Clinical trial NCT03490292
Conditions: Resectable Esophageal Cancer GastroEsophageal Cancer
Sponsor: University of Wisconsin, Madison
Start date: 2018-05-29; Completion date: 2023-07-12
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 2 part Phase I/II clinical trial evaluating the safety, tolerability and efficacy of avelumab in combination with chemoradiation in patients with resectable esophageal and gastroesophageal cancer.

Part 1: This is the run-in phase of the trial. This portion will determine the safety and tolerability of avelumab in combination with chemoradiotherapy in 6 patients. The proposed combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.

Part 2: This is a Phase 2 portion of the trial, which will evaluate the efficacy of the proposed treatment regimen in patients with stage II/III resectable esophageal and gastroesophageal cancer

Detailed description:
Background:

Neoadjuvant chemoradiation is part of the standard of care for patients with stage II and III resectable esophageal and gastroesophageal cancer. This approach is based on the results of a large randomized clinical trial (CROSS) that demonstrated superior survival in patients receiving neoadjuvant chemoradiotherapy followed by surgical resection compared to patients treated with surgery alone. Pathological complete response at the time of resection is strongly linked to better survival. However, with current strategies pathological complete response is achieved only in a minority (29%) of patients. Remaining patients, especially those with positive lymph nodes at the time of the resection, are at significant risk for recurrences. Five-year survival rate for these patients is only 37%, and overall survival is as low as 9 months for those with persistent lymph node disease. Among patients who develop recurrent disease, most present with distant metastases outside of the radiation field. This is not surprising since the accepted treatment paradigm for this disease does not target possible disseminated microscopic systemic disease. Hence, novel strategies are needed to improve outcomes of these patients. We propose conducting a phase I/II clinical trial evaluating a role of immune checkpoint inhibitor in combination with chemoradiotherapy and post-operatively in the management of resectable esophageal cancer.

Study Rationale:

1. A number of preclinical and clinical studies demonstrated synergism between radiation and immunotherapy, suggesting that combining these approaches can enhance anti-tumor activity and increase treatment efficacy.
2. Immune checkpoint inhibitors have demonstrated promising activity in a subset of patients with metastatic esophageal and gastric cancers. Moving these agents into neoadjuvant setting may increase the cure rate of this disease compared to the standard approach.
3. Current neoadjuvant therapy does not target any potential microscopic disease outside of the radiation field since chemotherapy serves primarily as a radiation sensitizer. Immunotherapy treatment will target both local and systemic disease.

Hypothesis:

We hypothesize that co-administration of avelumab with chemoradiation will be well tolerated and will increase pathological complete response rate in resected tumor specimens. We hypothesize that avelumab treatment will also decrease the rates of disease recurrence.

Study Design:

This is a 2 part Phase I/II clinical trial evaluating the safety, tolerability and efficacy of avelumab in combination with chemoradiation in patients with resectable esophageal and gastroesophageal cancer.

Part 1: This is the run-in phase of the trial. This portion will determine the safety and tolerability of avelumab in combination with chemoradiotherapy in 6 patients. The proposed combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.

Part 2: This is a Phase 2 portion of the trial, which will evaluate the efficacy of the proposed treatment regimen in patients with stage II/III resectable esophageal and gastroesophageal cancer.

Objectives:

Primary: Evaluate the safety of avelumab in combination with chemoradiation in patients with resectable esophageal cancer and gastroesophageal receiving perioperative therapy.

Secondary: Obtain efficacy data and further safety data of the proposed drug combination in this patient population.

Exploratory objectives: The translational focus of the study will evaluate changes in tumor microenvironment that occur in response to radiation and immunotherapy.

Endpoints:

Part 1 - Primary endpoint: Establish safety and tolerability of the proposed treatment.

Part 2 - Primary Endpoint: Pathological complete response rate.

Part 2 - Secondary Endpoints:

1. Safety and tolerability.
2. Disease free survival.
3. Incidence of surgical complications.
4. Rate of R0 resection.

Number of centers \& patients: One center.

Part 1: total of 6 eligible patients will be accrued to evaluate the safety and tolerability of the proposed combination.

Part 2: 18 patients will be enrolled in the phase 2 portion of the trial.

Population:

Patients with histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and gastroesophagus who are candidates for neoadjuvant therapy and surgical resection.

Investigational drugs:

Avelumab (Provided by EMD Serono). IND information to be added as needed.

Arms: arm 1: 6 patients enrolled will receive weekly carboplatin (AUC2) and paclitaxel (50 mg/m2) \[intravenous infusion on days 1, 8, 15, 22, \& 29\] while undergoing radiation therapy \[23 fractions, M-F, estimated completion day 35\].

Avelumab combined with Chemoradiation - Avelumab (10 mg/kg IV) every 2 weeks starting on the day of the last chemotherapy infusion (day 29). A total of 3 doses administered during the pre-operative period and an additional 6 doses of avelumab post-operatively.

Trial enrollment will resume after at least 5 patients do not have a dose-limiting toxicity (DLT) during the DLT evaluation period or until all 6 patients are seen for post-operative evaluation. If 2 or more patients experience dose limiting toxicities associated with the proposed treatments, further accrual of the subjects will be halted and trial will be suspended. Trial may be reopened in the future with appropriate schedule and dose modifications of the proposed treatment. arm 2: Following a determination of safe and tolerable treatment outcome of the Run-In Phase, Part 2 of the trial will enroll 18 additional patients to evaluate activity of the proposed treatment and to obtain further safety information (carboplatin, paclitaxel, radiation \& Avelumab combined with Chemoradiation).
Interventions: intervention 1: Avelumab combined with Chemoradiation intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: Radiation
Intervention descriptions: intervention 1: Co-administration of avelumab with chemoradiation in pre-operative period. intervention 2: Weekly Carboplatin (AUC2) \[intravenous infusion on days 1, 8, 15, 22, \& 29\] intervention 3: Weekly paclitaxel \[intravenous infusion on days 1, 8, 15, 22, \& 29\] intervention 4: Radiation therapy \[23 fractions, M-F, estimated completion day 35\]

Protocol documents:
Prot_SAP_000.pdf: 
1(65) 
Drug Substance: 
Avelumab 
Study Number: 
UW17106 
Version Number:  
Version 7 
Version Date: 
05 July 2021 
IND #: 
Exempt 
PHASE I/II TRIAL OF PERIOPERATIVE AVELUMAB IN 
COMBINATION WITH CHEMORADIATION IN THE TREATMENT OF 
STAGE II/III RESECTABLE ESOPHAGEAL AND 
GASTROESOPHAGEAL JUNCTION CANCER 
NCT03490292


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 6, 11/11/2018 
 
2(65) 
Principal Investigator 
Nataliya Uboha, MD, PhD 
Assistant Professor 
University of Wisconsin 
600 Highland Avenue 
Madison, WI 53792 
nvuboha@medicine.wisc.edu  
 
Co-Principal Investigator 
Michael Bassetti, MD, PhD 
Assistant Professor 
University of Wisconsin 
600 Highland Avenue 
Madison, WI 53792 
bassetti@humonc.wisc.edu 
 
Sub-Investigators 
Dustin Deming, MD 
600 Highland Avenue 
Madison, WI 53792 
ddeming@medicine.wisc.edu 
 
Noelle LoConte, MD 
600 Highland Avenue  
Madison, WI 53792 
Ns3@medicine.wisc.edu  
 
Sam J. Lubner, MD 
600 Highland Avenue 
Madison, WI 53792 
sjlubner@medicine.wisc.edu 
 
Daniel Mulkerin, MD 
600 Highland Avenue 
Madison, WI 53792 
Dm2@medicine.wisc.edu  
 
Pathology  
Kristina A. Matkowskyj, MD, PhD 
600 Highland Ave, L5/183 CSC  
Madison, WI 53792 
matkowskyj@wisc.edu 
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 6, 11/11/2018 
 
3(65) 
Statistician  
Jens Eickhoff, PhD 
600 Highland Avenue  
Madison, WI 53792 
eickhoff@biostat.wisc.edu 
 
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
4(65) 
PROTOCOL SYNOPSIS 
Title of study:   
Phase I/II Trial of Avelumab In Combination With Chemoradiation In The Treatment Of Stage 
II/III Resectable Esophageal and Gastroesophageal Junction Cancer.  
Study Phase: I/II 
Background: 
Neoadjuvant chemoradiation is part of the standard of care for patients with stage II and III 
resectable esophageal and gastroesophageal junction (E/GEJ) cancer. This approach is based on 
the results of a large randomized clinical trial (CROSS) that demonstrated superior survival in 
patients receiving neoadjuvant chemoradiotherapy followed by surgical resection compared to 
patients treated with surgery alone.  Pathological complete response at the time of resection is 
strongly linked to better survival.  However, with current strategies pathological complete 
response is achieved only in a minority (29%) of patients.  Remaining patients, especially those 
with positive lymph nodes at the time of the resection, are at significant risk for recurrences.  
Five-year survival rate for these patients is only 37%, and overall survival is as low as 9 months 
for those with persistent lymph node disease.  Among patients who develop recurrent disease, 
most present with distant metastases outside of the radiation field.  This is not surprising since 
the accepted treatment paradigm for this disease does not target possible disseminated 
microscopic systemic disease.  Hence, novel strategies are needed to improve outcomes of these 
patients.  We propose conducting a phase I/II clinical trial evaluating a role of immune 
checkpoint inhibitor in combination with chemoradiotherapy and post-operatively in the 
management of resectable esophageal cancer. 
Study Rationale:   
1. 
A number of preclinical and clinical studies demonstrated synergism between radiation 
and immunotherapy, suggesting that combining these approaches can enhance anti-tumor 
activity and increase treatment efficacy. 
2. 
Immune checkpoint inhibitors have demonstrated promising activity in a subset of 
patients with metastatic esophageal and gastric cancers. Moving these agents into 
neoadjuvant setting may increase the cure rate of this disease compared to the standard 
approach. 
3. 
Current neoadjuvant therapy does not target any potential microscopic disease outside of 
the radiation field since chemotherapy serves primarily as a radiation sensitizer. 
Immunotherapy treatment will target both local and systemic disease. 
Hypothesis: 
We hypothesize that co-administration of avelumab with chemoradiation will be well tolerated 
and will increase pathological complete response rate in resected tumor specimens. We 
hypothesize that avelumab treatment will also decrease the rates of disease recurrence. 
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
5(65) 
Study Design:   
This is a 2 part Phase I/II clinical trial evaluating the safety, tolerability and efficacy of 
avelumab in combination with chemoradiation in patients with resectable esophageal and GEJ 
(E/GEJ) cancer. 
Part 1: This is the run-in phase of the trial. This portion will determine the safety and 
tolerability of avelumab in combination with chemoradiotherapy in 6 patients. The proposed 
combination will be considered as safe if dose limiting toxicities are observed in at most 1 
patient.  
Part 2:  This is a Phase 2 portion of the trial, which will evaluate the efficacy of the 
proposed treatment regimen in patients with stage II/III resectable E/GEJ cancer. 
Objectives: 
Primary:  Evaluate the safety of avelumab in combination with chemoradiation in patients with 
resectable esophageal cancer receiving perioperative therapy.   
Secondary:  Obtain efficacy data and further safety data of the proposed drug combination in this 
patient population.  
Exploratory objectives: 
The translational focus of the study will evaluate changes in tumor microenvironment that occur 
in response to radiation and immunotherapy.  
Endpoints:   
Part 1: 
Primary endpoint:  
1. Establish safety and tolerability of the proposed treatment. 
Part 2: 
Primary Endpoint:  
1. Pathological complete response rate. 
Secondary Endpoint: 
1. Safety and tolerability. 
2. Disease free survival. 
3. Incidence of surgical complications. 
4. Rate of R0 resection. 
Number of centers & patients:    
One center. 
Part 1: total of 6 eligible patients will be accrued to evaluate the safety and tolerability of the 
proposed combination.  
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
6(65) 
Part 2: 18 patients will be enrolled in the phase 2 portion of the trial. 
Population:   
Patients with histologically confirmed, potentially curable squamous-cell carcinoma, 
adenocarcinoma, or large-cell undifferentiated carcinoma of E/GEJ who are candidates for 
neoadjuvant therapy and surgical resection. 
Investigational drugs:   
Avelumab (Provided by EMD Serono). 
IND information to be added as needed. 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
7(65) 
TABLE OF CONTENTS 
 PAGE 
TITLE PAGE 
1 
TABLE OF CONTENTS 
7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
11 
EVALUATION SCHEDULE 
13 
1. 
BACKGROUND AND RATIONALE 
15 
1.1 
Esophageal Cancer 
15 
1.2 
Current Treatment Paradigm of Resectable Esophageal Cancer. 
15 
1.3 
Immunotherapy in the Treatment of Gastroesophageal Cancers 
16 
1.4 
Avelumab 
16 
 
Pharmacology and Pre-Clinical Data 
16 
 
Clinical Experience with Avelumab 
17 
1.5 
Rationale for Adding Avelumab to Neoadjuvant Chemoradiation. 
17 
1.6 
Benefit/Risk and Ethical Assessment 
18 
2. 
STUDY OBJECTIVES/ENDPOINTS 
18 
2.1 
Part 1 
18 
2.2 
Part 2 
18 
3. 
STUDY PLAN AND PROCEDURES 
19 
3.1 
Overall Study Design 
19 
3.2 
Part 1: Run-In Phase 
19 
 
Definitions of Dose-Limiting Toxicities 
19 
3.3 
Part 2: Expansion Cohort 
20 
3.4 
Post-Treatment Surveillance 
20 
3.5 
Rationale for Study Design and Doses 
20 
4. 
PATIENT SELECTION CRITERIA 
21 
4.1 
Study Population 
21 
4.2 
Inclusion Criteria 
21 
4.3 
Exclusion Criteria 
22 
4.4 
Replacement Criteria 
23 
5. 
TREATMENTS 
23 
5.1 
Chemotherapy Administration 
23 
5.2 
Avelumab Administration 
24 
 
Dosing and Administration of Avelumab 
24 
 
Packaging, Labeling, Storing and Preparation 
24 
 
Avelumab Product Accountability 
25 
5.3 
Radiation Therapy 
25 
 
Dose Specification 
25 
 
Volume Definitions 
25 
 
Treatment Planning 
26 
 
Quality Control 
26 
 
Treatment Verification 
27 
 
External Beam Equipment 
27 
5.4 
Surgical Resection 
27 
5.5 
Concomitant and post-study treatment(s) 
27 
5.6 
Restrictions During the Study 
27 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
8(65) 
 
Administration of Other Anti-Cancer Agents 
27 
 
Immunosuppressive Agents 
27 
 
Pregnancy and Contraception 
28 
6. 
STUDY PROCEDURES. 
28 
6.1 
Visit Schedule and Assessments 
28 
6.2 
Radiological Evaluations 
32 
6.3 
Procedures for Handling Subjects Incorrectly Enrolled or Initiated On 
Investigational Product. 
32 
7. 
TOXICITY MANAGEMENT 
33 
7.1 
General Toxicity Management Guidelines 
33 
7.2 
Hematologic Toxicity 
33 
7.3 
Non-Hematologic Toxicity During Chemoradiation 
33 
7.4 
Immune-Mediated Toxicities of Avelumab 
34 
7.5 
Treatment Modification for Symptoms of Infusion-Related Reactions Caused 
by Avelumab 
44 
7.6 
Indications for Treatment Discontinuation 
44 
7.7 
Procedures for Discontinuation of a Subject From Investigational Product 
45 
7.8 
Withdrawal From Study 
45 
8. 
STUDY EFFICACY ASSESSMENTS 
45 
8.1 
Pathology Evaluation 
45 
 
Pathologic Complete Response 
45 
 
Assessment of Treatment Effect 
45 
 
R0 Assessment 
46 
8.2 
Disease Surveillance 
46 
8.3 
Surgical Outcomes 
46 
9. 
CORRELATIVE STUDIES 
46 
9.1 
Correlative Objectives 
46 
9.2 
Correlative Studies 
47 
 
PD-L1 Immunohistochemistry (IHC) 
47 
 
Tumor Infiltrating Lymphocytes and Examination of the Immune Context 
47 
 
Versican Proteolysis 
47 
9.3 
Sample Collection and Banking 
48 
 
Pretreatment Specimen Collection 
48 
 
Resection Specimen Collection 
48 
 
Peripheral Blood Collection 
48 
10. 
STUDY SAFETY ASSESSMENTS 
48 
10.1 
Definitions 
48 
 
Adverse Events 
48 
 
Serious Adverse Event 
49 
10.2 
Recording of Adverse Events 
49 
 
Adverse Events Based on Signs and Symptoms 
50 
 
Adverse Events Based on Examinations and Tests 
50 
 
Disease Progression 
50 
 
New Cancers 
51 
 
Lack of Efficacy 
51 
 
Deaths 
51 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
9(65) 
11. 
DATA AND SAFETY MONITORING PLAN 
52 
11.1 
Oversight and Monitoring Plan 
52 
11.2 
Monitoring and Reporting Guidelines 
52 
 
Intermediate Monitoring 
52 
11.3 
Serious Adverse Event – Reporting within 24 Hours 
53 
11.4 
Serious Adverse Event – Reporting within 10 Days 
53 
11.5 
Sponsor-Investigator Responsibilities for SAE Review 
53 
11.6 
Study Progress Review 
54 
12. 
EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS 
54 
12.1 
SAE Requiring [24] Hour Reporting Occurs at UWCCC 
56 
 
Report to the UWCCC: 
56 
 
Reporting to EMD Serono 
56 
 
Report to the IRB 
57 
12.2 
SAE Requiring [10] Day Reporting Occurs at UWCCC 
57 
 
Report to the UWCCC: 
57 
 
Report to the Sponsor: 
57 
 
Report to the IRB: 
57 
12.3 
Other Reporting Requirements 
57 
 
Reporting to the FDA 
57 
13. 
ETHICAL AND REGULATORY REQUIREMENTS 
58 
13.1 
Ethical conduct of the study 
58 
13.2 
Subject data protection 
58 
13.3 
Ethics and regulatory review 
58 
 
Informed consent 
58 
 
Changes to the protocol and informed consent form 
58 
 
Audits and inspections 
58 
14. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
59 
14.1 
Sample Size and Power Calculation 
59 
 
Part 1- Run-in Phase 
59 
 
Part 2 – Expansion Phase 
60 
14.2 
Analysis Plan 
60 
 
General 
60 
 
Demographics 
61 
 
Primary Endpoints 
61 
 
Secondary Endpoints 
61 
15. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR 
61 
15.1 
Pregnancy 
61 
 
Maternal Exposure 
61 
 
Paternal Exposure 
62 
16. 
LIST OF REFERENCES 
63 
APPENDIX A. ECOG PERFORMANCE STATUS. 
65 
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
10(65) 
LIST OF TABLES 
Table 1: Management of Immune-mediated Avelumab Toxicities. 
Table 2: FDA Reporting Requirements. 
LIST OF APPENDICES 
Appendix A: ECOG Performance Status. 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
11(65) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or special 
term 
Explanation 
3D-CRT 
ADCC 
ADR 
AE 
ALT 
ANC 
AST 
BUN 
CBC 
cc 
CR 
CT 
CTCAE 
CTV 
DFS 
DLT 
DSMC 
E/GEJ 
EC 
ECOG 
EOT 
FDA 
FFPE 
GC 
GEJ 
GERD 
GI 
GTV 
Gy 
HPF 
HSR 
ICF 
IFN-ᵞ 
3-D conformal radiotherapy 
Antibody-dependent cell-mediated cytotoxicity 
Adverse drug reaction 
Adverse event 
Alanine aminotransferase 
Absolute neutrophil count 
Aspartate aminotransferase 
Blood urea nitrogen 
Complete blood count 
Cubic centimeter 
Complete response 
Computed tomography 
Common Terminology Criteria for Adverse Events 
Clinical tumor volume 
Disease free survival 
Dose Limiting Toxicity 
Data and Safety Monitoring Committee 
Esophageal and gastroesophageal junction 
Esophageal cancer 
Eastern Cooperative Oncology Group 
End of treatment 
Food and Drug Administration 
Formalin fixed paraffin embedded 
Gastric cancer 
Gastroesophageal junction 
Gastroesophageal reflux disease 
Gastrointestinal 
Gross tumor volume 
Gray 
High power field 
Hypersensitivity reaction 
Informed consent form 
Interferon gamma 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
12(65) 
IGRT 
IHC 
IL 
IMRT 
irAE 
ITV 
IV 
Kg 
LFT 
MoAb 
NCI 
OAE 
pCR 
PET 
PD-1 
PD-L1 
PI 
PLT 
PRMC 
PS 
PTV 
SAE 
SCC 
TIL 
TSH 
ULN 
UWCCC 
VCAN 
VMAT 
Image-guided radiotherapy 
Immunohistochemistry 
Intensity modulated radiotherapy 
Interleukin 
Immune mediated adverse event 
Internal target volume 
Intravenous 
Kilogram 
Liver function tests 
Monoclonal antibody 
National Cancer Institute 
Other significant adverse events 
Pathological complete response 
Positron emission tomography 
Programmed death 1 
Programmed death ligand 1 
Principal investigator 
Platelets 
Protocol Review Monitoring Committee 
Performance status 
Planning target volume 
Serious adverse event 
Squamous cell carcinoma 
Tumor-infiltrating lymphocytes 
Thyroid stimulating hormone 
Upper limit of normal 
University of Wisconsin Carbone Cancer Center 
Versican 
Volumetric Modulated Arc Therapy 
 
 
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
13(65) 
EVALUATION SCHEDULE 
Pre-Operative Phase: 
Treatment Days 
Screeninga 
1 
(+/- 2 
days) 
8 
(+/- 2 
days) 
15 
(+/- 2 
days) 
22 
(+/- 2 
days) 
29 
(+/- 2 
days) 
43 
(+/- 3 
days) 
57 
(+/- 3 
days) 
71 
(+/- 7 
days) 
~80-
100 
(+/- 5 
days) 
Carboplatin (AUC2), 
Paclitaxel (50 mg/m2), IV; 
weekly 
 
x 
x 
x 
x 
x 
 
 
 
 
Radiation Therapy 
 
23 fractions, given M-F; estimated 
completion day 35  
 
 
 
 
Avelumab (10 mg/kg IV), 
Q14 days 
 
 
 
 
 
x 
x 
x 
 
 
Surgical Resection 
 
 
 
 
 
 
 
 
 
x 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
Medications 
x 
x 
 
x 
 
x 
x 
x 
x 
 
Physical exam 
x 
x 
 
x 
 
x 
x 
x 
x 
 
Vital Signsb 
x 
x 
 
x 
 
x 
x 
x 
x 
 
Lab Testsc  
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Pregnancy Testd 
x 
 
 
 
 
 
 
 
 
 
AE’s Evaluation 
 
x 
 
x 
 
x 
x 
x 
x 
 
Radiologic Evaluatione 
x 
 
 
 
 
 
 
 
x 
 
Plasma for Correlates 
 
 
 
 
 
x 
 
x 
 
 
Serum for Correlates 
 
 
 
 
 
x 
 
x 
 
 
Tissue for Correlatesf 
 
x 
 
 
 
 
 
 
 
x 
a. Screening period of 21 days. 
b. Vital signs should include blood pressure, heart rate, respirations, temperature, height and weight.  Height will be 
measured at screening visit only. 
c. During the screening period, lab tests will include complete blood count (CBC), absolute neutrophil count (ANC), 
platelets (PLT), albumin, alkaline phosphatase, total bilirubin, bicarbonate, blood urea nitrogen (BUN), calcium, 
chloride, creatinine, glucose, potassium, total protein, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), sodium, and Hepatitis B/C testing Labs done during the screening period will be used for eligibility 
determination.  On days 1, 8, 15, and 22 lab collection will include CBC, ANC, PLT, bicarbonate, BUN, chloride, 
creatinine, glucose, potassium, and sodium. On day 29, 43, 57 and 71 lab tests will include the same labs as 
performed during the screening period.  Thyroid stimulating hormone (TSH) and free T4 will be tested on days 29 
and 71 only.  
d. Urine or serum pregnancy test (women of childbearing potential) will be obtained at the time of study enrollment.  
Urine pregnancy test will also be performed at least once a month while on treatment. 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
14(65) 
e. Baseline PET/CT must be performed within 3 weeks of trial enrollment to ensure subjects have no evidence of 
metastatic disease and are eligible for participation.  While on study, subjects will undergo a restaging PET/CT ~ 1-2 
weeks after the last dose of avelumab to evaluate treatment response.   
f. Archival tissue at baseline. Some of the tissue from surgical resection will be used for correlative studies. See 
section 9.3 
Post-Operative Phase: 
 
Treatment 
Days 
0a 
1b 
(+/- 3 
days) 
15 
(+/- 3 
days) 
29 
(+/- 3 
days) 
43 
(+/- 3 
days) 
57 
(+/- 3 
days) 
71 
(+/- 3 
days) 
30-day 
Follow-
upf 
(+/- 7 days) 
Surveillanceg 
Long-
Term 
Follow-
up 
Avelumab IV 
(10 mg/kg IV), 
every 14 days 
 
x 
x 
x 
x 
x 
x 
 
 
 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Physical Exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vital Signsc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Lab Testsd  
 
x 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy Testi 
 
x 
 
 
 
 
 
 
 
 
AE’s Evaluation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Radiologic 
Evaluatione 
 
x 
 
 
 
 
 
 x 
x 
 
Plasma for 
Correlates  
 
x 
 
 
 
 
x 
 
xh 
 
Serum for 
Correlates 
 
x 
 
 
 
 
x 
 
xh 
 
Survivalg 
 
 
 
 
 
 
 
 
 
x 
a. This first post-operative visit should occur 2-4 weeks after surgical resection, unless there are complications that 
delay this follow-up appointment. 
b. Avelumab treatment should begin within 12 weeks after the surgical resection. It can begin as early as it is deemed 
to be safe from the standpoint of surgical recovery in the opinion of the treating physician. Avelumab will be 
continued for a total of ~ 3 months (i.e. for three 28 day cycles or 6 doses every 14 days) post-operatively.  
c. Vital signs should include blood pressure, heart rate, respirations, temperature, and weight. Height required at day 
0.    
d. Prior to each post-operative avelumab treatment, labs will include CBC, ANC, PLT, albumin, alkaline 
phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, 
ALT, sodium.  TSH and free T4 will be checked on day 1 and day 57.  Labs during follow-up visit (~ 30 days after 
adjuvant therapy completion) will include the same labs as on day 1 of adjuvant avelumab treatment initiation.  
e. A new baseline CT of chest without contrast, and CT abdomen and pelvis with contrast will be obtained within 2 
weeks prior to the first dose of adjuvant avelumab administration.  The first surveillance scan (CT of chest, abdomen 
and pelvis) will be obtained within 7 days prior to the visit at 30 days post last dose of adjuvant treatment.  
f. Follow-up visit will occur ~30 days after last dose of adjuvant treatment. At ~90 days after last dose of avelumab 
treatment, patients will be contacted via telephone to assess for any delayed immune-related toxicities. If there are 
any signals of such toxicities, a clinic visit will be scheduled for a more detailed assessment by the study physician. 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
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g. Subjects will be followed with active surveillance while on trial for 12 months after the completion of all planned 
treatments (calculated from 14 days after last dose of adjuvant treatment).  Subjects will have clinic visits 
approximately every 16 weeks (+/- 14 days) after the first post-treatment radiological evaluation.  Surveillance scans 
(CT of chest, abdomen, and pelvis) will be obtained approximately every 16 weeks, starting after the completion of 
all adjuvant therapy, during the 12 months of surveillance while on the study.  After final surveillance visit at 12 
months post adjuvant therapy completion, patients will be followed per discretion of their treating provider.  
Survival and disease status data will be collected over a time period of up to 3 years from medical records and phone 
interviews.  Labs are not mandatory during surveillance visits, but labs may be obtained as clinically indicated in the 
opinion of the treating physician.  
h. Final correlative blood samples will be drawn at last planned surveillance visit ~ 12 months after adjuvant therapy 
completion (completion = 14 days after last dose).  
i. Urine pregnancy test will be performed prior to start of adjuvant treatment and at least once a month while on 
treatment. 
1. 
BACKGROUND AND RATIONALE 
1.1 
Esophageal Cancer 
Esophageal cancer is a major health problem in the world.  In Western countries, lower 
esophagus is the most common site for esophageal cancers, and these tumors frequently involve 
gastroesophageal junction (GEJ).  There are two major histological subtypes of esophageal 
cancer: squamous carcinoma and adenocarcinoma.  Although the incidence of squamous cell 
esophageal cancer has been declining, esophageal adenocarcinoma has one of the fastest growing 
incidence among solid tumors in the Western world.  Esophageal adenocarcinoma is more 
common in males, but over the last few decades its rates among women have been increasing as 
well 1.  Tobacco and alcohol abuse are major risk factors for esophageal SCC, while obesity and 
gastroesophageal reflux disease (GERD) predispose to the development of esophageal 
adenocarcinoma.  The majority of patients are diagnosed with at least stage II disease, which 
requires multimodality therapy.  Despite aggressive treatments of potentially curative esophageal 
cancer, about 50% of patients ultimately developed recurrent disease 2.  Further treatment 
strategies are needed to improve recurrence free survival in this patient population since 
metastatic esophageal cancer is universally fatal with current treatment options.   
1.2 
Current Treatment Paradigm of Resectable Esophageal Cancer. 
Trimodality therapy is the standard approach in the treatment of resectable stage II or higher 
esophageal cancer.  This method is based on the results of a large randomized clinical trial 
(CROSS) that demonstrated superior survival in patients receiving neoadjuvant 
chemoradiotherapy followed by surgical resection compared to patients treated with surgery 
alone 2,3.  In this trial, subjects with trimodality arm were treated concurrent chemoradiation that 
consisted of weekly radiosensitizing carboplatin (AUC 2) and paclitaxel (50 mg/m2) for 5 weeks 
along with daily radiation for a total dose of 41 Gray (Gy) in 23 fractions 3. This treatment was 
well tolerated.  Over 90% of patients received all scheduled treatments, and there was no 
increase in postoperative complications.  Neoadjuvant therapy resulted in higher rates of R0 
resection and lower rates of lymph node involvement in resected specimen compared to the 
control arm.  Pathological complete response was see in 29% of patients (23% for 
adenocarcinomas and 49% for SCC) 3.  Pathological complete response at the time of resection 
is strongly linked to better survival.  CROSS trial demonstrated superior survival in patients 


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treated with trimodality therapy.  However, with current strategies pathological complete 
response is achieved in a minority of patients.  The remaining patients, especially those with 
positive lymph nodes at the time of the resection, are at significant risk for recurrences.  Five-
year survival rate for these patients is only 37%, and overall survival is as low as 9 months for 
those with persistent lymph node disease at the time of resection 4,5.  Among patients who 
develop recurrent disease, most present with distant metastases outside of the radiation field 6.  
This is not surprising since the accepted treatment paradigm for this disease does not target 
possible disseminated microscopic disease present at the time of diagnosis.  Utilized 
chemotherapy regimen serves primarily as a radiation sensitizer and has limited activity outside 
of the radiation field.  Prolonged recovery after extensive surgery makes it challenging for many 
patients to receive additional therapies in post-operative settings.  In a similar patient population 
with resectable gastric cancer treated with peri-operative chemotherapy, less than 50% of 
patients were able to receive all planned post-operative treatments 7.  In May 2021, adjuvant 
nivolumab was approved in adjuvant setting, This approval was based on the results from 
randomized phase 3 trial that enrolled patients with resectable esophageal and GEJ cancers 
treated with preoperative chemoradiation per CROSS and who had residual disease at the time of 
resection. The benefits were most pronounced in patients with SCC.  \These results suggest that 
novel strategies that involve immunotherapy are warranted to improve outcomes in patients with 
upper gastrointestinal (UGI) malignancies.   
1.3 
Immunotherapy in the Treatment of Gastroesophageal Cancers 
Programmed death ligand 1(PD-L1) is a transmembrane protein that is expressed in about 40% 
of UGI tumors.  PDL1 is one of the ligands for programmed death 1 (PD-1), which is an 
inhibitory receptor that belongs to the CD28-B7 family. Binding to PD1 results in down 
regulation of the T cell immune response allowing PDL1 positive tumors to evade immune 
mediated cell death.  PDL1 expression has been shown to be associated with greater depth of 
muscle invasion, the presence of lymph node metastasis, and overall worse prognosis8,9.  A 
number of immunotherapy agents have demonstrated activity against metastatic 
gastroesophageal cancers.  Nivolumab, an antibody that blocks PD1 receptor, is not approved in 
combination with chemotherapy for patients with untreated advanced gastric, esophageal and 
GEJ adenocarcinoma based on the results of phase 3 trial Checkmate 649 11.  Pembrolizumab 
(another anti PD1 antibody) is approved in combination with chemotherapy in the 1st line 
treatment of advanced esophageal cancer based on the results of phase 4 Keynote 590 trial.  Both 
of these agents have also demonstrated activity in more advanced setting in biomarker defined 
patient population 12,13. Avelumab has been found to have encouraging results in this disease 
when looking at biomarker defined patient population 14. Most recently, nivolumab was 
approved in the adjuvant setting after resection of esophageal and GEJ cancers treated with 
preoperative chemoradiation and who had residual disease at the time of resection 16. 
1.4 
Avelumab 
 Pharmacology and Pre-Clinical Data 
Avelumab is a full human antibody of the immunoglobulin G 1 isotype that specifically targets 
and blocks programmed death ligand 1 (PD-L1), the ligand for program death 1 (PD-1) receptor. 
The nonclinical pharmacology studies have shown that avelumab functionally enhances T cell 


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activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors in vivo 
resulting in the restoration of cytotoxic T cell response. Avelumab binds to human PD-L1 with a 
high affinity of 0.7 nM and not to any other B7 family proteins, and competitively blocks the 
interaction of PD-L1 with PD-1. The in vitro study results have shown that by binding to PD-L1, 
avelumab effectively enhances T cell activation as measured by interleukin (IL)-2 or interferon-
gamma (IFN-ᵞ production.  In addition, as a fully human IgG1 antibody, avelumab has the 
potential to trigger the antibody-dependent cell-mediated cytotoxicity (ADCC) against target 
cells expressing PD-L1.  In pre-clinical studies, avelumab has demonstrated anti-tumor activity 
against murine MC38 colon carcinoma tumors that are characterized by a high level of PD-L1 
expression. The combination of avelumab with commonly used cancer treatments, such as 
cytotoxic agents and radiation therapy, resulted in an improved anti-tumor activity.  Radiation 
therapy in particular was found to be a highly synergistic with avelumab; this treated resulted in 
complete regression of established tumors probably through generating anti-tumor immune 
memory. 
 Clinical Experience with Avelumab  
There are a number of ongoing Phase 1, 2, and 3 clinical trials evaluating avelumab in the 
treatment of different malignancies. Avelumab has been studied for its activity in gastric and 
esophageal cancer.  In a Phase 1B trial presented at ASCO 2016 meeting, avelumab was 
explored for its activity against gastroesophageal cancer. In this early trial avelumab treatment 
resulted in 15% RR in patients who have progressed on standard chemotherapy 15. Avelumab is 
currently being investigated in a randomized trial in similar setting, as well as for its role as 
maintenance therapy in metastatic disease.  The safety for avelumab is based on 1300 subjects 
treated across different trials.  Most of the observed adverse events (AEs) were either in line with 
those expected in subjects with advanced solid tumors or with class effects of monoclonal 
antibodies (MoAbs) blocking the PD-1/PD-L1 axis.  In addition, infusion-related reactions 
including drug hypersensitivity reactions and immune-mediated adverse reactions have been 
identified as important risks for avelumab.  Respective risk mitigation measures have been 
implemented in all ongoing clinical studies with avelumab. 
1.5 
Rationale for Adding Avelumab to Neoadjuvant Chemoradiation. 
A number of preclinical and clinical studies demonstrated synergism between radiation and 
immunotherapy, suggesting that combining these approaches can enhance anti-tumor activity 
and increase treatment efficacy 17-19. Local radiotherapy is thought to induce an 
immunostimulatory form of cell death via activation of multiple pro-inflammatory pathways 
and induction of changes in tumor microenvironment 19.  Although radiation induces 
chemokines that promote recruitment of effector CD8 cell and T-helper CD4 cells, it has also 
been shown to induce local upregulation of the PD-L1, which blocks antitumor immunity 18,20,21.  
In esophageal cancers, neoadjuvant chemoradiation has been shown to upregulate PDL1 
expression by over 50% compared to pre-treatment baseline 22. In preclinical models, 
combination of radiation with immune checkpoint inhibitors demonstrated impressive 
synergism 17,21.  In clinical practice, treatment with ipilimumab or granulocyte–macrophage 
colony-stimulating factor has been shown to increase the incidence of abscopal events in 
patients with melanoma 23.  There a number of ongoing clinical trials evaluating synergism 
between in radiation and immunotherapy in other disease types, including lung cancer, 


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melanoma, and other solid tumors (clinicatrials.gov).  Hence, given the fact that a number of 
immune checkpoint inhibitors have demonstrated promising activity in a subset of patients with 
metastatic esophageal and gastric cancers, moving these agents into neoadjuvant setting and 
combining with chemoradiation may increase the cure rate of this disease 24.  This approach 
takes advantage of the discussed synergism between immunotherapy and radiation.  In addition, 
immunotherapy treatment will target both local and systemic disease, which is not addressed 
with the current treatment paradigm.  
 
1.6 
Benefit/Risk and Ethical Assessment 
Based on current clinical experience with immunotherapy in metastatic setting, we hypothesize 
that adding avelumab to the neoadjuvant therapy can increase cure rate in some patients with this 
disease.  Although increased toxicities may be seen when avelumab is combined with 
chemoradiation, we anticipate that overall the proposed regimen will be tolerable and will 
provide additional efficacy for a patient population with significant recurrence rates using current 
treatment strategies. This clinical trial is designed to avoid compromises to standard neoadjuvant 
therapy in the studied patient population.  In addition, a run-in phase is built in to ensure there is 
appropriate safety evaluation of the proposed treatment. No new safety signal were seen during 
evaluation of toxicities after the first 6 patients enrolled in this trial.  If this study has promising 
results, future trials may also explore the use of this approach in larger randomized trials. 
2. 
STUDY OBJECTIVES/ENDPOINTS 
2.1 
Part 1 
The primary objective of part 1 of the trial is to evaluate the safety of avelumab when combined 
with chemoradiation in the treatment of resectable E/GEJ cancer. 
 
2.2 
Part 2 
Part 2 will further evaluate the safety and tolerability of the studied drug combination.  It will 
also study activity of avelumab in combination with neoadjuvant chemoradiation in the treatment 
of resectable E/GEJ cancer. 
Primary Endpoint: 
 Pathologic complete response (pCR) rate. 
 
Secondary Endpoints: 
 Safety and tolerability. 
 Disease free survival. 
 Incidence of surgical complications. 
 Rate of R0 resection. 


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3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall Study Design 
The study is a two-part phase 1/2 clinical trial conducted in one center.  Part 1 is a run-in phase 
with the objective to assess the safety and tolerability of avelumab in combination with 
chemoradiation.  Adjuvant avelumab treatment will not be included in DLT evaluation.  Part 1 
will enroll 6 patients, after which further accrual will be stopped temporarily while safety data is 
being obtained.  The second part of the trial will be an open-label phase 2 study.  Part 2 will 
obtain further safety data of the proposed drug combination and will evaluate the anti-tumor 
efficacy of perioperative avelumab and chemoradiation in this patient population.  Part 2 of the 
trial will enroll 18 additional patients.   
The study will consist of 3 parts: a 21 day screening period, treatment procedures (neoadjuvant 
therapy, resection and adjuvant therapy), active surveillance for a year after the completion of 
adjuvant therapy.  After the final planned active surveillance visit at 12 months post treatment 
completion, survival data and disease status will be collected via phone calls or medical record 
review every 6 months during the following 3 years.   
3.2 
Part 1: Run-In Phase 
Six patients will be enrolled in the run-in phase. The goal of this part is to establish safety and 
tolerability of avelumab when used in combination with chemoradiation.    Safety evaluation will 
last until the first post-operative clinic visit at about 2-4 weeks after resection.  Trial enrollment 
will resume after at least 5 patients do not have a DLT during the DLT evaluation period or until 
all 6 patients are seen for post-operative evaluation.  Subjects during the run-in phase will be 
allowed to proceed with adjuvant avelumab therapy while DLT evaluations on other subjects are 
ongoing.  If 2 or more patients experience dose-limiting toxicities (DLT) associated with the 
proposed treatments, further accrual of the subjects will be halted and trial will be suspended.  
Trial may be reopened in the future with appropriate schedule and dose modifications of the 
proposed treatment.  
 Definitions of Dose-Limiting Toxicities  
For the purposes of this trial DLT will be defined as an adverse event (AE) that occurs after 
avelumab administration during preoperative period that is clinically significant and/or 
unacceptable, and is judged to be a related to the avelumab treatment by the investigator.  DLT 
evaluations will occur only during the first part of the trial.  Common Terminology Criteria for 
Adverse Events (CTCAE) v 5.0 will be used in DLT definition. 
Definition of DLTs: 
 Any complication directly related to neoadjuvant therapy with avelumab that results in 
the delay in surgical resection, such that resection occurs more than 10 weeks post 
chemoradiation completion. 
 Any complications from neoadjuvant therapy that precludes surgical resection. Disease 
progression that prevents surgical resection is not considered a DLT. Medical 
comorbidities that are not related to neoadjuvant therapy in the opinion of the 
investigator, but which preclude safe surgical resection, are not considered a DLT.  


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 Any grade 3 immune mediated event (with the exception of esophagitis) that fails to 
resolve with treatment interruption and systemic steroid administration (if needed) prior 
to surgical resection. 
 Any grade 4 treatment related non-hematologic toxicities excluding alopecia. 
 Any avelumab related toxicity that prevents completion of at least 2 of the 3 planned 
doses in neoadjuvant setting.  
3.3 
Part 2: Expansion Cohort 
The second part of the trial will enroll 18 additional patients to evaluate activity of the proposed 
treatment and to obtain further safety information.  
3.4 
Post-Treatment Surveillance 
All patients treated on this study will be followed with active surveillance for 1 year after all 
planned treatment completion while on protocol. Active surveillance will include clinic visit 
every 16 weeks and surveillance CT of chest, abdomen and pelvis every 16 weeks during the 
first year after the treatment completion.  Clinic visits and scans can be performed more 
frequently if clinically indicated.  During surveillance visits, labs will be performed only if 
clinically indicated.  Additional procedures, such as endoscopy should be performed as clinically 
indicated.  After the study is completed at 1 year post the completion of adjuvant therapy, active 
surveillance will be continued per discretion of the treating physician.  Surveillance tests after 1 
year will not be mandated by the protocol.  Survival data and disease status will be collected 
from either patients or treating physicians every 6 months for up to 3 years after the study 
completion.   
3.5 
Rationale for Study Design and Doses 
The study will use previously established doses of carboplatin and paclitaxel when used in 
combination with radiation in neoadjuvant setting for the treatment of E/GEJ cancer. This 
treatment paradigm was established based on the on randomized phase III trial evaluating this 
approach 3.  Avelumab will be administered at its standard dose of 10 mg/kg IV every 2 weeks. 
During pre-operative period, three doses of avelumab will be administered starting on day 29 of 
treatment.  It will be started on the same day as the last (fifth) chemotherapy infusion. The 
schedule of avelumab administration was chosen to optimize the synergism between 
chemoradiation and immunotherapy, but also to avoid any compromise to the standard of care 
chemoradiation administered to this patient population.  A total of 3 months (6 treatments every 
2 weeks) of adjuvant avelumab will be administered post-operatively.  Additional avelumab 
treatments were built into the protocol to maximize potential benefits of avelumab on systemic 
recurrences.  Three months duration was chosen to mimic perioperative gastric cancer treatment 
standards, where 9 weeks of preoperative and 9 weeks post-operative chemotherapy is typically 
recommended based on MAGIC trial 7. Similar to this approach, with the proposed treatment 
schema patients will receive a total of 18 weeks of avelumab.  


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4. 
PATIENT SELECTION CRITERIA 
4.1 
Study Population 
This study will enroll patients with stage II/III E/GEJ cancer who are candidates for neoadjuvant 
therapy and surgical resection with curative intent. 
4.2 
Inclusion Criteria 
1. Patients with histologically confirmed, potentially curable squamous-cell carcinoma, 
adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and GEJ 
(Siewert type 1-3). 
2. Locoregional disease with clinical stage of T1N1 or T2-3N0-2. 
3. No clinical evidence of metastatic spread. Staging should include endoscopic ultrasound 
and PET/CT as recommended by NCCN guidelines. PET/CT should be performed within 
3 weeks of signing informed consent. 
4. Age 18 years or older. 
5. ECOG performance status 0-2. 
6. Subjects must be deemed to be potential surgical candidates by an evaluating surgeon. 
7. Adequate organ function: 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. Hemoglobin ≥ 9 g/dL (transfusions allowed) 
c. Platelets ≥ 100 x 109/L 
d. AST/ALT ≤  2.5 x ULN  
e. Total serum bilirubin of ≤1.5 x institutional upper limit of normal (ULN)  
f. Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault 
formula  
8. Female patients of childbearing potential must have a negative pregnancy test (urine or 
serum) within 21 days prior to the start of the study drug treatment and must agree to use 
adequate birth control if conception is possible during the study and up to 30 days after 
the completion of adjuvant therapy.  
9. Male patients must agree to use adequate birth control during the study and up to 30 days 
after the last avelumab dose.  
10. Women who are nursing must discontinue breast-feeding prior to the enrollment in the 
trial. 
11. Patient must be able and willing to comply with study procedures as per protocol. 
12. Patient able to understand and willing to sign and date the written voluntary informed 
consent form (ICF) at screening visit prior to any protocol-specific procedures. 
 


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4.3 
Exclusion Criteria 
1. Prior history of radiation to the mediastinum. 
2. Diagnosis of cervical esophageal carcinoma. 
3. Other active malignancy within the last 3 years (except for non-melanoma skin cancer, a 
non-invasive/in situ cancer, or indolent non metastatic Gleason 6 prostate cancer). 
4. Subjects with an active or known autoimmune disease. Subjects with type I diabetes 
mellitus, hypo- or hyperthyroidism only requiring hormone replacement/suppression, 
skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
immunosuppressive treatment are eligible. 
5. Current use of immunosuppressive medication, except for the following:  
a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection) 
b. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or 
equivalent  
c.  Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
6. Active infection requiring systemic therapy at the time of study treatment initiation. 
7. Prior organ transplantation including allogenic stem-cell transplantation. 
8. Known history of testing positive for HIV or known immunodeficiency syndrome 
9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test positive) 
10. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited 
except for administration of inactivated vaccines.. 
11. Major surgery within prior 4 weeks of treatment initiation (the surgical incision should be 
fully healed prior to all neoadjuvant treatment initiation). 
12. Any prior anticancer therapy for esophageal cancer. 
13. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to carboplatin, paclitaxel or avelumab, including known severe 
hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3). 
14. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior 
to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association 
Classification Class II), or serious cardiac arrhythmia requiring medication. Patients with 
stable rate-controlled atrial fibrillation will be allowed to participate. 
 


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15. Other severe acute or chronic medical conditions including  immune colitis, 
inflammatory bowel disease,  immune pneumonitis, pulmonary fibrosis or psychiatric 
conditions including recent (within the past year) or active suicidal ideation or behavior; 
or laboratory abnormalities that may increase the risk associated with study participation 
or study treatment administration or may interfere with the interpretation of study results 
and, in the judgment of the investigator, would make the patient inappropriate for entry 
into this study 
16. Psychological, familial, or sociological condition potentially hampering compliance with 
the study protocol and follow-up schedule.  
4.4 
Replacement Criteria 
 In Part 1 of the study, patients who discontinue the study due to a DLT will not be 
replaced. 
 Patients who discontinue the study prior to receiving any avelumab doses will be 
replaced in parts 1 and 2 of the study.   
 Patients who are not taken to surgery because of issues unrelated to neoadjuvant 
therapy (such as undiagnosed prior comorbidities, patient preference) will be replaced 
in parts 1 and 2.  
 Patients who develop progressive disease after avelumab has been started will not be 
replaced.   
5. 
TREATMENTS 
All patients will receive weekly carboplatin and paclitaxel while undergoing radiation therapy.  
Chemotherapy will be started on day 1 of radiation and will be given every 7 days. A total of 5 
planned weekly chemotherapy treatments will be administered during the course of the study.  
Radiation will be administered Monday – Friday until the planned course is completed.  
Avelumab will be given every two weeks starting on the same day as the last chemotherapy 
infusion (day 29).  If the last dose of chemotherapy is omitted due to cytopenias, avelumab will 
still be administered as originally planned.  Avelumab will be continued after radiation is 
completed. A total of 3 doses of avelumab will be administered during the preoperative period.  
Additional 6 doses of avelumab will be administered post-operatively.  
5.1 
Chemotherapy Administration 
Paclitaxel 50 mg/m2 and Carboplatin (AUC 2) will be given via intravenous infusion on days 1, 
8, 15, 22 and 29.  Standard of care procedures and institutional guidelines will be followed 
during the administration of these agents. Detailed information about carboplatin and paclitaxel 
can be obtained from drug package inserts. 
Patients who start treatment with paclitaxel are at risk for hypersensitivity reaction (HSR).  All 
patients should be premedicated prior to paclitaxel administration in order to prevent severe 
HSRs.  Premedication regimen will consist of dexamethasone 12 and 6 hours before treatment, 


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diphenhydramine (or its equivalent) 50 mg IV 30 minutes prior to chemotherapy, and ranitidine 
50 mg IV 30 minutes prior to chemotherapy. Oral dexamethasone doses will be 20 mg before 
day 1 treatment, 12 mg before day 8 treatment, and 8 mg before day 15 treatment.  Patients who 
do not take dexamethasone at home will receive IV dexamethasone before paclitaxel infusion: 20 
mg IV prior to day 1 treatment and 8 mg IV before day 8 and day 15 of treatment.  Patients who 
do not experience hypersensitivity reaction during the first 3 paclitaxel infusions with the above 
premedication regimen will be asked to stop further premedication with dexamethasone during 
subsequent treatments since their risk for subsequent significant HSR is very low 25. This change 
in premedication is done to prevent any potential counteractivity of the steroids with 
immunotherapy. These patients will continue to receive diphenhydramine and ranitidine.  
Dexamethasone can be reinstituted as needed if HSR were to develop.  Subjects can continue 
with the study protocol even if dexamethasone is required for premedication prior to 
chemotherapy infusion.  
5.2 
Avelumab Administration 
 Dosing and Administration of Avelumab 
Avelumab 10mg/kg will be administered intravenously every 2 weeks for 3 doses prior to 
surgery and for 6 doses as adjuvant treatment postoperatively.  Avelumab dose will be adjusted 
accordingly if subject’s weight changes more than 10% compared to prior treatment or baseline.  
A new baseline weight will be obtained prior to the first post-operative avelumab dose 
administration.  In order to mitigate infusion related reactions, a premedication with an 
antihistamine and with paracetamol (acetaminophen) 30 to 60 minutes prior to the first 4 
infusions of avelumab is mandatory (for example, 25-50 mg diphenhydramine (IV or oral) and 
500-650 mg acetaminophen.  Premedication should be administered for subsequent avelumab 
infusions based upon clinical judgment and presence/severity of prior infusion reactions. This 
may be modified based on local treatment standards and guidelines, as appropriate.   
Avelumab will be diluted in Sodium Chloride 0.9% 250mL and infused IV over 60 minutes (-
10/+20 minutes) via a 0.2 micron in line filter. Immediately following the infusion of avelumab, 
it is recommended (but not mandatory) to conduct a normal saline flush using the same tubing 
and 25-100 mL normal saline infused at the same rate to clear the infusion set of residual drug. 
Avelumab should be administered in a setting that allows for immediate access to an intensive 
care unit or equivalent environment and administration of therapy for anaphylaxis, such as the 
ability to implement immediate resuscitation measures.  Steroids (dexamethasone 10 mg), 
epinephrine (1:1,000 dilution), antihistamines, bronchodilators, or equivalents, and oxygen 
should be available for immediate access along with equipment for assisted ventilation.  
Following the avelumab infusion, patients must be observed for 30 minutes post infusion for 
potential infusion related reactions. 
 Packaging, Labeling, Storing and Preparation 
Avelumab is provided by EMD Serono in a form of a sterile, clear, colorless and non-pyrogenic 
solution for intravenous infusion.  It will be presented in Type I glass vials filled with 10 mL of 
liquid (200 mg/vial), closed with a rubber septum and sealed with an aluminum flip off seal. 


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Each single-use vial contains 200 mg of avelumab, formulated as a 20 mg/mL preservative-free 
acetate buffered solution at pH 5.2 in presence of Polysorbate 20 and Mannitol.  This product 
will require further dilution prior to IV infusion.  Vials must be stored under refrigeration at 
(2ºC-8ºC) in an environment with temperature control devices.  Temperatures must be recorded 
on a daily basis.  Vials must not be stored at room temperature, frozen or shaken vigorously. 
Vials must be warmed up to room temperature by removal from the refrigerator for 30 (+20) 
minutes before preparing each dose.  Avelumab infusion solution should be prepared by dilution 
in 0.9% Sodium Chloride (Normal Saline) (or in 0.45% Sodium Chloride, only if the first option 
is not applicable). The verified avelumab concentration range in the infusion solution is 0.016 
mg/mL to 8 mg/mL.  Any unused portion of the solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and institutional procedures. 
 Avelumab Product Accountability 
Avelumab must not be used for any purpose other than this clinical trial.  The administration of 
trial drug to subjects who have not been enrolled is considered a protocol deviation.  
Rigorous drug accountability will be maintained at all times and will include (at minimum) the 
following information: record of product receipt, perpetual inventory (including batch/lot 
number and quantity), subject dosing and utilization, and disposal.  All clinical study drug 
provided by EMD Serono will be fully reconciled and any unused vials will be either returned to 
the EMD Serono or destroyed after trial completion with required documentation.   
5.3 
Radiation Therapy 
The radiation will be administered concurrently with the chemotherapy.  Both 3-D conformal 
radiotherapy (3D-CRT) and intensity modulated radiotherapy (IMRT) will be allowed.  The 
IMRT may be delivered with either conventional IMRT, Volumetric Modulated Arc Therapy 
(VMAT) or helical IMRT (tomotherapy).  
 Dose Specification 
The planned total dose will be 41.4 Gray (Gy) in 23 fractions at 1.80 Gy/day.  Patients will be 
treated 5 days/week; patients will receive the 41.4 Gy over an approximately 4-1/2-week period.  
The daily prescription dose will be to the selected isodose curve, 95% of which must encompass 
the entire planning target volume (PTV).   
 Volume Definitions 
Gross tumor volume (GTV) will include all FDG avid regions by PET/CT or areas of 
involvement identified by EUS or CT (whichever is larger).  Clinical tumor volume (CTV) 
consists of a minimum of 4 cm proximal and distal and 1 cm lateral beyond the GTV of the 
primary tumor. In addition, involved regional lymph nodes will have a ≥ 1 cm CTV in all 
dimensions, and the involved nodal region can be included at the physician’s discretion. CTVs 
may be edited off of uninvolved normal tissues. 
 


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Version 7, 07/05/2021 
 
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PTV will provide a margin around the CTV to compensate for variability in treatment setup, 
breathing, or motion during treatment.  A margin around the CTV will define the PTV.  The PTV 
volume must include a minimum of 0.3 cm and a maximum of 2 cm around the CTV. Margins 
can be adjusted as necessary to avoid excessive normal organ exposure, as defined in section 
5.2.5.  Use of cross-sectional imaging based image-guided radiotherapy (IGRT) may further 
limit PTV volume. 
 Treatment Planning 
A PET and CT scan (preferably a PET/CT) for diagnosis and volumetric treatment planning is 
required.  Planning and treatment will be performed with the patient in supine position with body 
immobilization.  Treatment will be given free breathing or at breath hold with gating per the 
treating physician’s discretion. Three mm or smaller CT slices will be obtained from the thoracic 
inlet to the mid-abdomen as part of the PET/CT.  A 4D CT simulation may be obtained to 
evaluate internal target motion and create an internal target volume (ITV) for better definition of 
PTV margins.  All plans will be limited to the dose constraints as described below.  
The spinal cord, liver, lung, and heart will be contoured in their entirety.  The lungs, heart, spinal 
cord, and liver will be the considered the primary dose-limiting structures.  When planning the 
beam arrangement to the PTV, the lungs, heart, spinal cord, and liver should be out of the field to 
the greatest extent possible.  The dose per fraction to the lungs, heart, and spinal cord should be 
maintained at 2 Gy or less per fraction to the greatest extent possible.  If tolerance dose to any of 
the normal organs is exceeded in a treatment plan, alternate beam arrangements should be used. 
Maximum dose to the PTV should not exceed the prescription dose by >10 %. The maximum 
point dose to critical normal structures outside the PTV including the unspecified tissue should 
not exceed the prescription dose. The treating physician must carefully consider the tolerance 
dose/volume to each critical normal structure and unspecified tissue. 
5.3.3.1 
Critical structures 
 Spinal cord dose will be limited to < 0.1 cc of the cord receiving ≥ 40.0 Gy.   
 Heart:  Heart mean dose of < 25 Gy.  
 Liver:  mean liver dose not to exceed 25 Gy. 
 Lung:  the volume(V) of lung outside of the PTV that receives 20 Gy will be limited to < 
30% (V 20 < 30%). Mean lung dose < 18 Gy. 
 Kidney:  combined kidneys V 20<33%, each individual kidney V 20<50%. 
 Quality Control 
Dose heterogeneity:  Maximum dose to PTV should not exceed the prescription dose by > 10%. 
The maximum point dose to critical normal structures outside the PTV including the unspecified 
tissue should not exceed the prescription dose.  The treating physician must carefully consider 
the tolerance dose/volume to each critical normal structure and unspecified tissue. 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
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 Treatment Verification 
First day portal, CT or MRI images of each field must be obtained for position verification.  At 
least once weekly verification films or images will be obtained per institutional guidelines.  For 
IMRT or PTV margins of less than 5mm, daily 3D imaging is required. 
 External Beam Equipment 
Mega-voltage radiation therapy will be used.  IMRT treatment planning and delivery, including 
with tomotherapy, can be used in lieu of 3D conformal planning as described above. 
5.4 
Surgical Resection 
Surgical resection will be performed ~8 weeks after the completion of chemoradiation.  The most 
appropriate surgical intervention will be chosen by the operating surgeon.  Resected specimen 
will be evaluated in our pathology department for any residual disease and treatment effect.  Part 
of the resected specimen will also be evaluated in Dr. Deming’s research laboratory for 
correlative biomarkers.   
5.5 
Concomitant and post-study treatment(s) 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient from ≤ 7 days prior to the first day of neoadjuvant treatment initiation to the 
end of treatment visit.  All concomitant therapy, including anesthetic agents, vitamins, 
homeopathic/herbal remedies, nutritional supplements, will be recorded during the screening and 
treatment period, starting from the date of signature of informed consent, and ending at follow up 
visit.  Vaccination with live vaccines within 4 weeks of the first dose of avelumab and while on 
trial is prohibited. 
5.6 
Restrictions During the Study 
 Administration of Other Anti-Cancer Agents 
Administration of anti-cancer agents other than those specified in the protocol is not allowed 
during study enrolment.  
 Immunosuppressive Agents 
The use of immunosuppressive agents is prohibited during the treatment with avelumab and until 
surgical resection, including immunosuppressive doses of systemic corticosteroids.  Subjects will 
be allowed to use topical, ocular, intra-articular, intranasal and inhalational corticosteroids (with 
minimal systemic absorption).  Physiologic replacement doses of systemic corticosteroids are 
permitted at doses of ≤ 10 mg of daily prednisone (or equivalent). A brief course of 
corticosteroids for prophylaxis (e.g., for contrast dye allergy or to prevent taxane related 
hypersensitivity reaction) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted.  However, it is preferable 
that steroid premedication is reduced or omitted by week 22 of treatment if no hypersensitivity 
reaction with taxanes has been observed during prior weeks.  
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
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 Pregnancy and Contraception 
All patients must be made fully aware of the information relating to the potential for 
reproductive toxicity as detailed in the Informed Consent Form.  Patients of child bearing 
potential and their partners, who are sexually active, must agree to the use of two highly effective 
forms of contraception throughout their participation in the study and for 30 days after the 
completion of the adjuvant therapy. 
Women of childbearing potential 
Females of childbearing potential should use reliable methods of contraception from the time of 
screening until 30 days post the completion of adjuvant therapy.  Acceptable methods of 
contraception include tubal ligation, oral, transdermal or intra-vaginal hormonal contraceptives, 
medroxyprogesterone injections (e.g,. Depo-Provera), copper-banded intra-uterine devices, 
hormone impregnated intra-uterine systems and vasectomised partners.  All methods of 
contraception should be used in combination with the use of a condom by their male sexual 
partner for intercourse. 
Males 
Male patients must use a condom during sexual intercourse with female sexual partners 
including a pregnant partner during the study and for 30 days after the completion of adjuvant 
therapy.  Male patients should avoid procreation during the trial and for 30 days after the 
completion of adjuvant therapy. 
6. 
STUDY PROCEDURES. 
Patients who are eligible for the study will be enrolled in the clinical trial after they provide 
informed consent for study participation.  There will be no randomization in this trial.  This is an 
open label trial.   
6.1 
Visit Schedule and Assessments  
Screening Visit (within 21 days of treatment initiation): 
 
Review eligibility criteria 
 
Demographic data  
 
Review cancer history 
 
Review past medical history and surgical history  
 
Vital Signs (weight, height, blood pressure, heart rate, temperature) 
 
ECOG performance status determination (Appendix B) 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Medication reconciliation 
 
Lab work: CBC, ANC, PLT, albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT, sodium, Hepatitis B/C testing  
 
Obtain informed consent for trial enrollment  


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
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Days 1, 8, 15, 22 (+/- 2 days): 
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation (day 1 and 15 only) 
 
ECOG performance status determination (day 1 and 15 only) 
 
Complete physical examination (on days 1 and 15 only); complete neurological exam 
is not required unless clinically indicated 
 
Review occurrence or change of existing conditions (day 1 and 15 only) 
 
Review adverse events 
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
 
Lab work: CBC, ANC, PLT, bicarbonate, BUN, chloride, creatinine, glucose, 
potassium, and sodium 
 
Carboplatin and paclitaxel administration 
 
Radiation will be continued daily, Monday – Friday (excluding weekends and 
holidays) to complete a planned course 
 
Urine pregnancy test in females of childbearing potential should be performed prior 
to all treatment initiation and at least monthly during the duration of active 
perioperative treatment while on the study. Urine pregnancy test will not be 
performed on monthly basis after all the adjuvant treatment is completed. Urine 
pregnancy test will not be repeated during hospitalization for surgical resection. 
 
Day 29 (+/- 2 days): 
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation 
 
ECOG performance status determination 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Review occurrence or change of existing conditions 
 
Review adverse events that have occurred since the previous visit (starting with cycle 
2) 
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
 
Lab work: CBC, ANC, PLT, albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT, sodium, TSH, free T4 
 
Carboplatin and paclitaxel administration 
 
Avelumab administration, after chemotherapy administration is complete. 
Premedication will be repeated prior to the avelumab administration.  
 
Radiation will be continued daily, Monday – Friday (excluding weekends and 
holidays) to complete a planned course 
 
Blood draw for correlative studies 
 
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
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Day 43, 57 (+/- 3 days):  
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation 
 
ECOG performance status determination 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Review occurrence or change of existing conditions 
 
Review adverse events  
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
 
Lab work: CBC, ANC, PLT, albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT, sodium.  
 
Avelumab administration 
 
Blood draw for correlative studies (Day 57 only) 
 
Day 71 (+/- 7 days): 
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation 
 
ECOG performance status determination 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Review occurrence or change of existing conditions 
 
Review adverse events  
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
 
Lab work: CBC, ANC, PLT, albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT, sodium,TSH and free T4. 
 
Restaging PET/CT should be performed prior to this visit 
 
Day 80-100 (+/- 5 days): 
 
Surgical resection 
 
Tumor sample collected for correlative studies 
 
Post-Operative Follow-up (2-4 weeks after the surgical resection): 
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation 
 
ECOG performance status determination 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Review occurrence or change of existing conditions 


Clinical Study Protocol  
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Study Code UW17106 
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 
Review adverse events  
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
 
Adjuvant Avelumab every 2 weeks for a total of 6 doses (i.e. three 28 day cycles), starting 
within 12 weeks after surgical resection:  
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation 
 
ECOG performance status determination 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Review occurrence or change of existing conditions 
 
Review adverse events  
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
 
Lab work: CBC, ANC, PLT, albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT, sodium.  TSH and free T4 will be obtained on day 1 and day 57 of 
treatment. 
 
New baseline CT of chest, abdomen and pelvis must be obtained within two weeks 
prior to the first dose of adjuvant avelumab administration.  
 
Blood draws for correlative studies on first and last days of avelumab administration, 
pre infusion.  
 
Follow-up Visit, 30 days (+/- 7 days) after adjuvant treatment completion: 
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation 
 
ECOG performance status determination 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Review occurrence or change of existing conditions 
 
Review adverse events  
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
 
Lab work: CBC, ANC, PLT, albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT, sodium, TSH and free T4. 
 
CT of chest, abdomen and pelvis will be obtained prior to this visit. 
 
~90 days after avelumab treatment completion, patients will be contacted via 
telephone to assess for any delayed immune-related toxicities. If there are any signals 
of such toxicities, a clinic visit will be scheduled for a more detailed assessment.  
 
 


Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
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Surveillance Follow Up (every 16 weeks +/- 14 days) after adjuvant therapy completion for 
a duration of 12 months:  
 
Vital Signs (weight, blood pressure, heart rate, temperature) 
 
Medication reconciliation 
 
ECOG performance status determination 
 
Complete physical examination; complete neurological exam is not required unless 
clinically indicated 
 
Review occurrence or change of existing conditions 
 
Review adverse events  
 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit. 
 
Surveillance CT chest, abdomen and pelvis should be obtained prior to follow-up 
visits, approximately every 4 months during the first year adjuvant therapy 
completion. 
 
Labs are not required, but can be obtained as clinically indicated in the opinion of the 
treating physician. 
 
Survival Follow-Up: 
 
Subjects will be followed for survival and disease progression after completing the 
final surveillance visit.  Survival follow up should continue at least every 6 months 
for 3 years after final surveillance visit or death, whichever is sooner.  When possible, 
the following information will be obtained from subjects (via telephone is acceptable) 
or medical record (if available): 
o Disease status and date of disease progression or recurrence (if known and 
applicable) 
o Anti-cancer therapy received since end of treatment visit 
o Date of death (if applicable) 
6.2 
Radiological Evaluations 
Subjects will be required to have a restaging PET/CT about 2 weeks after the last avelumab dose 
to evaluate treatment response and to rule out progressive metastatic disease. After surgical 
resection, subjects will undergo surveillance CT of chest, abdomen and pelvis every 16 weeks 
during the first 12 months. There is no requirement for disease assessment after the end of 
treatment visit.  Subjects who stop study treatment before completion for any reason will not be 
required to follow study imaging requirements. 
6.3 
Procedures for Handling Subjects Incorrectly Enrolled or Initiated On 
Investigational Product. 
Subjects who are incorrectly enrolled in the study will be withdrawn from study participation and 
replaced.  If study treatments have been initiated, patients will be monitored for development of 
any toxicities. 


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Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
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7. 
TOXICITY MANAGEMENT 
7.1 
General Toxicity Management Guidelines  
These guidelines are applicable for toxicity management during the study duration with the 
exception of the DLT evaluation period in part 1. Any toxicity observed during the course of the 
study should be managed by interruption and/ or dose reduction of the drug if deemed 
appropriate by the Investigator. In general, any Grade 4 AE will require treatment 
discontinuation with avelumab except for single laboratory values out of normal range that are 
unlikely related to study treatment as assessed by the Investigator, do not have any clinical 
correlate, and resolve within 7 days with adequate medical management. 
7.2 
Hematologic Toxicity 
During the pre-operative phase, if on days 8, 15, 22, 29 ANC is < 1000 and PLT < 50, 
chemotherapy should not be administered and delayed by one week. On day 29, which is the last 
treatment, chemotherapy can be administered if ANC is ≥ 750.  Since bone marrow toxicity is 
not specifically associated with avelumab, avelumab can be administered even with the above 
labs.  However, avelumab should be held for grade 4 thrombocytopenia, grade 3 
thrombocytopenia with bleeding, grade 4 neutropenia or any febrile neutropenia.  The first dose 
of avelumab can be delayed up to 10 days if needed. If the last dose of chemotherapy is not given 
because of hematologic toxicity and avelumab needs to be delayed, avelumab can be started as 
soon as there is adequate bone marrow recovery.  
7.3 
Non-Hematologic Toxicity During Chemoradiation 
Any Grade ≥ 3 non-hematological treatment related toxicity (except for alopecia or esophagitis) 
during chemoradiation should result in dose delays of chemotherapy and appropriate supportive 
measures should be instituted until toxicity resolves to Grade ≤ 2.  Radiation should continue as 
planned unless toxicities are thought to be specifically radiation related and would not resolve 
without radiation interruption in the opinion of the investigator.   
Intravenous therapy and radiation can continue with ongoing grade 3 esophagitis, which can be 
seen in the setting of esophageal chemoradiation. Appropriate supportive measures should be 
initiated per institutional practice standards.  In some instances, medical support with intravenous 
hydration and parenteral nutrition may be necessary for support in order to complete the planned 
neoadjuvant treatment.  In the event of grade 4 treatment induced esophagitis all of the treatment 
should be held until esophagitis resolves to grade ≤ 3.  
If radiation has to be interrupted for toxicity, additional radiation days may be added at the end 
of the treatment.  Chemotherapy will be added as needed to match weekly radiation schedule. 
Avelumab may potentially be started after day 29, but its start date must coincide with the last 
chemotherapy infusion or be given on the day chemotherapy was planned (if chemotherapy was 
held for hematologic toxicities as detailed above).  


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Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
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7.4 
Immune-Mediated Toxicities of Avelumab 
Avelumab treatment may result in toxicities related to the activation of immune system and its 
off-target effects.  These immune-related AEs (irAEs) may be seen after the first dose or as late 
as weeks after the last dose of avelumab.   
Dose reduction of avelumab is not allowed.  Dose delays or treatment discontinuation may be 
necessary depending on the grade and timing of the AE.  If AEs require more than 2 week delay 
for the scheduled dose, then avelumab treatment must be discontinued. This does not apply to the 
first dose of avelumab in neoadjuvant setting, which may be delayed to match the last dose of 
chemotherapy.  
Any Grade 3 avelumab attributed AEs require treatment discontinuation with avelumab 
except for any of the following:  
 Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management. 
 Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to Grade ≤ 1.  
 Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test 
increase) that are unlikely related to study treatment according to the Investigator, do not 
have any clinical correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical 
management. Asymptomatic elevation of amylase or lipase do not require drug 
interruption or discontinuation, even if these lab abnormalities are thought to be related to 
avelumab. 
 Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 
 Change in ECOG PS to ≥ 3 that does not resolve to ≤ 2 within 14 days (infusions should 
not be given if the ECOG PS is ≥ 3 on the day of study drug administration). 
 Grade 3 esophagitis during neoadjuvant therapy does not necessitate treatment 
discontinuation. 
Any Grade 2 avelumab attributed AEs should be managed as follows: 
 If a Grade 2 AE resolves to Grade ≤ 1 by the next scheduled avelumab administration, 
treatment may continue. 
 If a Grade 2 AE does not resolve to Grade ≤ 1 by the next scheduled avelumab 
administration, infusions should not be given. If treatment is delayed by more than 2 
weeks, the subject should permanently discontinue treatment with avelumab (except for 
hormone insufficiencies that can be managed by replacement therapy; for these hormone 
insufficiencies, up to 2 subsequent doses may be omitted). This is not applicable to 
esophagitis during neoadjuvant phase of the treatment.  
 


Clinical Study Protocol  
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Study Code UW17106 
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 Upon the second occurrence of the same Grade 2 AE (except for hormone insufficiencies 
that can be managed by replacement therapy) in the same subject, treatment with 
avelumab has to be permanently discontinued. This is not applicable to esophagitis 
during neoadjuvant phase of the treatment.  
 No treatment interruptions/discontinuation is needed for asymptomatic elevation of 
amylase or lipase. 
For any additional immune mediated toxicities that are not listed in Table 1 below, treatment 
should be held for any AE of Grade 2 or higher until resolution down to grade 1 or 0. Treatment 
should be discontinued permanently if toxicities remain at grade 2 or above for over 2 weeks 
despite supportive measures (including steroids if needed). 
Table 1: Management of Immune-Related Adverse Events. 
GASTROINTESTINAL irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v5.0) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: increase of < 4 
stools/day over baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (for 
example, loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 4  
Grade 2 
Diarrhea:  increase of 4 to 6 
stools per day over baseline; IV 
fluids indicated < 24 hours; not 
interfering with ADL 
Colitis:  abdominal pain; blood 
in stool  
Delay avelumab therapy 
Symptomatic treatment 
If improves to Grade < 1: Resume avelumab 
therapy 
If persists > 5 to 7 days or recurs: Treat as 
Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): increase of 
≥ 7 stools per day over 
baseline; hospitalization 
indicated; limiting self care 
ADL   
Colitis (Grade 3):  severe 
abdominal pain, peritoneal 
signs. 
Grade 4:  life-threatening, 
urgent intervention indicated 
Withhold avelumab for Grade 
3. 
Permanently discontinue 
avelumab therapy for Grade 4 
or recurrent Grade 3. 
1 to 2 mg/kg/day prednisolone 
IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade < 1, then taper 
over at least 1 month; resume avelumab therapy 
following steroids taper (for initial Grade 3). 
 
If worsens, persists > 3 to 5 days, or recurs after 
improvement: 
Add infliximab 5 mg/kg (if no contraindication), 
Note: Infliximab should not be used in cases of 
perforation or sepsis  


Clinical Study Protocol  
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Study Code UW17106 
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DERMATOLOGICAL irAEs 
Grade of Rash 
(NCI-CTCAE v5.0) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Continue avelumab therapy  
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy 
Consider skin biopsy  
 
Consider 0.5 to 1 mg/kg/day prednisolone or 
oral equivalent. Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume avelumab therapy following steroids 
taper. 
If worsens: Treat as Grade 3 to 4  
Grade 3 to 4 
Covering > 30% body surface 
area; life threatening 
consequences  
Withhold avelumab for Grade 
3. 
Permanently  discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy  
Dermatology consult  
1 to 2 mg/kg/day prednisolone 
or equivalent  
Add prophylactic antibiotics 
for opportunistic infections 
If improves to < Grade 1:  
Taper steroids over at least 1 month , resume 
avelumab therapy following steroids taper (for 
initial Grade 3)  
 
 


Clinical Study Protocol  
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Study Code UW17106 
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PULMONARY irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Asymptomatic; clinical or 
diagnostic observations only, 
intervention not indicated  
Consider withholding 
avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens: Treat as Grade 2 or Grade 3 to 4  
Grade 2 
Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL 
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily, 
consider hospitalization  
1 mg/kg/day prednisolone or 
equivalent  
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade < 1, taper 
steroids over at least 1 month  
If not improving after 2 weeks or worsening: 
 or worsening:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Severe symptoms; limiting self 
care ADL; oxygen indicated ; 
life-threatening respiratory 
compromise– urgent 
intervention indicated(e.g., 
tracheotomy or intubation) 
Permanently discontinue 
avelumab therapy 
Hospitalize  
Pulmonary and Infectious 
Disease consults 
1.0 to 2.0 mg/kg/day 
prednisolone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade < 1:  
Taper steroids over at least 6 weeks  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  


Clinical Study Protocol  
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Study Code UW17106 
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HEPATIC irAEs 
Grade of Liver Test 
Elevation 
(NCI-CTCAE v5) 
Initial Management 
Follow-up 
Grade 1 
AST or ALT > ULN to 3 x 
ULN; >1.5 to 3.0x baseline if 
baseline was abnormal and / or 
total bilirubin > ULN to 1.5 x 
ULN; >1.0 to 1.5x baseline if 
baseline was abnormal  
Continue avelumab therapy 
Continue liver function monitoring  
If worsens: Treat as Grade 2 or 3 to 4  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN; >3.0 to 5.0x baseline if 
baseline was abnormal and / or 
total bilirubin > 1.5 to ≤ 3 x 
ULN ; >1.5 to 3.0x baseline if 
baseline was abnormal 
Delay avelumab therapy 
Increase frequency of 
monitoring to every 3 days  
If returns to baseline: resume routine 
monitoring, resume avelumab therapy 
If elevations persist > 5 to 7 days or worsen:  
0.5 to 1 mg/kg/day methylprednisolone or oral 
equivalent and when LFT returns to Grade 1 or 
baseline, taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume avelumab 
therapy 
Grade 3 to 4 
AST or ALT > 5 x ULN; >5.0x 
baseline if baseline was 
abnormal and / or total 
bilirubin > 3 x ULN; >3.0x 
baseline if baseline was 
abnormal  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 2 
days  
1 to 2 mg/kg/day prednisolone 
or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult 
gastroenterologist/hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
If returns to Grade < 1:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, worsens or 
rebounds:  
Add mycophenolate mofetil 1 gram (g) twice 
daily  
If no response within an additional 3 to 5 days, 
consider other immunosuppressants per local 
guidelines  


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Renal irAEs 
Grade of Creatinine 
Increased 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 
1.5 x ULN 
Continue avelumab therapy 
Continue renal function monitoring  
If worsens: 
Treat as Grade 2 to 3 or 4 
Grade 2 to 3 
Creatinine increased > 1.5 and 
< 6 x ULN 
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics 
for opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade < 1: 
Taper steroids over at least 1 month, and resume 
avelumab therapy following steroids taper. 
If worsens: 
Treat as Grade 4 
Grade 4 
Creatinine increased > 6 x 
ULN 
Permanently discontinue 
avelumab therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics 
for opportunistic infections 
Consider renal biopsy 
If returns to Grade < 1: 
Taper steroids over at least 1 month 
 
 


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CARDIAC irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis.  
Withhold avelumab therapy 
Hospitalize. 
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility  
experienced in advanced heart 
failure and arrhythmia 
management 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
Guideline based supportive 
treatment as per cardiology 
consult.* 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If symptoms improve and immune-mediated 
etiology is ruled out, re-start avelumab therapy. 
 
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-mediated 
etiology is suspected or confirmed following 
cardiology consult, manage as immune-
mediated myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
Prednisolone 1 to 2 mg/kg/day 
or equivalent. 
Add prophylactic antibiotics 
for opportunistic infections. 
Once improving, taper steroids over at least 1 
month. 
 
If no improvement or worsening, consider 
additional immunosuppressants (e.g. 
azathioprine, cyclosporine A) 
 
*Local guidelines, or e.g. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 


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ENDOCRINE irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if 
needed 
Start thyroid hormone 
replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / 
hypophysitis) 
Continue hormone replacement/suppression and 
monitoring of endocrine function as appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
 
Rule-out secondary 
endocrinopathies  (i.e. 
hypopituitarism / 
hypophysitis) 
Resume avelumab once symptoms and/or 
laboratory tests improve to Grade ≤ 1 (with or 
without hormone replacement/suppression). 
 
Continue hormone replacement/suppression and 
monitoring of endocrine function as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e.  subnormal 
serum FT4 with 
inappropriately low TSH 
and/or low serum cortisol 
with inappropriately low 
ACTH) : 
 
Resume avelumab once symptoms and hormone 
tests improve to Grade ≤ 1 (with or without 
hormone replacement). 
 
In addition, for hypophysitis with abnormal 
MRI, resume avelumab only once shrinkage of 
the pituitary gland on MRI/CT scan is 
documented. 
 


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 
Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women) 
 
Hormone 
replacement/suppressive 
therapy as appropriate 
 
Perform pituitary MRI 
and visual field 
examination as indicated 
 
If hypophysitis confirmed: 
 
Continue avelumab if 
mild symptoms with 
normal MRI. Repeat the 
MRI in 1 month 
 
Withhold avelumab if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper 
during at least 1 month. 
 
Add prophylactic 
antibiotics for 
opportunistic infections. 
Continue hormone replacement/suppression 
therapy as appropriate. 
 
 


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Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential irAE 
Withhold avelumab therapy 
pending clinical investigation 
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider re-
starting avelumab therapy 
If irAE is confirmed, treat as Grade 2 or 3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Specialty consult as 
appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month and resume 
avelumab therapy following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Specialty consult as 
appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month. 
Grade 4 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics 
for opportunistic infections 
Specialty consult. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
Requirement for 10 mg per 
day or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue 
avelumab therapy 
Specialty consult 
 
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB; 
CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth 
factor 1; irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance 
imaging; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal. 


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7.5 
Treatment Modification for Symptoms of Infusion-Related Reactions 
Caused by Avelumab 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs=nonsteroidal anti-inflammatory drugs 
7.6 
Indications for Treatment Discontinuation 
Patient must be removed from the study protocol for one of the following reasons: 
 Development of metastatic disease. 
 Development of locoregional recurrence after the resection. 
 Development of locally advanced disease while on neoadjuvant treatment that precludes 
adequate and safe surgical resection.  
 Intercurrent illness that prevents further administration of treatment or surgical resection. 
 Unacceptable adverse event(s). 
 Severe non-compliance to study protocol as judged by the investigator. 
 Patient becomes pregnant. 
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
 
Decrease the study drug infusion rate by 50% and 
monitor closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for  
24 h. 
 
Temporarily discontinue drug infusion. 
 
Resume infusion at 50% of previous rate once infusion-
related reaction has resolved or decreased to at least 
Grade 1 in severity, and monitor closely for any 
worsening.  
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
 
Stop the avelumab infusion immediately and disconnect 
infusion tubing from the subject. 
 
Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any further 
avelumab treatment. 
- If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it must remain 
decreased for the next scheduled infusion.  If no infusion reaction is observed in the next scheduled infusion, the 
infusion rate may be returned to baseline at the subsequent infusions based on investigator’s medical judgment.- If 
hypersensitivity reaction occurs, the subject must be treated according to the best available medical practice. 


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 Patient is determined to be incorrectly enrolled (i.e., the patient does not meet the 
required inclusion/exclusion criteria for the study). 
 Patient decides to withdraw from the study (the subject is at any time free to discontinue 
treatment, without prejudice to further treatment). 
7.7 
Procedures for Discontinuation of a Subject From Investigational 
Product  
All reasons for discontinuation of treatment must be documented clearly.  Any patient 
discontinuing investigational therapy should be seen at 30 days post treatment discontinuation 
for the evaluations, as outlined in the study schedule, or before new treatment initiation 
(whichever comes first).  The patient’s tumor status should be assessed clinically and, if 
appropriate, disease recurrence or progression should be confirmed by radiological assessment.  
After discontinuation of the study medications, all ongoing or new AEs or SAEs must be 
followed until resolution unless, in the investigator’s opinion, the condition is unlikely to resolve 
due to the patients underlying disease, or the patient is lost to follow up, or a new treatment has 
been started. 
7.8 
Withdrawal From Study 
Subjects who withdraw from the study before treatment initiation will be replaced by other 
eligible patients.  In part 1 of the study, patients who withdraw from the study before any 
avelumab administration will be replaced. 
8. 
STUDY EFFICACY ASSESSMENTS 
8.1 
Pathology Evaluation 
Assessment of the histopathologic response to the treatment will be performed by the 
pathologist.  Esophagogastrectomy specimens will be processed according to standard operating 
procedures within the UWHC Department of Pathology.   
 Pathologic Complete Response 
The pathologist will review the slides from the tissue sections submitted in order to assess 
pathologic compete response (pCR).  pCR is defined as an absence of any viable tumor at 
microscopic examination of the primary tumor and any lymph nodes sampled after surgery 
following neoadjuvant therapy.  Participants with invalid/missing pCR assessments will be 
defined as non-responders.  In patients not achieving pCR, measurement of residual disease will 
be performed. 
 Assessment of Treatment Effect 
Response of tumor to previous chemotherapy and/or radiation therapy will be reported.  Several 
systems for tumor response have been advocated, and a modified Ryan scheme is suggested by 
the CAP/AJCC, which has been shown to provide good interobserver reproducibility and provide 
prognostic significance in rectal cancer 26.  Sizable pools of acellular mucin may be present after 
chemoradiation but should not be interpreted as representing residual tumor. 


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 No viable cancer cells (complete response, score 0) 
 Single cells or rare small groups of cancer cells (near complete response, score 1) 
 Residual cancer with evident tumor regression, but more than single cells or rare small 
groups of cancer cells (partial response, score 2) 
 Extensive residual cancer with no evident tumor regression (poor or no response, score 3) 
 R0 Assessment 
Margins include the proximal, distal, and radial margins.  The radial margin represents the 
adventitial soft tissue margin closest to the deepest penetration of residual tumor.  The distance 
from the tumor edge to the closest resection margin(s) will be measured and reported. 
Microscopic involvement of tumor directly at the resection margin (‘‘tumor transected’’) will be 
reported and is defined as (R1). 
8.2 
Disease Surveillance 
After completion of planned treatments, all subjects will be followed with active surveillance to 
monitor for recurrence.  Patients will undergo surveillance scans every 16 weeks during the first 
12 months after adjuvant therapy completion.  Patients may also undergo endoscopic procedures 
as clinically indicated.  Recurrence is defined as the appearance of one or more new lesions, 
which can be local, regional, or distant.  Disease recurrence may be documented with either 
radiological findings of recurrent disease or pathological assessment, whichever is available first.  
Biopsies are recommended, but not required, to confirm recurrent disease.  Locoregional 
recurrences can be detected with endoscopic procedures and biopsies.  Disease free survival is 
defined as the time period from completion of adjuvant therapy till the finding of recurrent 
disease or death, whichever comes first. 
8.3 
Surgical Outcomes 
All patients will be followed post-operatively. Any delays of planned surgery or surgical 
complications will be recorded.  Rates of surgical complications will be compared to the 
historical controls from our institution. 
9. 
CORRELATIVE STUDIES 
9.1 
Correlative Objectives 
1) To correlate PD-L1 staining with clinical and biomarkers of response. 
2) To evaluate changes in tumor infiltrating lymphocytes following treatment with 
avelumab and chemoradiation.  
3) To characterize the immune infiltrate following treatment with avelumab and 
chemoradiation. 
4) To determine the pretreatment versican proteolysis phenotype and correlate with clinical 
outcomes and changes in the immune contexture. 
5) To collect and bank tissues for future investigations.  


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9.2 
Correlative Studies 
All of the correlative studies will be performed in Dr. Deming’s laboratory. Twenty FFPE slides 
will be needed for the proposed correlates. 
 PD-L1 Immunohistochemistry (IHC) 
PD-L1 staining has been the best studied of all immune biomarkers in the setting of checkpoint 
blockade.  The presence of PD-L1 has been associated with an enhanced treatment benefit rate to 
checkpoint blockade in many settings.  Standardized protocols have now been developed for 
anti-PD-L1 immunohistochemistry (IHC).  Pre-treatment PD-L1 staining will be performed on 
the pre-treatment biopsy tissue. This staining will be scored as the percent of positive staining 
cells per high power field (hpf).  
 Tumor Infiltrating Lymphocytes and Examination of the Immune Context 
Multiple investigations have now demonstrated a correlation between the presence of tumor-
infiltrating lymphocytes (TILs) in cancer tissue and a favorable prognosis.  An increase in TILs 
is commonly being used as a surrogate marker for the development of an immune response in the 
setting of immune-based anti-cancer therapies.  As part of this clinical trial, the presence of TILs 
and other immune cell populations will be determined, comparing pretreatment biopsy tissue and 
the resection specimen following avelumab in combination with chemoradiation.  
IHC studies will be performed on formalin-fixed/paraffin-embedded tumor tissue. IHC will be 
performed per standardized protocols for CD3, CD4, CD8, CD20 and CD45RO and potentially 
other biomarkers of response.  Omission of the primary antibody will be used as a negative 
control along with positive control tissue.  Semi-automated quantitative brightfield assessment of 
expression will be performed using the Vectra imaging system (PerkinElmer) and inForm 
analysis software system.  A scanning protocol will be generated based on the tissue size and 
location of the cancer within the sample.  Biomarker quantification will be calculated as a 
continuous variable (mean optical density) and also as quartiles (ex. 0, 1+, 2+, or 3+).   
 Versican Proteolysis 
Versican (VCAN) is a tumor matrix proteoglycan with known immunoregulatory properties that 
when cleaved by ADAM-TS proteases releases an immunostimulatory fragment, versikine. 
Tumors displaying a VCAN proteolysis predominant phenotype (low staining for VCAN and 
intense staining for versikine) have been shown to have a greater CD8+ T cell infiltration.  In 
these investigations VCAN proteolysis will be examined as an immune biomarker. IHC will be 
performed for the total (intact) VCAN and versikine. Biomarker quantification will be performed 
in quartiles (0, 1+, 2+, or 3+). The VCAN proteolysis predominant phenotype will be classified 
as VCAN <2+ and versikine > 2+. 
 
 


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9.3 
Sample Collection and Banking 
If the subject agrees, leftover samples will be banked for future research. The link connecting 
subject information and coded samples will be held by the GI research staff and will be 
accessible to the UWCCC biobank. The Deming Laboratory staff will not have access to this 
information. Subjects may withdraw any unused samples from the optional banking by 
contacting the principal investigator. 
 Pretreatment Specimen Collection 
A total of 10 formalin fixed paraffin embedded (FFPE) slides from the diagnostic biopsy will be 
collected and transferred to the Deming Laboratory in the McArdle Laboratory for Cancer 
Research. These samples will be coded prior to transfer and labeled with the study number, 
subject ID and date.   
 Resection Specimen Collection 
The University of Wisconsin Carbone Cancer Center Biobank will be notified of all subjects 
undergoing resection as part of this protocol.  At the time of the operation, the tissue will be 
transferred to surgical pathology and residual tissue will be collected by the Biobank staff.  
Tissue will be then be coded and transferred to Deming Laboratory staff for storage and future 
studies including but not limited to tissue culture, RNA, DNA and protein analyses.  Samples 
will be coded and labeled with the study number, subject ID and date. In patients with complete 
pathologic response, tissue sections that include tumor bed/scar (determined by a pathologist) 
will be submitted for correlative studies. 
 Peripheral Blood Collection 
Plasma and serum samples will be collected (50 ml per draw in a heparinized tube green top for 
plasma and 10 ml per draw in red top tube for serum) as per the study calendar, These samples 
will then be coded and transferred to the Deming Laboratory for storage and analysis. Samples 
will be labeled with the study number, subject ID and date.. Collected samples will be used for 
exploratory studies evaluating potential circulating markers of response.  These studies may 
include, but are not limited to, CD4/CD8 ratio determination, TCR subtyping, cell free tumor 
DNA evaluation, and measuring serum circulating chemokines and cytokines.  The samples will 
also be banked for future studies. 
10. 
STUDY SAFETY ASSESSMENTS 
The Principal Investigator (PI) is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
10.1 
Definitions  
 Adverse Events 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition can 


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be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g. laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time during treatment and 
during the 30 day follow-up period. The term AE is used to include both serious and non-serious 
AEs. 
 Serious Adverse Event 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfills one or more of the 
following criteria: 
 Results in death 
 Is immediately life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization (>24 
hours). Hospitalization for a planned procedure, such as feeding tube placement, 
esophageal stent placement or esophagectomy, is not considered an SAE. 
 Results in persistent or significant disability or incapacity  
 Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon medical judgement, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
 The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the investigator(s) and communicated to EMD Serono or designee. 
10.2 
Recording of Adverse Events 
Non-serious adverse events and SAEs will be collected from the time the study drug is given, 
throughout the treatment period and up to and including the 30 day follow-up period.  After 
withdrawal from treatment, subjects must be followed-up for all existing and new AEs for 30 
calendar days after the last dose of trial drug and/or until event resolution. All new AEs 
occurring during that period must be recorded (if SAEs, they must be reported to the FDA and 
EMD Serono See section 11). In addition, all grades of adverse drug reactions (ADRs, AEs 
related to study medication) and any AE that results in treatment discontinuation will be recorded 
as study data on CRFs. 
 
All study-related toxicities/SAEs must be followed until resolution, unless in the Investigator’s 
opinion, the condition is unlikely to resolve.  
 
The following variables will be collected for each AE: 
 AE (verbatim) 
 The date when the AE started and stopped 
 Changes in NCI CTCAE (version 5.0) grade and the maximum CTC grade attained 
 Whether the AE is serious or not 


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 Investigator causality rating against the investigational combination (yes or no)  
 Action taken with regard to investigational combination agent 
 Outcome. 
In addition, the following variables will be collected for SAEs: 
 Date AE met criteria for serious AE 
 Date Investigator became aware of serious AE 
 AE is serious due to criteria listed in Section 9.1.2 
 Date of hospitalization 
 Date of discharge 
 Probable cause of death (if applicable) 
 Date of death (if applicable) 
 Autopsy performed (if applicable) 
 Description of AE 
 Causality assessment in relation to Study procedure(s) 
 Causality assessment in relation to study drug combination 
 Adverse Events Based on Signs and Symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
 Adverse Events Based on Examinations and Tests 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should only be reported as AEs if they fulfill any of the SAE criteria or are the reason for 
discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information.  Wherever possible the reporting investigator will use 
the clinical, rather than the laboratory term (e.g. anemia versus low hemoglobin value).  In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
 Disease Progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new or progression of existing metastasis during the study should be considered 


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as disease progression and not an AE.  Events, which are unequivocally due to disease 
progression, should not be reported as an AE during the study. 
 New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the serious criteria (see Section 10.1.2).  New primary cancers are those that are 
not the primary reason for the administration of the study treatment and have developed after the 
inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
 Lack of Efficacy 
When there is deterioration in the condition for which the study treatment(s) is being used, there 
may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the PI or 
the reporting physician considers that the study treatment contributed to the deterioration of the 
condition, or local regulations state to the contrary, the deterioration should be considered to be a 
lack of efficacy and not an AE. 
 Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported to 
EMD Serono or designee within 24 hours from the time site personnel become aware of the 
death. See section 11.  
When reporting a death in the CRF, it will be required to identify which of the following best 
describes the category of death: 
 Toxicity for study medication. 
 Radiological disease progression. 
 Clinical disease progression. 
 Other causes. 
Death should be reported in the following manner: 
 Death clearly the result of disease progression should be reported and should be 
documented in the eCRF, but it should not be reported as an SAE. 
 Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the study monitor as a SAE within 24 hours 
(see Section 11 for further details).  The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death. 


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 Deaths with an unknown cause should always be reported as a SAE.  A post mortem 
maybe helpful in the assessment of the cause of death, and if performed a copy of the 
post-mortem results should be forwarded to EMD Serono within the usual timeframes. 
11. 
DATA AND SAFETY MONITORING PLAN 
11.1 
Oversight and Monitoring Plan 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the regular 
review and monitoring of all ongoing clinical research in the UWCCC. A summary of DSMC 
activities are as follows: 
 Reviews all clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity.  
 Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as defined in the 
protocol, for all clinical trials conducted at the UWCCC, and studies conducted at external 
sites for which the UWCCC acts as an oversight body.  
 Reviews all reports generated through the UWCCC DSMS elements (Internal Audits, 
Quality Assurance Reviews, Response Reviews, Compliance Reviews, and Protocol 
Summary Reports) described in Section II of this document.  
 Notifies the protocol PI of DSMC decisions and, if applicable, any requirements for 
corrective action related to data or safety issues.  
 Notifies the CRC of DSMC decisions and any correspondence from the DSMC to the 
protocol Principal Investigator.  
 Works in conjunction with the UW Health Sciences IRB in the review of relevant safety 
information as well as protocol deviations, non-compliance, and unanticipated problems 
reported by the UWCCC research staff.  
 Ensures that notification of SAEs requiring expedited reporting is provided to external 
sites participating in multi-institutional clinical trials coordinated by the UWCCC. 
11.2 
Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study sponsorship and 
risk level of the protocol as determined by the PRMC. All protocols (including Intervention 
Trials, Non-Intervention Trials, Behavioral and Nutritional Studies, and trials conducted under a 
Training Grant) are evaluated by the PRMC at the time of committee review. UWCCC 
monitoring requirements for trials without an acceptable external DSMB are as follows: 
 Intermediate Monitoring 
Protocols subject to intermediate monitoring generally include UW Institutional Phase I/II and 
Phase II Trials. These protocols undergo review of subject safety at regularly scheduled DOT 
meetings where the results of each subject’s treatment are discussed and the discussion is 
documented in the DOT meeting minutes. The discussion includes the number of subjects 
enrolled, significant toxicities, dose adjustments, and responses observed. Protocol Summary 
Reports are submitted on a quarterly basis by the study team for review by the DSMC.  


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11.3 
Serious Adverse Event – Reporting within 24 Hours 
Serious Adverse Events requiring reporting within 24 hours (as described in the protocol) must 
also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu within one business day. The OnCore SAE Details Report must 
be submitted along with other report materials as appropriate (NCI AdEERS form or FDA 
Medwatch Form #3500 and/or any other documentation available at that time of initial 
reporting). The DSMC Chair will review the information and determine if immediate action is 
required. Within 10 working days, all available subsequent SAE documentation must be 
submitted electronically along with a 24 hour follow-up SAE Details Report and a completed 
UWCCC SAE Routing Form to saenotify@uwcarbone.wisc.edu. All information is entered and 
tracked in the UWCCC database. 
The PI notifies all investigators involved with the study at the UWCCC, the IRB, and the funding 
agency and provides documentation of these notifications to the DSMC. For this trial, since the 
UW PI serves as the sponsor-investigator, the PI will review the event to determine whether the 
SAE requires reporting to the FDA and other participating investigators.  
See Section 12 for detailed instructions on SAE reporting. 
11.4 
Serious Adverse Event – Reporting within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described in the protocol) must 
also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu. The OnCore SAE Details Report must be submitted along with 
other report materials as appropriate (NCI AdEERS form or FDA Medwatch Form #3500 and/or 
any other documentation available at the time of initial reporting). The DSMC Chair will review 
the information and determine if further action is required. All information is entered and tracked 
in the UWCCC database.  
The PI notifies all investigators involved with the study at the UWCCC, the IRB, and the funding 
agency and provides documentation of these notifications to the DSMC.  
The PI will also review the event to determine whether the SAE requires reporting to the FDA 
and other participating investigators.  
See Section 12 for detailed instructions on SAE reporting. 
11.5 
Sponsor-Investigator Responsibilities for SAE Review  
For this clinical trial, the UWCCC PI is acting as the Sponsor-Investigator (i.e., the PI holds the 
IND).  As such, the PI assumes responsibilities of the study sponsor in accordance with FDA 21 
CFR 312.32. In this capacity, the UWCCC PI reviews all reports of serious adverse events 
occurring on the study at the UWCCC and participating external sites and makes a determination 
of 1) suspectedness (i.e., whether there is a reasonable possibility that the drug caused the AE); 
and 2) unexpectedness (the event is not listed in the Investigator’s Brochure or is not listed at 
the specificity or severity that has been observed) in the context of this study. SAE with 


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suspected causality to study drug and deemed unexpected are reported as IND Safety Reports by 
the UWCCC PI to the FDA and all participating investigators on the study within 15 calendar 
days.  All fatal or life-threatening SAE that are unexpected and have suspected causality to the 
study drug will be reported by the UWCCC PI to the FDA and all participating investigators on 
the study within 7 calendar days. 
Refer to Section 12.3.1 for UWCCC PI instructions for reporting to the FDA. 
11.6 
Study Progress Review 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC in the timeframe 
determined by the risk level of the study (quarterly; semi-annually; or annually). The PSR 
provides a cumulative report of SAEs, as well as instances of noncompliance, protocol 
deviations, and unanticipated problems, toxicities and responses that have occurred on the 
protocol in the timeframe specified. PSRs for those protocols scheduled for review are reviewed 
at each DSMC meeting. 
Protocol Summary Reports enable DSMC committee members to assess whether significant 
benefits or risks are occurring that would warrant study suspension or closure. This information 
is evaluated by the DSMC in conjunction with other reports of quality assurance activities (e.g., 
reports from Internal Audits, Quality Assurance Reviews) occurring since the prior review of the 
protocol by the DSMC. Additionally, the DSMC requires the study team to submit external 
DSMB or DSMC reports if available and any other pertinent study-related information 
In the event that there is significant risk warranting study suspension or closure, the DSMC will 
notify the PI of the DSMC findings and ensure the appropriate action is taken for the protocol 
(e.g., suspension or closure). The DSMC ensures that the PI reports any temporary or permanent 
suspension of a clinical trial to EMD Serono and other appropriate agencies. DSMC findings and 
requirements for follow-up action are submitted to the CRC. 
12. 
EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS 
Depending on the nature, severity, and attribution of the serious adverse event an SAE report 
will be phoned in, submitted in writing, or both according to Table 2 below. All serious adverse 
events must also be reported to the UWCCC Data and Safety Monitoring Committee Chair. All 
serious adverse events must also be reported to the UW IRB (if applicable), and any funding 
agency not already included in the list. 
Determine the reporting time line for the SAE in question by using the following table. Then 
refer to section 12.1. 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1,2. 
 


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Table 2. FDA Reporting Requirements.  
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the University of Wisconsin Carbone Cancer 
Center and any other parties outlined in the protocol ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event (the patient was at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe). 
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and 
ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
UWCCC within the timeframes detailed in the table below: 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
hospitalization  ≥ 
24 hrs 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
 24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of 
the initial 24-hour report. 
 10 Calendar Days – A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE 


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1 Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 All Grade 3, 4, and 5 AEs 
Expedited 10 calendar day reports for: 
 Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was 
last administered.  Footnote “1” above applies after this reporting period. 
12.1 
SAE Requiring [24] Hour Reporting Occurs at UWCCC 
 Report to the UWCCC: 
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting Workflow for 
DOTs on the UWCCC website (http://kb.wisc.edu/uwccc) for specific instructions on how and 
what to report to the UWCCC for [24] hour initial and follow-up reports. A follow-up report is 
required to be submitted within 10 days of the initial [24] hour report. 
For this protocol, the following UWCCC entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. UWCCC PI: Nataliya Uboha, MD, PhD 
c. UWCCC PM: Renae Quale 
d. Any other appropriate parties listed on the SAE Routing Form (for follow-up reports 
only) 
 Reporting to EMD Serono 
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form provided. Dr. Uboha 
will assume responsibility for submitting the reportable event(s) to EMD Serono as well as 
ensuring that any local reporting requirements are completed in parallel. 
 Serious Adverse Events 
 Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 
 Occupational exposure (even if not associated with an adverse event) 
 Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs. 
 
 
 


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Contact information for submission of reportable events to EMD Serono: 
Fax: +49 6151 72 6914 
OR 
E-mail: GlobalDrugSafety@merckgroup.com 
 
Specifying: 
 PROTOCOL Number and/or Title 
 EMD Serono assigned Study Number 
 SUBJECT Number 
 SITE Number/PI Name 
 SAE/ONSET DATE 
 Report to the IRB 
Consult the UW-IRB website for reporting guidelines.  
12.2 
SAE Requiring [10] Day Reporting Occurs at UWCCC 
 Report to the UWCCC: 
Reference the SAE SOP and the SAE Reporting Workflow for DOTs on the UWCCC website 
(http://kb.wisc.edu/uwccc) for specific instructions on how and what to report to the UWCCC for 
[10] day reports.  
For this protocol, the following entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. Any appropriate parties listed on SAE Routing form 
 Report to the Sponsor: 
See section 12.1.2 - SAEs must be reported to EMD Serono or designee within 24 hours.  
 Report to the IRB: 
Consult the UW-IRB website for reporting guidelines. 
12.3 
Other Reporting Requirements 
 Reporting to the FDA 
Serious Adverse Events occurring on studies on which a UW PI is acting as sponsor-investigator 
must be reported to the FDA within the appropriate time frame.  Mandatory and voluntary 
reporting guidelines and instructions are outlined on the FDA website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 


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13. 
ETHICAL AND REGULATORY REQUIREMENTS 
13.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements. 
13.2 
Subject data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy 
legislation.  In accordance with the Health Information Portability and Accountability Act 
(HIPAA), the written Informed Consent Form must include a subject authorization to release 
medical information to EMD Serono Inc. and/or allow EMD Serono Inc., a regulatory authority, 
or Institutional Review Board (IRB) access to subject’s medical information that includes all 
hospital records relevant to the study, including subjects’ medical history. 
13.3 
Ethics and regulatory review 
 Informed consent 
Provision of written Informed Consent will be obtained prior to any study-related procedures. 
The principal investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Subjects will also 
be notified that they are free to discontinue from the study at any time.  The subject will be given 
the opportunity to ask questions and allowed time to consider the information provided.  The 
original, signed written Informed Consent Form will be stored for the duration of the study. A 
copy of the signed written Informed Consent Form will be given to the subject. 
 Changes to the protocol and informed consent form 
In the event that there are any changes to the protocol, these changes will have to be first 
reviewed by the sponsor-investigator, and then the amendment and updated consent will be 
submitted for approval by the institutional IRB. Once approved, an amendment to the protocol 
and consent form will be generated.  Subjects will be notified of the protocol changes and will be 
provided with the updated ICF for their signature. They will also be provided with a copy of the 
updated ICF for their records.  The funding agency (EMD Serono) will also be updated about 
any changes to the protocol or consent form.   
 Audits and inspections 
The PI will monitor the clinical trial for safety. The PI will assess all expedited adverse events 
and will periodically review all adverse events observed on the trial. UW Carbone Cancer Center 
standard operating procedures (SOPs) for assessment and reporting of adverse events will be 
followed, which are in compliance with 21 CFR 312.32 and 312.22. The clinical trial data 
consisting of all required observations, AEs, and laboratory data will be entered into a 
computerized database in a timely manner. The accuracy and completeness of the database, 
timely submission of SAEs and compliance with the protocol, is assured by periodic auditing 


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conducted by the UW Carbone Cancer Center Office of Protocol Review and Monitoring, which 
reports to the UW Data and Safety Monitoring Committee (DSMC) Committee. Safety data will 
be submitted to the DSMC at least once yearly or more often as required by the DSMP. On a 
regular interval basis, status reports of all laboratory parameters, AEs and SAEs are reviewed by 
the PI to view composite data across subjects. Regular meetings will be held to discuss ongoing 
patient treatment and adverse events. 
Expedited SAE reports submitted by the Investigator to FDA will also be copied to relevant 
institutional safety committees within the timeframes required by UW. These will also be copied 
to EMD Serono or designee.  The Toxicity List, in addition to the Investigator’s Brochure, will 
be used as a reference for reporting any new SAE. Possible actions taken by the PIs or the UW 
DSMC if a new unexpected toxicity is identified from the above safety review, or if the periodic 
review of all adverse events and laboratory data indicates a pattern of incidence or severity of 
toxicity that raises a safety concern, can be to: 
1. Revise consent form 
2. Amend the protocol 
3. Suspend the protocol 
All AEs found to be expected or non-serious will be included in the Annual Report to EMD 
Serono. 
14. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
14.1 
Sample Size and Power Calculation 
 Part 1- Run-in Phase  
A total number of 6 subjects will be enrolled during the run-in phase of the trial. A sample size 
of 6 is sufficient to estimate the true dose limiting toxicity rate of the proposed 
avelumab/chemoradiation therapy with adequate accuracy. Specifically, the true dose limiting 
toxicity rate will be estimated with a standard error of 20%.The proposed treatment combination 
will be considered as safe if dose limiting toxicities are observed in at most 1 patient. The 
following table shows the probabilities that dose limiting toxicities are observed in at most one 
patient for various toxicity rates. 
 
Table 7: Operating Characteristics of run-in phase – probabilities that the proposed 
avelumab/chemoradiation therapy will be considered as safe for various true dose 
limiting toxicity rates ranging between 0.05 and 0.30. 
 
True DLT rate 
 
0.05 
0.10 
0.15 
0.20 
0.25 0.30 
Probability that DLTs are observed in 
at most one  patient (treatment 
combination will be declared as safe) 
0.97 
0.89 
0.78 
0.66 
0.53 0.42 


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For example, if the true DLT rate is 10%, then the probability that the proposed treatment will be 
declared as safe is 89%. 
 Part 2 – Expansion Phase 
This is a Phase 2 portion of the trial, which will evaluate the efficacy of the proposed 
avelumab/chemoradiation therapy in patients with stage II/III resectable esophageal cancer. The 
primary endpoint for the phase II component is the pathological complete response rate. A 
pathological complete response rate of 29% (95% CI: 23-37%) has been reported for standard 
preoperative chemoradiotherapy 3.  A pathological complete response rate of 20% or less, i.e., 
less than the lower 95% confidence bound of the reported response rate for standard care, will be 
considered as unacceptably low for this patient population.  It is hypothesized that the co-
administration of avelumab with chemoradiation will substantially increase pathological 
complete response rate to 40% or above. A single-stage design will be used to evaluate the 
pathological response rate.  The null hypothesis that the pathological complete response rate is at 
most 20% versus will be tested against the alternative hypothesis that the rate it greater than 
20%.  With a sample size of 24 patients, an anticipated pathological response rate of 40% will be 
detected with 80% power at the one-sided 0.1 significance level. The following table shows the 
operating characteristics of the two-state study design. 
 
Table 8: Operating characteristics of single-stage study design for expansion cohort.  
 
True Pathological Complete Response Rate 
 
25% 
30% 
35% 
40% 
45% 
50% 
Probability that the proposed 
avelumab/chemoradiation therapy 
will be declared as effective 
(rejecting the null hypothesis that 
the pathological complete response 
rate is at most 20%) 
0.23 
0.44 
0.64 
0.81 
0.91 
0.97 
 
For example, if the true pathological complete response rate is 45%, then the probability of 
declaring the proposed avelumab/chemoradiation therapy was effective is 91%. 
14.2 
Analysis Plan 
 General 
Descriptive statistics will primarily be generated to summarize the data.  For continuous 
variable, descriptive statistics may include the number of subjects reflected in the calculation 
(n), mean, standard deviation, median, minimum, and maximum; frequencies and percentages 
may be displayed for categorical data (e.g., toxicities, responses).  Data analysis will be 
performed using SAS® (SAS Institute Inc., Cary, North Carolina) version 9.4.  
 


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 Demographics 
All demographic variables (e.g., gender, age, weight, etc.) will be summarized by standard 
descriptive statistics, i.e., in terms of means, standard deviations, medians, and ranges for 
variables on a continuous scale, and in terms of frequency tables for variables on a categorical 
scale. 
 
 Primary Endpoints 
Part 1:  All patients who receive at least one dose of avelumab will be evaluated for toxicity and 
tolerability. Toxicities observed will be summarized in terms of types and severities by 
Common Terminology Criteria for Adverse Events (CTCAE) v 45.0. The number and severity 
of toxicity incidents will be analyzed descriptively in tabular format. The 90% confidence 
interval for the dose limiting toxicity rate (DLT) will be constructed using the Wilson score 
method.  
 
Part 2: Pathologic compete response (pCR) is defined as an absence of any viable tumor at 
microscopic examination of the primary tumor and any lymph nodes sampled after surgery 
following neoadjuvant therapy.  Participants with invalid/missing pCR assessments will be 
defined as non-responders.  The number and frequency of patients with a pCR will be 
summarized in tabular format.  The pCR rate will be reported along with the corresponding 90% 
confidence interval which will be constructed using the Wilson score method.  
 
 Secondary Endpoints 
Disease free survival (DFS) will be defined as the number of days from the day of resection to 
the day a subject experiences an event of disease recurrence or death, whichever comes first. If a 
subject has not experienced an event of disease recurrence progression or death at the time of 
analysis, then the subject’s data will be censored at the date of the last available evaluation. DFS 
will be summarized using point estimates of the median time to progression and the associated 
95% confidence interval. The data will be presented graphically using Kaplan-Meier plots. 
Incidence of survival complications and the rate of R0 resection will be calculated and report 
along with the corresponding 95% confidence intervals which will be constructed using the 
Wilson score method.  
15. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY 
THE INVESTIGATOR 
15.1 
Pregnancy 
After investigator first becomes aware of its occurrence, he/she should follow the same process 
for reporting as described for the SAEs. 
 Maternal Exposure 
If a patient becomes pregnant during the course of the study, all treatments should be 
discontinued immediately. The outcome of any conception occurring from the date of the first 
dose until 3 months after the last dose should be followed up and documented. 


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Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs.  Elective abortions without complications should not be handled 
as AEs.  The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the patient was withdrawn from the study.  
 Paternal Exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 30 
days after the completion of adjuvant therapy. Pregnancy of the patient’s partners is not 
considered to be an adverse event.  However, the outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should if possible be followed up and documented.  The outcome of any conception occurring 
from the date of the first dose until 3 months after the last dose should be followed up and 
documented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16. 
LIST OF REFERENCES 
 
1. 
Raman R, Deorah S, McDowell BD, et al: Changing incidence of esophageal 
cancer among white women: analysis of SEER data (1992-2010). Contemp Oncol (Pozn) 
19:338-40, 2015 
 
2. 
Shapiro J, van Lanschot JJ, Hulshof MC, et al: Effectiveness of neoadjuvant 
chemoradiotherapy for early-stage esophageal cancer. J Clin Oncol 33:288-9, 2015 
 
3. 
van Hagen P, Hulshof MC, van Lanschot JJ, et al: Preoperative 
chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074-84, 2012 
 
4. 
Scheer RV, Fakiris AJ, Johnstone PA: Quantifying the benefit of a pathologic 
complete response after neoadjuvant chemoradiotherapy in the treatment of esophageal cancer. 
Int J Radiat Oncol Biol Phys 80:996-1001, 2011 
 
5. 
Reynolds JV, Muldoon C, Hollywood D, et al: Long-term outcomes following 
neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg 245:707-16, 2007 
 
6. 
Meguid RA, Hooker CM, Taylor JT, et al: Recurrence after neoadjuvant 
chemoradiation and surgery for esophageal cancer: does the pattern of recurrence differ for 
patients with complete response and those with partial or no response? J Thorac Cardiovasc Surg 
138:1309-17, 2009 
 
7. 
Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy 
versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006 
 
8. 
Tanaka K, Miyata H, Sugimura K, et al: Negative influence of programmed 
death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy. Cancer 
Sci 107:726-33, 2016 
 
9. 
Ohigashi Y, Sho M, Yamada Y, et al: Clinical significance of programmed death-
1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin 
Cancer Res 11:2947-53, 2005 
 
10. 
Kang Y-K: Nivolumab (ONO-4538/BMS-936558) as salvage treatment after 
second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer 
(AGC): A double-blinded, randomized, phase III trial. J Clin Oncol 35, 2017 
 
11. 
Janjigian YY, Shitara K, Moehler M, et al: First-line nivolumab plus 
chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and 
oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet, 
2021 
 
12. 
Kato K, Cho BC, Takahashi M, et al: Nivolumab versus chemotherapy in patients 
with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous 
chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet 
Oncol 20:1506-1517, 2019 
 
13. 
Shitara K, Ozguroglu M, Bang YJ, et al: Pembrolizumab versus paclitaxel for 
previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a 
randomised, open-label, controlled, phase 3 trial. Lancet 392:123-133, 2018 
 
14. 
Moehler M, Dvorkin M, Boku N, et al: Phase III Trial of Avelumab Maintenance 
After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With 
Gastric Cancers: Results From JAVELIN Gastric 100. J Clin Oncol 39:966-977, 2021 
 
15. 
Chung HC: Safety, PD-L1 expression, and clinical activity of avelumab 
(MSB0010718C), an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal 
junction cancer. journal of Clinical Oncology 34:Abstr 167, 2016 


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16. 
Kelly RJ, Ajani JA, Kuzdzal J, et al: Adjuvant Nivolumab in Resected 
Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 384:1191-1203, 2021 
 
17. 
Twyman-Saint Victor C, Rech AJ, Maity A, et al: Radiation and dual checkpoint 
blockade activate non-redundant immune mechanisms in cancer. Nature 520:373-7, 2015 
 
18. 
Deng L, Liang H, Burnette B, et al: Irradiation and anti-PD-L1 treatment 
synergistically promote antitumor immunity in mice. J Clin Invest 124:687-95, 2014 
 
19. 
Formenti SC, Demaria S: Combining radiotherapy and cancer immunotherapy: a 
paradigm shift. J Natl Cancer Inst 105:256-65, 2013 
 
20. 
Matsumura S, Demaria S: Up-regulation of the pro-inflammatory chemokine 
CXCL16 is a common response of tumor cells to ionizing radiation. Radiat Res 173:418-25, 
2010 
 
21. 
Matsumura S, Wang B, Kawashima N, et al: Radiation-induced CXCL16 release 
by breast cancer cells attracts effector T cells. J Immunol 181:3099-107, 2008 
 
22. 
Kelly R: Checkpoint expression pre and post chemoradiation in operable 
esophageal cancer. Journal of Clinical Oncology 35, 2017 
 
23. 
Chandra RA, Wilhite TJ, Balboni TA, et al: A systematic evaluation of abscopal 
responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. 
Oncoimmunology 4:e1046028, 2015 
 
24. 
Muro K, Chung HC, Shankaran V, et al: Pembrolizumab for patients with PD-L1-
positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. 
Lancet Oncol 17:717-26, 2016 
 
25. 
Berger MJ, Dunlea LJ, Rettig AE, et al: Feasibility of stopping paclitaxel 
premedication after two doses in patients not experiencing a previous infusion hypersensitivity 
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Clinical Study Protocol  
Drug Substance Avelumab  
 
Study Code UW17106 
Version 7, 07/05/2021 
 
65(65) 
APPENDIX A. ECOG PERFORMANCE STATUS. 
ECOG 
Performance Status 
Activity 
0 
Fully active, able to carry on all pre-disease performance without 
restrictions. 
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 self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  100% 
confined to bed or chair.