and is usually found based on eye problems 
such as dry eye, eye swelling, eye pain, eye infection, blurred vision, and more 
• Hemophagocytic lymphohistiocytosis -an abnormal immune response with activation of 
certain types of white blood cells (lymphocytes and macrophages) and the release of 
inflammatory proteins which then cause a variety of symptoms such as fevers, rash, 
anemia, enlarged lymph nodes, enlarged liver, enlarged spleen, and more 
• Inflammation of the blood vessels (vasculitis) - – may cause fever, headache, weight loss, 
general aches and pains 
• Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is made 
in the liver). This can cause symptoms similar to those seen with inflammation of the 
liver (hepatitis) such as pain in right side of your belly, yellow eyes and skin, feeling 
tired, and itching (sclerosing cholangitis) 
 
There are reported cases of fatal pneumonitis (Inflammation of the lungs) in patients who 
received pembrolizumab. 
 
A total of 6 cases of myocarditis (Inflammation of the heart muscle) have been reported in 
patients treated with pembrolizumab in clinical trials or in an expanded access program. There 
was 1 fatal case reported in a clinical trial. 


 
 
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We do not know all the side effects that may occur with pembrolizumab. The side effects of 
pembrolizumab may cause delays to your treatment with radiation and/or chemotherapy and may 
also delay your surgery. 
 
Other less common side effects have been reported. The study doctor or staff can discuss these 
with you. 
 
There may be other side effects or risks that are not known at this time. 
 
Known potential adverse events from esophageal/gastric surgery or postoperative period 
(usually up to 60 days, but can be longer) 
 
Common potential toxicities, >10%:  
• Central nervous system: Pain. Pain at the wound site may be chronic. 
• Endocrine & metabolic: Hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia, 
abnormal glucose levels 
• Gastrointestinal: Flatulence; cramping; bloating; nausea; vomiting; diarrhea; 
constipation; abdominal pain; trouble and/or pain with swallowing; delayed gastric 
emptying or other digestive dysfunction (e.g., dumping); reflux; decreased movement of 
the bowels (ileus) that could lead to complications that include but are not limited to 
small bowel dilatation, delay in conduit emptying, distension, pain, delay in reaching 
enteral nutrition goals, prolonged nasogastric tube requirement, wound complications, 
bacteremia (gut translocation), and abscess formation.  Symptoms of dumping syndrome 
include nausea, diarrhea, weakness, sweating, dizziness or feeling faint. 
• Hematologic: High white count, anemia, thrombocytopenia; deep venous thrombosis 
• Cardiovascular:  Abnormal heart rhythm which can cause irregular and/or forceful 
beating of the heart (palpitations, tachycardia), lightheadedness, fainting, and/or 
decreased blood pressure and be associated with EKG, cardiac imaging (including 
depressed ejection fraction), and/or biochemical abnormalities; edema of the extremities  
• Respiratory, thoracic, or mediastinal:  : Incomplete expansion of the lungs (atelectasis) 
with retention of secretions and shortness of breath that may require procedural 
intervention; pulmonary embolism; edema, effusion, shortness of breath, injury to 
diaphragm, lung damage, ventilator dependence or prolonged ventilation, respiratory 
failure, coughing, aspiration; laryngopharyngeal dysfunction including but not limited to 
issues with swallowing, airway protection, and speech. 
• Nutrition:  Poor nutritional status requiring enteral or parenteral feeding; poor appetite; 
weight loss 
• Infection: pneumonia or thoracic, wound, urinary, intra-abdominal, bowel (e.g., c dif) 
• Constitutional: Fatigue, fever 


 
 
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Less common potential toxicities, rare to 10%:  
• Blood and lymphatic:  Bleeding during or after the operation, which may require a blood 
transfusion; thrombosis with/without embolic event 
• Respiratory, thoracic, or mediastinal:  Laryngopharyngeal dysfunction including but not 
limited to issues with recurrent laryngeal nerve injury, voice/pharyngeal fatigue, vocal 
cord paralysis, sensory or motor dysfunction; thoracic dissection including but not limited 
to dissection of lymphatic, vascular, or other tissues and blood loss 
• Cardiac: Myocardial infarction 
• Other: A leak from the thoracic duct (a lymph vessel) that can be damaged during 
surgery, which could result in fluid around the lungs, shortness of breath, and loss of 
protein leading to malnutrition.  Anastomotic leak which could result in fever, increased 
white cell count, and low blood pressure.  Leaks could lead to increased fluid in the 
abdominal cavity.  Fistula formation including but not limited to esophagus and 
tracheobronchial tree, or between bowel and other organs 
• Gastrointestinal: esophageal/anastomotic stricture, fibrosis, or perforation; serious ileus 
or small bowel dilatation can lead to bacteremia, sepsis, perforation, peritoneal infection, 
abscess; bowel necrosis or ischemia 
• Death 
 
Any of the above postoperative complications can lead to prolonged hospitalization, permanent 
injury, or other complications including death 
 
Known Potential Adverse Events of Radiation Therapy  
 
Common (>20%) 
• Inflammation of the esophagus  
• Narrowing or scarring of the esophagus, which can cause problems with swallowing  
• Fatigue  
• Decrease in blood counts, which can cause infection, bleeding, and bruising  
• Tanning and redness of the skin in the treatment area  
• Nausea/vomiting  
 
Occasional (4-20%) 
• Growth of fibrous tissues underneath your skin  
• Diarrhea  
• Weight loss  
 
 
 


 
 
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Rare (1-3%) 
• Inflammation of the muscle tissue of the heart  
• Inflammation and/or scarring of the lung tissue or the lining around the lung 
• Inflammation of the spinal cord 
• Bleeding from the esophagus and stomach  
 
Standard of Care Risks 
 
Your doctor will discuss the risks of these tests and procedures, which are part of regular care for 
your cancer: 
• Bronchoscopy 
• Pulmonary function testing (PFT) 
• FDG-PET/CT of whole body 
• CT scan of chest, abdomen and pelvis 
• EGD with biopsy 
• Endoscopic esophageal ultrasound 
• Electrocardiogram (ECG) and troponin T blood test 
• Surgery to remove the cancer 
• Chemotherapy with carboplatin and paclitaxel  
• Risks of radiation therapy 
 
Risks and Side Effects of Paclitaxel (see package insert for most current list) 
 
Common known potential risks and side effects (happen >10% of the time): 
• Skin becomes red and may feel hot (flushing) 
• Heart rhythm abnormal as seen on electrocardiogram (ECG/EKG abnormal) 
• Swelling in hands, lower legs and feet (edema) 
• Decreased blood pressure (hypotension) 
• Loss of hair (alopecia) 
• Rash 
• Feeling sick to your stomach, throwing up (nausea/vomiting) 
• Loose stools (diarrhea) 
• Swelling or sores in your mouth and throat or other parts of your body (mucositis, 
stomatitis) 
• Belly pain (abdominal pain - reported with intraperitoneal paclitaxel) 
 
 


 
 
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• Lowered blood counts of white cells, which may increase your risk of infection 
(neutropenia, leukopenia) lowered counts of red cells, which may make you feel tired 
(anemia) lowered counts of platelets (thrombocytopenia) which may increase your risk of 
bleeding 
• Elevated liver enzymes as seen on a blood test (alkaline phosphatase increased, AST 
increased) 
• Injection site reaction  redness, tenderness, skin discoloration, swelling (erythema) 
• Numbness or tingling in your hands and feet (peripheral neuropathy) 
• Pain and aching in your joints and muscles (arthralgia, myalgia) 
• Weakness 
• Kidney problems as seen on blood test (creatinine increased) 
• Allergic or immune reaction can include many different symptoms such as rash, swelling 
in mouth and throat, trouble breathing (hypersensitivity reaction) 
• Increased risk of infection 
 
Less common known potential risks and side effects (happen 1% - 10% of the time): 
• Abnormal heart rhythms – slow, fast, or irregular (bradycardia, tachycardia, rhythm 
abnormalities) 
• High blood pressure (hypertension) 
• Fainting (syncope) 
• Blood clots (venous thrombosis) 
• Nail changes (may discolor or fall out) 
• High fever and low counts of white blood cells (febrile neutropenia) 
• Abnormal liver blood tests (bilirubin increased) 
• Trouble breathing (dyspnea) 
 
Rare known potential risks and side effects (happen <1% of the time and limited to 
important or life-threatening): 
• Severe immune system reaction that requires emergency medical response (anaphylaxis) 
• Loss of control over muscles (ataxia) 
• Heart problems which may be serious including heart attack, heart failure (atrial 
fibrillation, AV block, cardiac conduction abnormalities, CHF, MI, supraventricular 
tachycardia, ventricular tachycardia [asymptomatic]) 
• Back pain 
• Having no energy, feeling tired and unwell (malaise) 
• Infection in the eye (conjunctivitis) 
• Loss of fluid in the body that may require hospitalization (dehydration) 
• Liver problems or liver failure (hepatic encephalopathy, hepatic necrosis) 


 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
• Blocking of the small bowel or colon (intestinal obstruction, paralytic ileus) 
• Hole in the wall of the small bowel or colon (intestinal perforation) 
• Swelling and pain in small and large bowels (enterocolitis) which may be life threatening 
(neutropenic enterocolitis) 
• Injury to the colon due to loss of blood flow (ischemic colitis) 
• Infection in the veins (phlebitis) 
• Rash on skin with bumps and pimples (maculopapular rash) 
• Skin infection that feels hot and tender and may spread rapidly (cellulitis) 
• Skin loss, hardening or sores especially if the drug leaks under the skin (exfoliation, 
fibrosis, induration, necrolysis, necrotic changes and ulceration following extravasation, 
extravasation recall) 
• Flu-like symptoms with painful red or purplish rash that spreads and blisters (Stevens-
Johnson syndrome) 
• Life threatening skin reaction where skin swells, blisters and detaches – requires 
hospitalization (toxic epidermal necrolysis [TENS]) 
• Brain disease, damage or malfunction (neuroencephalopathy) 
• Loss of hearing (ototoxicity) 
• Swelling and inflammation of the pancreas (pancreatitis) 
• Swelling of the lungs which may cause trouble breathing (interstitial pneumonia) 
• Clot or blockage in the lung (pulmonary embolism) 
• Fibrous growths in the lung tissue that make it hard to breathe (pulmonary fibrosis) 
• Radiation recall – swelling and redness in areas of the body that have been previously 
treated with radiation 
• Damage to the lungs from radiation treatment (radiation pneumonitis) 
• Kidney problems, kidney failure (renal insufficiency) 
• Seizures 
• Eye problems such as blurred vision, double vision (visual disturbances) 
 
Risks and Side Effects of Carboplatin (see package insert for most current list) 
 
Likely Risks of Carboplatin 
• Pain 
• Decreased sodium levels in the blood (hyponatremia) 
• Decreased magnesium levels in the blood (hypomagnesmia) 
• Abnormally low calcium in the blood stream, that can result in muscle cramps, 
abdominal cramps, spasms (hypocalcemia) 
• Low potassium levels in the blood (hypokalemia) 
• Nausea 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
• Vomiting 
• Stomach pain or abdominal pain 
• Decreased production  within  the  bone marrow that causes decreased production of red 
cells, white cells, or platelets (myelosuppression) 
• Decreased white blood cells, which are the infection fighting cells, which could put you 
at risk for infection (leukopenia) 
• Decrease in red blood cells, which are the oxygen carrying cells, which could make you 
feel tired (anemia) 
• A low number of white blood cells, which are the infection fighting cells, which could 
put you at risk for infection (neutropenia) 
• Decreased number of blood cells (platelets) that help to clot the blood (which could put 
you at increased risk of bleeding) (thrombocytopenia) 
• Alkaline phosphatase increased 
• Increased levels of liver enzymes in the blood that may be a sign of liver damage from 
disease or drugs (AST increased) 
• Weakness 
• Creatinine clearance decreased 
• Increased concentration of nitrogen in the form of urea in the blood (BUN increase) 
 
Less likely risks of Carboplatin 
• Poison or toxin affecting the nerves or nervous tissue (neurotoxicity)  
• Hair loss (alopecia) 
• Difficulty passing stool (constipation) 
• Loose stools (diarrhea) 
• Mouth Sores (stomatitis) 
• Inflammation and/or sores in the mouth that may make swallowing difficult and are 
painful (mucositis) 
• Change in taste sensation (dysgeusia) 
• Bleeding (hemorrhagic complications) 
• Elevation of a liver pigment (bilirubin) in the blood indicating liver problems 
• Pain at the injection site 
• Numbness, tingling, or inflammation of the nerves (usually in the hands and feet), which 
may be painful (peripheral neuropathy) 
• Eye problems – blurring, double vision, floaters (visual disturbance) 
• Hearing or balance problems (ototoxicity) 
• Blood test showing kidney problems (creatinine increased) 
• Infection 
• Increased sensitivity to pain, touch, taste,  (Hypersensitivity) 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
Rare but serious risks of Carboplatin 
• Severe allergic reaction (anaphylaxis) can include potentially deadly anaphylactic shock 
• Loss of appetite, not feeling hungry (anorexia) 
• Narrowing of the bronchioles (breathing tubes in the lungs) which can make it difficult to 
breath (bronchospasm) 
• Cardiac failure 
• Lack of oxygen to the brain caused by either bleeding in the brain or blood clot. Also 
called a stroke (cerebrovascular accident) 
• Blood Clot (embolism) 
• Redness of the skin (erythema) 
• Fever 
• A disorder that usually occurs when an infection in the digestive system produces toxic 
substances that destroy red blood cells (Hemolytic uremic syndrome, [HUS]) HUS often 
affects the kidneys 
• Hyper/hypotension (high/low blood pressure) 
• Weakness, feeling tired, unwell (malaise) 
• Damage to the skin from leakage of fluid out of the vein which may cause pain, 
reddening, or irritation on the surrounding tissue (extravasation) 
• Damage to the kidneys (Nephrotoxicity) 
• Itching (pruritus) 
• Rash 
• Secondary malignancies such as leukemia, lymphoma 
• Dark red, raised, itchy bumps or hives (urticaria) 
• Vision loss 
 
Radiation Risk 
You will be exposed to radiation from the FDG PET/CT and CT scans required for your care. 
The amount of radiation has a low risk of harmful effects. 
 
Blood draws 
The risks of drawing blood include pain, bruising, lightheadedness, and/or fainting, or rarely, 
infection at the site of the needle stick. 
 
Pregnancy and Birth Control 
It is not known if the study drugs may affect an unborn or nursing baby or if the study drugs have 
an effect on sperm. Chemotherapy can cause harm to an unborn child. If you are pregnant, trying 
to become pregnant or breast-feeding, you may not be in the study. The study doctor will 
perform a blood or urine pregnancy test before the start of and during the study, if you are able to 
have a baby. 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
 
For Persons Able to Become Pregnant 
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below: 
• Intrauterine device (IUD) 
• Vasectomy of a female subject’s male partner  
• Contraceptive rod implanted into the skin 
 
OR 
 
You must agree to use two of the methods listed below: 
• Hormonal methods, such as birth control pills, patches, injections, or vaginal ring 
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, 
cream, or gel that kills sperm) 
• For women who have never given birth to a child the following options are also allowed 
in combination with another method: 
o Cervical cap with spermicide 
o Contraceptive sponge 
 
You must use birth control for the entire study and for at least 120 days after your last dose of 
pembrolizumab. 
 
If you miss a period, or think you might be pregnant during the study, you must tell the Principal 
Investigator immediately. The Principal Investigator may ask for your permission to collect 
information about the outcome of your pregnancy and your newborn. 
 
For Persons Able to Father a Child 
If you are sexually active, and able to father a child, you must agree to use one of the birth 
control methods listed below: 
• Vasectomy 
• Intrauterine device (IUD) used by female partner 
• Contraceptive rod implanted into the skin of female partner 
 
OR 
 
You must agree to use two of the methods listed below: 
• Hormonal methods, such as birth control pills, patches, injections, or vaginal ring used by 
female partner 
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, 
cream, or gel that kills sperm) 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
 
You must use birth control for the entire study and for at least 120 days after your last dose of 
pembrolizumab. 
 
If your partner thinks she might have become pregnant while you are in the study or for 30 days 
after your last dose of pembrolizumab, you must tell the Principal Investigator immediately. The 
Principal Investigator may ask for your partner’s permission to collect information about the 
outcome of her pregnancy and her newborn. You won’t have to stop taking the study drug or 
stop taking part in the study if your partner becomes pregnant. 
 
Other Risks 
Many side effects go away shortly after the pembrolizumab is stopped, but in some cases side 
effects can be serious, long lasting, or may never go away There may be a risk of death. Some 
side effects may not be known. Side effects may range from mild to life-threatening. Other drugs 
may be given to make side effects less serious and less uncomfortable. Talk to the researcher 
and/or your healthcare provider about side effects and ask any other questions. 
 
 
7. 
Are there reasons you might leave this research study early? 
 
 
You may decide to stop at any time. You should tell the Principal Investigator if you decide to 
stop and you will be advised whether any additional tests may need to be done for your safety. 
 
In addition, the Principal Investigator or Mayo Clinic may stop you from taking part in this study 
at any time: 
• if it is in your best interest, 
• if you don’t follow the study procedures, 
• if the study is stopped. 
 
If you leave this research study early, or are withdrawn from the study, no more information 
about you will be collected; however, information already collected about you in the study may 
continue to be used. 
 
We will tell you about any new information that may affect your willingness to stay in the 
research study. 
 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
 
 
8. 
What if you are injured from your participation in this research study? 
 
 
Where to get help: 
If you think you have suffered a research-related injury, you should promptly notify the Principal 
Investigator listed in the Contact Information at the beginning of this form. Mayo Clinic will 
offer care for research-related injuries, including first aid, emergency treatment and follow-up 
care as needed. 
 
Who will pay for the treatment of research related injuries: 
Care for such research-related injuries will be billed in the ordinary manner, to you or your 
insurance. You will be responsible for all treatment costs not covered by your insurance, 
including deductibles, co-payments and coinsurance. 
 
 
9. 
What are the possible benefits from being in this research study? 
 
 
This study may not make your health better. However, it may help other cancer patients in the 
future. 
 
 
10. 
What alternative do you have if you choose not to participate in this 
research study? 
 
 
You don’t have to be in this study to receive treatment for your condition. Your other choices 
may include:  
• Treatment for your cancer without being on a study 
• Treatment on a different research study 
• No treatment 
 
Talk to the Principal Investigator or your doctor if you have any questions about any of these 
treatments or procedures. 
 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
 
 
11. 
What tests or procedures will you need to pay for if you take part in this 
research study?  
 
 
The study drug will be given to you at no cost; however, you may need to pay for the 
administration of the study drug during the neoadjuvant portion of treatment. You and/or your 
insurance might also have to pay for other drugs or treatments given to help control side effects. 
You and/or your insurance will need to pay for all tests and procedures needed for your clinical 
care, including copayments and deductibles.  
 
The following tests/procedures are being done for research purposes only and the costs will be 
covered by this study: 
• Additional EGD and biopsy if tissue from your original EGD biopsy is inadequate or 
does not arrive in a timely manner; and if you agree to undergo the additional procedure 
• Research testing on blood samples 
• Research testing on tissue samples 
• Adjuvant treatment with pembrolizumab given in the Clinical Research and Trials Unit 
(CRTU) at Mayo Clinic Hospital in Rochester, MN. 
 
Before you take part in this study, you should call your insurer to find out if the cost of these 
tests and/or procedures will be covered. You will have to pay for any costs not covered by your 
insurance. 
 
If you have billing or insurance questions call Patient Account Services at the telephone 
number provided in the Contact Information section of this form. 
 
 
12. 
Will you be paid for taking part in this research study? 
 
 
You won’t be paid for taking part in this study. 
 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
QST-STD1Y 
QST-STD1N 
QST-STD2Y 
QST-STD2N 
QST-STD3Y 
QST-STD3N 
 
 
13. 
What will happen to your samples? 
 
 
Submission of blood and tissue samples is required to take part in this study. These samples will 
be collected prior to starting the study, during therapy, at the time of surgery to remove the 
cancer, and at the end of your treatment on this study. We will also collect a blood sample if your 
cancer comes back. 
 
In addition, we would like to keep your sample for future research that is not described in this 
consent form. You can still take part in this current study even if you don’t want your sample 
used for such future research. If you agree to give your sample, it will be the property of Mayo 
Clinic. 
 
Other researchers at Mayo Clinic who aren’t involved with this study may ask to use your 
sample for future research. Researchers at other institutions may also ask for a part of your 
sample for future studies. Your sample will be sent to researchers in a coded format, which 
protects your identity. 
 
Some future studies may examine your DNA, which is the genetic information you inherited 
from your parents (genetic testing). The Principal Investigator may contact you if there are 
findings which may be useful for your health care. You would be given general information on 
the potential risks, benefits, and costs of choosing to learn about the findings. 
 
Please read the following statements and mark your choices: 
 
1. I permit my sample to be stored and used in future research of cancer at Mayo Clinic: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
2. I permit my sample to be stored and used in future research at Mayo Clinic to learn about, 
prevent, or treat any other health problems: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
3. I permit Mayo Clinic to give my sample to researchers at other institutions: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
There is a very small chance that some commercial value may result from the use of your 
donated sample. If that happens, you won’t be offered a share in any profits. 
 
You may request to have your sample destroyed by writing to the Principal Investigator. 
The address is found in the “Contact Information" section of this consent form. 
 
Because we cannot predict how your sample will be used in the future, we cannot promise that 
samples can be retrieved and destroyed. 
 
 
14. 
How will your privacy and the confidentiality of your records be protected? 
 
 
Mayo Clinic is committed to protecting the confidentiality of information obtained about you in 
connection with this research study. Various methods are used to safeguard confidentiality. Some 
or all of the following may be used in this study: assigning a specific code or registration number 
to each participant’s data and samples, research materials stored in locked areas, password 
protected data stored on a computer. This code will be used if your study information is sent 
outside of Mayo Clinic. The groups or individuals who receive your coded information will use 
it only for the purposes described in this consent form. If the results of the research are made 
public, information that identifies you will not be used. 
 
During this research, information about your health will be collected. Under Federal law called 
the Privacy Rule, health information is private. However, there are exceptions to this rule, and 
you should know who may be able to see, use and share your health information for research and 
why they may need to do so. Information about you and your health cannot be used in this 
research study without your written permission. If you sign this form, it will provide that 
permission.   
 
Health information may be collected about you from: 
• Past, present and future medical records. 
• Research procedures, including research office visits, tests, interviews and 
questionnaires. 
 
Why will this information be used and/or given to others? 
• To do the research. 
• To report the results. 
• To see if the research was done correctly. 
 
 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
Who may use or share your health information? 
• Mayo Clinic research staff involved in this study.  
 
With whom may your health information be shared?  
• The Mayo Clinic Institutional Review Board that oversees the research 
• Other Mayo Clinic physicians involved in your clinical care 
• Researchers involved in this study at other institutions 
• Federal and State agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health and other United States 
agencies) or government agencies in other countries that oversee or review research 
• The sponsor(s) of this study and the people or groups it hires to help perform this 
research 
• A group that oversees the data (study information) and safety of this research 
 
In addition, individuals involved in study oversight and not employed by Mayo Clinic may be 
allowed to review your health information included in past, present, and future medical and/or 
research records. This review may be done on-site at Mayo Clinic or remotely (from an off-site 
location). These records contain information that directly identifies you. However, the 
individuals will not be allowed to record, print, or copy (using paper, digital, photographic or 
other methods), or remove your identifying information from Mayo Clinic. 
 
Is your health information protected after it has been shared with others? 
Mayo Clinic asks anyone who receives your health information from us to protect your privacy; 
however, once your information is shared outside Mayo Clinic, we cannot promise that it will 
remain private and it may no longer be protected by the Privacy Rule. 
 
Your Privacy Rights 
You do not have to sign this form, but if you do not, you cannot take part in this research study. 
 
If you cancel your permission to use or share your health information, your participation in this 
study will end and no more information about you will be collected; however, information 
already collected about you in the study may continue to be used. 
 
If you choose not to take part or if you withdraw from this study, it will not harm your 
relationship with your own doctors or with Mayo Clinic. 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
You can cancel your permission to use or share your health information at any time by sending a 
letter to the address below: 
 
Mayo Clinic 
Office for Human Research Protection 
ATTN:  Notice of Revocation of Authorization 
200 1st Street SW 
Rochester, MN  55905 
 
Alternatively, you may cancel your permission by emailing the Mayo Clinic Research Subject 
Advocate at: researchsubjectadvocate@mayo.edu. 
 
Please be sure to include in your letter or email: 
• The name of the Principal Investigator, 
• The study IRB number and /or study name, and 
• Your contact information. 
 
Your permission lasts forever, unless you cancel it.  
 
 


 
 
Approval Date:  
April 23, 2021 
Not to be used after: February 18, 2022 
 
 
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Name and Clinic Number 
Protocol #:  MC1541 
Version Date: 29Mar2021 
 
 
ENROLLMENT AND PERMISSION SIGNATURES: 
 
 
Your signature documents your permission to take part in this research.  
 
 
  
Printed Name  
 
 
Date (mm/dd/yyyy) 
 
 
Time (hh:mm am/pm)   
 
 
_______________________________ 
Signature 
 
 
Person Obtaining Consent  
• I have explained the research study to the participant. 
• I have answered all questions about this research study to the best of my ability. 
 
 
Printed Name  
 
 
Date (mm/dd/yyyy) 
 
 
Time (hh:mm am/pm) 
 
 
_______________________________ 
Signature 
 
chkEsi
dteParticipantSig
sigParticipant
prtParticipantName
prtPOCName
dtePOCSig
sigPOC
sigWitness