Clinical trial NCT04162665
Conditions: Gastric Adenocarcinoma
Sponsor: Washington University School of Medicine
Start date: 2020-02-14; Completion date: 2024-11-21
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Gastric cancer is a global health issue as the world's fifth most common malignancy and third leading cause of cancer mortality, respectively. Preoperative radiation therapy may improve overall survival (OS) but is seldom used. There is precedent for preoperative chemoradiation, as it is the standard of care for esophageal and gastroesophageal junction tumors. However, reluctance of physicians to prescribe preoperative radiation therapy in gastric cancer may be due to the large treatment fields necessary to account for stomach motion. Adaptive radiation therapy may permit decreased field sizes and more accurate dose delivery. In traditional CT based radiation delivery the same radiation plan is delivered each day without assessment of inter-fraction or intra-fraction motion. Adaptive radiation therapy permits the physician to contour the unique anatomy daily to generate a new plan to account for day to day organ motion. Real-time MR imaging is also used during the treatment so that radiation is only delivered when the tumor is within the pre-specified target area. Thus, adaptive radiation therapy may overcome traditional barriers of radiation delivery in gastric cancer and improve oncologic outcomes.

Detailed description:

Arms: arm 1: Consenting and eligible patients will receive adaptive short course radiation therapy (SCRT) (25 Gy at in 5 fractions), followed by standard of care total neoadjuvant chemotherapy followed by standard of care gastrectomy or esophagogastrectomy. The recommended SOC chemotherapy options are CAPOX, FOLFOX, or FLOT, but any SOC total neoadjuvant chemotherapy may be given at the discretion of the treating medical oncologist after consultation with the study chair. Patients who are not able to complete their full total neoadjuvant therapy regimen prior to surgery may complete chemotherapy postoperatively at the discretion of the treating physician.
Interventions: intervention 1: Adaptive short course radiation therapy intervention 2: Standard of care chemotherapy regimen
Intervention descriptions: intervention 1: Radiation must be livered with adaptive planning and MR gating or CBCT breath hold treatment. intervention 2: The recommendations are CAPOX, FOLFOX, or FLT.

Protocol documents:
Prot_SAP_000.pdf: 
Amendment 5 // Protocol Version 9: 16 April 2024 
 
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Pre-operative Adaptive Short Course Radiation Therapy in Gastric Cancer 
 
Washington University School of Medicine // Department of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224, St. Louis, MO  63110 
 
Protocol #: 201911059 // Amendment: 5 // Version: 9 
Version Date: 16 April 2024 
 
Coordinating Center: 
Washington University School of Medicine 
Principal Investigator: 
Hyun Kim, M.D. 
Phone: (314) 362-8502 // E-mail: kim.hyun@wustl.edu  
 
Sub-Investigators 
 
Institution 
 
 
Modality 
Ryan Fields, MD 
 
Washington University  
Surgery 
Dominic Sanford, MD  
Washington University  
Surgery 
Natasha Leigh, MD 
 
Washington University  
Surgery 
Roheena Panni, MD, PhD 
Washington University  
Surgery 
Pamela Samson, MD 
 
Washington University  
Radiation Oncology 
Carl DeSelm, MD, PhD  
Washington University  
Radiation Oncology 
Allen Mo, MD, PhD 
 
Washington University  
Radiation Oncology 
Katrina Pedersen, MD  
Washington University  
Medical Oncology 
Kian-Huat Lim, MD, PhD 
Washington University  
Medical Oncology 
Rama Suresh, MD 
 
Washington University  
Medical Oncology 
Benjamin Tan, MD 
 
Washington University  
Medical Oncology 
Patrick Grierson, MD 
 
Washington University  
Medical Oncology 
Haeseong Park, MD  
 
DFCI  
 
 
Medical Oncology 
 
Study Device:  
 
ViewRay and Ethos 
NCT#: 
NCT04162665 
Funded by: 
Department 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
 
 
 


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Pre-operative Adaptive Short Course Radiation Therapy in Gastric Cancer 
 
Protocol Revision History 
 
Initial Approval Version 4  
 
 
 
 
 
19 Nov 2019 
Amendment #1 Version 5 
 
 
 
 
 
 
17 Aug 2020 
Amendment #2 Version 6 
 
 
 
 
 
 
08 Feb 2021 
Amendment #3 Version 7 
 
 
 
 
 
 
14 June 2023 
Amendment #4 Version 8 
 
 
 
 
 
 
31 Oct 2023 
Amendment #5 Version 9 
 
 
 
 
 
 
16 April 2024 
 
 
 


Amendment 5 // Protocol Version 9: 16 April 2024 
 
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Pre-operative Adaptive Short Course Radiation Therapy in Gastric Cancer 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following ethical guidelines and regulations:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 


Amendment 5 // Protocol Version 9: 16 April 2024 
 
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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BMT 
Bone marrow transplant 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CR 
Complete response 
CRc 
Cytogenetic complete remission 
CRi 
Complete remission incomplete 
CRm 
Morphologic complete remission 
CRF 
Case report form 
CST 
Central standard time 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MDS 
Myelodysplastic syndrome 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Cancer Center Network 


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NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PI 
Principal investigator 
PR 
Partial response 
PSA 
Prostate-specific antigen 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RFS 
Relapse free survival 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SCT 
Stem cell transplant 
SD 
Stable disease 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
UPN 
Unique patient number 
US 
Ultrasound 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell (count) 
 
 


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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 9 
SCHEMA ...................................................................................................................................... 11 
1.0 
SCHEDULE OF ACTIVITIES ............................................................................................ 0 
2.0 
INTRODUCTION ............................................................................................................... 1 
2.1 
Study Rationale ................................................................................................................ 1 
2.2 
Background ...................................................................................................................... 1 
2.3 
Study Design .................................................................................................................... 5 
3.0 
OBJECTIVES AND ENDPOINTS ..................................................................................... 6 
4.0 
STUDY POPULATION ...................................................................................................... 7 
4.1 
Inclusion Criteria .............................................................................................................. 7 
4.2 
Exclusion Criteria ............................................................................................................. 8 
4.3 
Inclusion of Women and Minorities ................................................................................. 9 
5.0 
REGISTRATION PROCEDURES ..................................................................................... 9 
5.1 
Confirmation of Patient Eligibility ................................................................................... 9 
5.2 
Patient Registration in the Siteman Cancer Center OnCore Database . Error! Bookmark 
not defined. 
5.3 
Assignment of UPN ........................................................ Error! Bookmark not defined. 
5.4 
Screen Failures ............................................................................................................... 10 
5.5 
Strategies for Recruitment and Retention ...................................................................... 10 
6.0 
TREATMENT PLAN ........................................................................................................ 10 
6.1 
Safety Cohort and Early Stopping Rules ........................................................................ 11 
6.2 
Radiation Therapy Guidelines ........................................................................................ 11 
6.3 
Chemotherapy Guidelines .............................................................................................. 13 
6.4 
Surgery ........................................................................................................................... 14 
6.5 
Patient Clinical Outcomes Data ..................................................................................... 14 
6.6 
Definitions of Evaluability ............................................................................................. 14 
6.7 
Concomitant Therapy and Supportive Care Guidelines ................................................. 15 
6.8 
Women of Childbearing Potential .................................................................................. 15 
6.9 
Duration of Therapy ....................................................................................................... 16 
6.10 Duration of Follow-up .................................................................................................... 16 
6.11 Lost to Follow-Up .......................................................................................................... 16 
7.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 17 
7.1 
Dosing Adjustments for Radiation Therapy ................................................................... 17 
7.2 
Dosing Adjustments for Chemotherapy ......................................................................... 17 
8.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 17 
8.1 
WU PI Reporting Requirements .................................................................................... 18 
8.2 
Secondary Site Reporting Requirements ........................................................................ 19 
8.3 
Exceptions to Expedited Reporting ................................................................................ 19 
9.0 
CORRELATIVE STUDIES .............................................................................................. 19 
9.1 
Tissue for Research ........................................................................................................ 20 
9.2 
Blood for ctDNA ............................................................................................................ 21 
10.0 DATA SUBMISSION SCHEDULE ................................................................................. 22 
10.1 Adverse Event Collection in the Case Report Forms ..................................................... 23 
11.0 MEASUREMENT OF EFFECT........................................................................................ 23 
12.0 DATA AND SAFETY MONITORING ............................................................................ 23 


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13.0 AUDITING ........................................................................................................................ 24 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 25 
14.1 Statistical Hypotheses and Sample Size Determination ................................................. 25 
14.2 Analysis of the Primary Endpoint .................................................................................. 25 
14.3 Analysis of Secondary Endpoints .................................................................................. 25 
14.4 Baseline Descriptive Statistics ....................................................................................... 26 
15.0 MULTICENTER REGULATORY REQUIREMENTS ................................................... 26 
16.0 REFERENCES .................................................................................................................. 28 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 35 
APPENDIX B: Definitions for Adverse Event Reporting ............................................................ 36 
APPENDIX C: Reporting Timelines ............................................................................................ 38 
APPENDIX D: Washington University Unanticipated Problem Reporting Cover Sheet ............ 40 
APPENDIX E: Study-Specific DSM Tables ................................................................................ 41 
 
 


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PROTOCOL SUMMARY 
 
Title: 
Pre-operative Adaptive Short Course Radiation Therapy in Gastric 
Cancer 
Study Description: 
Hypothesis: Adaptive radiation therapy followed by sequential multi-
agent chemotherapy will result in a pathologic complete response 
(pCR) of at least 20%. 
 
In this study, patients with gastric adenocarcinoma will receive 
hypofractionated adaptive radiation therapy followed by total 
neoadjuvant chemotherapy followed by surgery.  
Objectives: 
Primary Objective: 
To quantify the pCR rate in gastric cancer patients treated with 
preoperative radiation followed by total neoadjuvant chemotherapy. 
 
Secondary Objectives: 
1. To quantify the proportion of patients able to complete a full 
course of total neoadjuvant chemotherapy 
2. To quantify the local control rate of gastric cancer patients 
treated with preoperative radiation followed by chemotherapy. 
3. To quantify the toxicity of gastric cancer patients treated with 
preoperative radiation followed by chemotherapy. 
4. To quantify the overall survival in gastric cancer patients treated 
with preoperative radiation followed by chemotherapy. 
5. To quantify the disease-free survival in gastric cancer patients 
treated with preoperative radiation followed by chemotherapy. 
 
Exploratory Objectives: 
1. To quantify the deviation in dose to the tumor due to variation 
in stomach position.  
2. To quantify the deviation in dose to the nearby OARs due to 
variation in OAR position. 
3. To determine the distribution of TCGA molecular subtypes in 
gastric adenocarcinoma after radiation and chemotherapy. 
4. To identify differentially expressed post-treatment biomarkers 
in gastric tumors. 
5. To correlate circulating tumor DNA (ctDNA) levels with 
clinical outcomes. 
Endpoints: 
Primary Endpoint:  
The rate of pCR (both ypT and ypN) in gastric cancer patients treated 
with 
preoperative 
radiation 
followed 
by 
total 
neoadjuvant 
chemotherapy. 
 
Secondary Endpoints: 
1. Proportion of patients able to complete a full course of total 
neoadjuvant chemotherapy 


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2. The local control rate at 1 year post RT. 
3. The rate of grade 3 or greater toxicity as defined by CTCAE v 
5.0  
4. The overall survival at 1 year post RT. 
5. The disease-free survival at 1 year post RT. 
 
Exploratory Endpoints: 
1. Average percent difference in coverage of PTV by 95% isodose 
line. 
2. Average percentage difference in dose to nearby OARs (i.e. 
duodenum, small bowel, large bowel) due to variation in OAR 
position. 
3. The percentage of patients in each TCGA molecular subtype 
after radiation and chemotherapy. 
4. The specific biomarkers 
5. ctDNA levels 
Study Population: 
Thirty-six adults of any gender who have a diagnosis of gastric cancer 
and are receiving preoperative radiation followed by total neoadjuvant 
chemotherapy will be enrolled.   
Phase: 
Not applicable. 
Description of Sites / 
Facilities Enrolling: 
This is a multicenter trial coordinated by and enrolling at Washington 
University in St. Louis. The study will also open to enrollment at other 
sites in the U.S. 
Description of Study 
Intervention: 
Patients undergoing preoperative radiation and chemotherapy for 
gastric cancer will undergo simulation for radiation treatment planning 
on a conventional referenced CT scanner and ViewRay or Ethos 
treatment machines.  High resolution volumetric MR or CBCT images 
will be acquired daily in the treatment position and OARs contoured by 
the radiation oncologist.  The new electronic density map will be used 
to recalculate dose from the initial radiation plan (based on CT/MR 
simulation) and treatment delivered to maximize coverage while not 
exceeding dosimetric constraints. 
Study Duration: 
36 months. 
Participant 
Duration: 
12 months. 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Plan 
 
Adaptive 25 Gy / 5 fractions 
 
followed by 
 
Total neoadjuvant chemotherapy 
 
followed by 
 
Surgery 
 
Eligible Patients 
Diagnosis of gastric adenocarcinoma 


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1.0 
SCHEDULE OF ACTIVITIES 
 
Screening procedures must take place within 60 days of registration. 
 
Screening 
Baseline 
Fx1 
Fx2 
Fx3 
Fx4 
Fx5 
Chemo4 
Surgery5 
3-mo 
F/U6 
6-mo 
F/U6 
12-mo 
F/U6 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
H&P, ECOG PS 
X 
 
 
 
 
 
 
 
 
X 
 
 
CBC w/diff1 
X 
 
 
 
 
 
 
 
 
 
 
 
CMP1 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
EUS 
X 
 
 
 
 
 
 
 
 
 
 
 
Institutional MRI 
screening questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
Simulation 
 
X 
 
 
 
 
 
 
 
 
 
 
CT C/A/P 
 
X 
 
 
 
 
 
 
X8 
 
X 
X 
PET/CT 
 
X11 
 
 
 
 
 
 
 
 
 
 
Adaptive SCRT3 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SOC chemotherapy10 
 
 
 
 
 
 
 
X 
X 
Gastrectomy 
 
 
 
 
 
 
 
 
X9 
 
 
 
Research blood for 
ctDNA 
 
X 
 
 
 
 
 
X7 
X7 
 
X7 
 
AE assessment 
 
AEs will be tracked from baseline through 12 months after surgery/definitive 
end of treatment.  Refer to Section 8.0 for more details. 
 
 
1. labs will be drawn as per SOC 
2. women of childbearing potential only 
3. patients will receive 5 fractions of radiotherapy delivered once daily; radiotherapy may take up to 10 business days (due to logistical delays) 
4. SOC chemotherapy will begin 2-4 weeks after completion of radiotherapy 
5. within 2-4 weeks after completion of SOC chemo 
6. follow-up visits will take place at 3 months (+/-2 weeks), 6 months (+/- 4 weeks), and 12 months (+/- 4 weeks) post-surgery; patients who don’t undergo surgery will have follow-
up visits at 3 months (+/-2 weeks), 6 months (+/- 4 weeks), and 12 months (+/- 4 weeks) from the date of definitive end of treatment. 
7. after completion of RT / prior to starting chemo, at completion of chemo / prior to surgery, and 6 months after surgery. See Section 9.2 for further details. 
8. prior to surgery 
9. tissue for research will be collected from patients who experience pCR 
10. Any SOC total neoadjuvant chemotherapy regimen may be given at the discretion of and under the supervision of the treating medical oncologist 
11. PET/CT is strongly encouraged at baseline but optional 
 


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2.0 
INTRODUCTION 
 
2.1 
Study Rationale 
 
Gastric cancer is a global health issue as the world’s fifth most common malignancy and 
third leading cause of cancer mortality, respectively1. Preoperative radiation therapy may 
improve overall survival (OS) but is seldom used2. There is precedent for preoperative 
chemoradiation, as it is the standard of care for esophageal and gastroesophageal junction 
tumors3. However, reluctance of physicians to prescribe preoperative radiation therapy in 
gastric cancer may be due to the large treatment fields necessary to account for stomach 
motion. Adaptive radiation therapy may permit decreased field sizes and more accurate 
dose delivery. In traditional CT based radiation delivery the same radiation plan is 
delivered each day without assessment of inter-fraction or intra-fraction motion. Adaptive 
radiation therapy permits the physician to contour the unique anatomy daily to generate a 
new plan to account for day to day organ motion. Real-time imaging is also used during 
the treatment so that radiation is only delivered when the tumor is within the pre-specified 
target area. Thus, adaptive radiation therapy may overcome traditional barriers of radiation 
delivery in gastric cancer and improve oncologic outcomes. 
 
Short course radiation therapy (SCRT) is an increasingly used treatment modality. In rectal 
adenocarcinoma, SCRT followed by chemotherapy results in double the pathologic 
complete response (pCR) as long course chemoradiation4. SCRT also allows the patient to 
proceed to multiagent chemotherapy sooner, as the concurrent chemotherapy delivered 
with long course chemoradiation is usually single agent or decreased systemic dosing. Thus 
preoperative SCRT followed by chemotherapy may permit more downstaging, pCR and 
decrease metastatic spread in gastric adenocarcinoma. 
 
2.2 
Background 
 
2.2.1 Gastric Cancer 
 
Gastric cancer is a global health issue with 952,000 new cases and 723,000 deaths 
in 2012, ranking as the world’s fifth most common malignancy and third leading 
cause of cancer mortality, respectively1. Perioperative chemotherapy followed by 
gastrectomy is the category 1 treatment recommendation in the National 
Comprehensive Cancer Network (NCCN) guidelines5 for locoregional disease, 
based on the results of the MAGIC and FLOT trials6. The role of radiation therapy 
in gastric cancer is supported in the adjuvant setting and improves OS, relapse free 
survival and local failure7,8. However, postoperative radiation fields are large and 
cause significant side effects, with reports of up to 32% acute grade 4 toxicity6.  
 
Gastric cancer patients with a pCR to preoperative chemoradiation therapy have an 
improved OS2,9. Despite large randomized studies indicating that pCR is rarely 
achievable with neoadjuvant chemotherapy alone10, preoperative chemoradiation 
remains a category 2B recommendation in NCCN guidelines. There is precedent 
for preoperative chemoradiation, as it is the standard of care for esophageal and 


Amendment 5 // Protocol Version 9: 16 April 2024 
 
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gastroesophageal junction tumors3. Single arm studies have shown pCR rates of 16-
30%2,11,12. Reluctance of physicians to prescribe preoperative radiation therapy in 
gastric cancer may be due to the large treatment fields necessary to account for 
stomach motion. Nearby OARs, including the heart, lungs, kidneys, liver, small and 
large bowel, limit the treatment dose and field size. Fluoroscopic and CT based 
studies in gastric lymphoma patients have demonstrated inter- and intra-fraction 
stomach movement requiring 3 cm margins13,14. Although preoperative 
chemoradiation therapy in gastric cancer is currently being evaluated in the 
international cooperative group TOPGEAR trial, traditional large fields are used 
without adaptation of radiation plans according to stomach movement15. 
 
2.2.2 Total Neoadjuvant Therapy 
 
Total neoadjuvant therapy is a treatment paradigm frequently used in rectal 
adenocarcinoma treatment. By delivering all the planned chemotherapy prior to 
surgical resection, compliance with chemotherapy increases from 50% to 80%16. 
Data indicate that this treatment paradigm increases pathologic complete response17 
and even permits patients to undergo nonoperative management (omitting 
expirative surgery) if there is a clinical complete response18–22. Data for total 
neoadjuvant therapy in gastric adenocarcinoma are limited. Delivering total 
neoadjuvant therapy in gastric cancer may increase the amount of chemotherapy 
tolerated by the patient, allow increased downstaging, and increase the pathologic 
complete response rate. Further, if this treatment paradigm results in a high clinical 
and pathologic complete response, it may be an alternative treatment option for 
those patients not eligible for surgery. 
 
2.2.3 Adaptive Radiation Therapy 
 
The ViewRay system is a MRgRT coupled LINAC machine (ViewRay Inc., 
Oakwood Village, OH). The 0.35 Tesla real-time MR imaging allows radiation to 
be delivered to the tumor only when the target is in the designated treatment area. 
Traditional 3D CT planned radiation contours include a margin to account for 
respiratory motion, internal organ motion and setup error. MRgRT may permit 
smaller margins resulting in lower dose to normal structures23. Daily plan 
adaptation is possible with physicians contouring OARs, and subsequent changes 
in beam arrangements or dose to meet dosimetric constraints. Not only can this 
imaging guided treatment ensure prescribed dose delivery, it may permit dose 
escalation or boost volumes for gross tumor23. To date there is no clinical trial that 
has prospectively evaluated the feasibility or oncologic outcomes of preoperative 
MRgRT plus concurrent chemotherapy in gastric cancer. 
 
At Washington University, we treat pancreas, liver, breast and other intra-
abdominal and thoracic tumors with MRgRT. Our preliminary data for stomach 
motion during definitive (non-operative) radiation treatment of gastric lymphoma 
(Figure 1) indicate that even with patient instructions for NPO 3 hours prior to 
treatment, the daily stomach position can vary up to 2.95 cm from the planning 


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position. Motion assessment of 5 patients with gastric lymphoma show a mean 
translational distance (calculated from x, y and z displacement) of 1.3 ± 0.5 cm. 
The patients’ average stomach volume was 763 cc, with 29.5 ± 19.0 cc outside the 
5 mm PTV margin due to daily changes in stomach position over 20 fractions. 
 
To date we have treated four patients with gastric adenocarcinoma with MRgRT 25 
Gy in 5 fractions. The patients were treated with this fractionation to palliate 
symptoms or due to medical inoperability. Patients tolerated the treatment without 
treatment related acute grade 3+ toxicity. One patient that subsequently underwent 
sequential chemotherapy and surgical resection was not noted to have increased 
fibrosis or issues with resectability. 
 
The Ethos system is a cone beam CT (CBCT) based radiation treatment device. It 
obtains high quality CBCT on-table images that allow the physician to contour the 
patients anatomy, just as in MRgRT. The Ethos system can be equipped with 
Identify, that permits surface monitoring of the patient’s breathing, allowing CBCT 
imaging and treatment to be delivered in the same anatomical position. Our data 
indicate high contour reliability and dosimetric feasibility of adaptive radiation 
therapy using the Ethos platform24,25. This is a highly reliable adaptive platform 
alternative to MRgRT. 
 
2.2.4 Correlative Studies Background 
 
With more effective chemotherapy and radiation treatment delivery it is 
increasingly important to identify molecular subtypes that may require dose 
escalated or targeted therapy. The traditional Lauren classification26 and World 
Health Organization27 systems categorize gastric tumors by histology and have had 
limited utility in guiding oncologic therapies or targeted drug discovery. Currently, 
the only clinically meaningful molecular biomarker is Her2/neu overexpression, 
with the TOGA trial demonstrating an OS advantage in Her2/neu positive gastric 
cancer patients treated with trastuzumab plus chemotherapy versus chemotherapy 
alone28. Unfortunately, only 6-20% of gastric adenocarcinomas demonstrate Her2 
overexpression and/or amplification29. Other attempts to classify gastric tumors via 
microarray and whole transcriptome sequencing were limited by small sample 
sizes, no associated clinical outcomes, and the use of immortalized cell lines instead 
of original patient pathology30–33. In contrast to the parallel technologies that guide 
the management of breast34,35 or prostate cancer36,37, there are no clinically 
implemented biomarker panels or strata that predict or prognosticate outcomes for 
gastric cancer. 
 


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TCGA performed a multiple platform analysis of 295 treatment naïve gastric cancer 
samples using array-based somatic copy number analysis, whole-exome 
sequencing, array-based DNA methylation profiling, messenger RNA sequencing, 
microRNA sequencing and reverse-phase 
protein array. They proposed a four 
molecular subgroup classification system 
(Figure 1)38. However, the study was 
performed on treatment naïve tissue, with 
the 
potential 
for 
high 
molecular 
heterogeneity inherent to gastric cancer39. 
Due to the sample size that was likely 
restricted by the high cost of multiple 
platform genomic analysis, it is possible 
that the heterogeneous cellular makeup of 
the gastric tumors deterred the detection of 
consistently 
differentially 
expressed 
biomarkers 
in 
the 
study. 
Data 
in 
esophageal adenocarcinoma indicate that 
chemotherapy reduces tumor heterogeneity (Figure 2)40 and post-chemotherapy 
cell populations may preferentially express genes that promote survival41. 
Evaluating biomarkers in a more molecularly uniform cell population may increase 
the ability to detect clinically significant molecular subgroups. 
 
There 
are 
growing 
data 
implicating 
the 
role 
of 
microRNAs (miRs), small non-
coding RNAs that regulate 
mRNA 
expression, 
in 
regulating 
response 
to 
chemotherapy 
and 
ionizing 
radiation49. Researchers have 
demonstrated that increased 
miR-21 and miR-106a may 
target phosphatase and tensin 
homolog (PTEN), resulting in 
gastric cancer resistance to 
cisplatin chemotherapy50,51. While miR data regarding radiation therapy are limited 
in gastric cancer due to only sporadic use of preoperative radiation, there are data 
indicating increased miR-31 levels confer radiation sensitization in esophageal 
adenocarcinoma53. The expression levels of these miRs after preoperative 
chemoradiation therapy in addition to their prognostic and therapeutic implications 
in gastric adenocarcinoma are not known. 
 
Cell-free DNA is a powerful non-invasive assay for quantitating tumor disease 
burden54,55. Circulating tumor DNA (ctDNA), the tumor component of cell-free 
DNA, is indicative of molecular residual disease in colorectal cancer patients and 
Figure 1. TCGA molecular subtypes of gastric 
adenocarcinoma. EBV, Epstein-Barr virus; MSI, 
microsatellite instability; SCNA, somatic copy-
number aberrations. 
Figure 2.DNA copy number as surrogates for tumor variation; 
decreased heterogeneity in the chemotherapy plus surgery 
(CS) vs surgery alone (S).  


Amendment 5 // Protocol Version 9: 16 April 2024 
 
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has prognostic value56,57. Other investigators have shown similar findings in breast 
58, lung59, cervical60, and pancreatic cancer61. There are limited data on ctDNA in 
gastric cancer62. 
 
2.3 
Study Design 
 
2.3.1 Overall Design 
 
The hypothesis of this study is that adaptive SCRT followed by multiagent 
chemotherapy will result in a pCR of at least 20%.  
 
Thirty-six patients with gastric adenocarcinoma will be enrolled in this study.  
There will be a lead-in cohort of 5-10 patients (see Safety Cohort and Early 
Stopping Rules) to ensure there are no grade 5 toxicities related to adaptive SCRT 
(or SOC chemotherapy after adaptive SCRT).  All patients will receive radiation 
delivered with MR or CBCT guidance followed by sequential chemotherapy.  
Gastrectomy will occur 2-4 weeks after the completion of chemotherapy.  
Pathologic response, plan dosimetry, and oncologic outcomes will be evaluated.  
FDG PET/CTs are strongly encouraged at baseline but optional. Patients will be 
followed on study for 12 months after surgery. 
 
2.3.2 Scientific Rationale for Study Design 
 
This study will be a non-randomized, single arm, phase II study with all patients 
receiving preoperative radiation therapy then SOC chemotherapy followed by 
surgical resection. The reason for performing a non-randomized trial is to evaluate 
the clinical efficacy of this treatment regimen in a timely manner. Due to the 
infrequent incidence of this disease in the United States (Washington University in 
St. Louis performs approximately 30-50 gastrectomies per year for gastric cancer), 
a randomized control trial would take many years to complete.  We will compare 
the dosimetric and clinical outcomes to historical controls. 
 
2.3.3 Justification for Dose 
 
Twenty-five Gy in 5 fractions is a dose fractionation used for aggressive palliation 
of intraabdominal malignancies. It is well tolerated and usually prescribed without 
dose constraints (if delivered with at least four fields). This dose and fractionation 
to the whole pelvis is a standard of care treatment regimen in patients with rectal 
adenocarcinoma.  This is also the dose and fractionation that is prescribed to the 
whole pelvis for non-operative management of rectal adenocarcinoma at our 
institution. at the time of this protocol submission, this short course radiation 
therapy followed by 4 months of chemotherapy leads to greater than 70% cCR of 
rectal adenocarcinoma in our institutional experience and prospective phase I trial 
(NORMAL-R, HRPO# 201512140). We anticipate it will be well tolerated in 
gastric adenocarcinoma patients with high clinical response when coupled with 
multi-agent chemotherapy. 


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3.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for Endpoints 
Primary 
To quantify the pCR rate in 
gastric cancer patients treated 
with preoperative radiation 
followed by total neoadjuvant 
chemotherapy. 
 
The rate of pCR (both ypT 
and ypN) in gastric cancer 
patients treated with 
preoperative radiation 
followed by total 
neoadjuvant chemotherapy. 
A complete pathologic 
response may result in 
improved oncologic 
outcomes. High rates of 
pCR may lead the way for 
future studies of non-
operative management of 
gastric cancer. 
Secondary 
To quantify the proportion of 
patients able to complete a full 
course of total neoadjuvant 
chemotherapy 
Proportion of patients able to 
complete a full course of 
total neoadjuvant 
chemotherapy. 
Evaluating the feasibility of 
total neoadjuvant therapy 
will help guide future trials 
seeking to maximize 
response prior to surgery.  
To quantify the local control rate 
of gastric cancer patients treated 
with preoperative radiation 
followed by chemotherapy.  
The local control rate at 1 
year post RT. 
Providing radiation therapy 
prior to chemotherapy and 
surgery may increase the 
local control rate. 
To quantify the toxicity of 
gastric patients treated with 
preoperative radiation followed 
by chemotherapy. 
The rate of grade 3 or greater 
toxicity as defined by 
CTCAE v 5.0. 
Adding radiation therapy to 
chemotherapy and surgery 
may increase the toxicity 
associated with treatment.  
To quantify the overall survival 
in gastric cancer patients treated 
with preoperative radiation 
followed by chemotherapy. 
The overall survival at 1 year 
post RT. 
By improving local control 
and pCR, overall survival 
may be improved. 
To quantify the disease free 
survival in gastric cancer 
patients treated with 
preoperative radiation followed 
by chemotherapy.  
The disease-free survival at 1 
year post RT. 
By improving the local 
control, disease free 
survival (locoregional and 
distant recurrence) may be 
improved as well. 
Tertiary/Exploratory 
To quantify the deviation in dose 
to the tumor due to variation in 
stomach position. 
 
Average percent difference 
in coverage of PTV by 95% 
isodose line. 
The average percent 
difference of the five 
treatments represents 
approximately what percent 
of the total planned 
prescription was delivered 
to the target. Under-dosing 
of the tumor due to organ 


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motion may result in 
decreased tumor control. 
To quantify the deviation in dose 
to OARs due to variation in 
OAR position. 
Average percentage 
difference in dose to nearby 
OARs (i.e. duodenum, small 
bowel, large bowel) due to 
variation in OAR position. 
The average percent 
difference of the five 
treatments represents 
approximately what percent 
of the total planned 
prescription was delivered 
to the OAR. Over-dosing of 
the OARs due to organ 
motion may result in 
increased toxicity. 
To determine the distribution of 
TCGA molecular subtypes in 
gastric adenocarcinoma after 
radiation and chemotherapy.  
The percentage of patients in 
each TCGA molecular 
subtype after radiation and 
chemotherapy. 
Treatment with radiation 
and chemotherapy may 
select for a different 
distribution of TCGA 
molecular subtypes. 
To identify differentially 
expressed post-treatment 
biomarkers  
The specific biomarkers  
Treatment with radiation 
and chemotherapy may 
select for a less 
heterogeneous, clinically 
significant biomarker 
enriched tumor subtype. 
To correlate circulating tumor 
DNA (ctDNA) levels with 
clinical outcomes. 
ctDNA levels 
ctDNA may detect 
treatment refractory disease 
and residual tumor earlier 
than traditional modalities. 
 
 
4.0 
STUDY POPULATION 
 
4.1 
Inclusion Criteria 
 
In order to participate in this study, a patient must meet all of the criteria listed in this 
section: 
 
1. Newly diagnosed histologically or cytologically gastric adenocarcinoma.  (Siewert III 
acceptable: the bulk of tumor should be in stomach; gastric tumors with extension to 
the gastroesophageal junction are permitted.)  Patients with T1-3N0-2 are eligible. 
Patients with N3, or T4 disease are not eligible. 
 
2. Known T-stage defined by EUS.  Must have had CT of the chest/abdomen/pelvis with 
IV contrast. 
 
3. Medically eligible to receive SOC chemotherapy. 
 


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4. At least 19 years of age. 
 
5. ECOG performance status ≤ 2 (see Appendix A) 
 
6. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500 cells/mm3 
b. Platelets ≥ 100,000 cells/mm3 
c. Creatinine clearance > 50 mL/min 
 
7. The effects of the various chemotherapy agents used in this study on the developing 
human fetus are unknown.  For this reason, women of childbearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control, 
abstinence) prior to study entry and for the duration of study participation.  Should a 
woman become pregnant or suspect she is pregnant while participating in this study, 
she must inform her treating physician immediately.  Men treated or enrolled on this 
protocol must also agree to use adequate contraception prior to the study, for the 
duration of the study, and one month after completion of the study 
 
8. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
4.2 
Exclusion Criteria 
 
In order to participate in this study, a patient must not meet any of the criteria listed in this 
section: 
 
1. Prior surgery, radiation, or chemotherapy for gastric or esophageal cancer. 
 
2. Prior surgery to the esophagus or stomach that would alter the radiation treatment field 
or stomach motion. 
 
3. Siewert I-II GE junction tumor. 
 
4. Any active malignancy within 2 years of enrollment that may alter the course of gastric 
cancer.  (Apparently cured localized malignancy or advanced, but indolent malignancy 
with significantly more favorable prognosis are allowed).  
 
5. Currently receiving any other investigational agents. 
 
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to chemotherapeutic agents used in the study. 
 
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, diabetes, symptomatic congestive heart failure, unstable angina pectoris, or 
cardiac arrhythmia that are considered clinically significant as determined by the 
treating physician. 


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8. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 
9. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or 
they have a history of AIDS-defining opportunistic infection within the 12 months prior 
to registration.  Concurrent treatment with effective ART according to DHHS treatment 
guidelines is recommended.  Recommend exclusion of specific ART agents based on 
predicted drug-drug interactions (i.e. for sensitive CYP3A4 substrates, concurrent 
strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers (efavirenz) should be 
contraindicated). 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
5.0 
REGISTRATION AND ENROLLMENT PROCEDURES 
 
The following steps must be taken before enrolling patients on this study: 
 
1. Registration of consented patient in the Siteman Cancer Center OnCore database 
2. Assignment of unique patient number (UPN) 
3. Confirmation of patient eligibility by Washington University School of Medicine (WUSM) 
 
Patients must not start any protocol intervention or procedures prior to signing of informed 
consent. All consented patients at all sites must be registered in the Siteman Cancer Center OnCore 
database at WUSM. 
 
5.1 
Registration in OnCore Database 
 
Patient registration to the Siteman Cancer Center OnCore database must occur within one 
business day of the patient signing consent. 
 
The following patient registration information must be scanned and emailed to the WUSM 
research coordinator on the day the patient signs consent: 
 
1. Complete and submit manual registration form: 
a. Your name and contact information (telephone number, fax number, and email 
address) 
b. Your site PI’s name, the registering MD’s name, and your institution name 
c. Patient’s race, ethnicity, sex, ZIP code, country, and DOB 
d. Three letters (or two letters and a dash) for the patient’s initials 
2. Currently approved protocol version date 
3. Copy of signed consent form (patient name may be blacked out) 
4. Planned date of enrollment 


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5.2 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study that will 
include a 3-digit site number (contact the study team for the site number) and a 2-digit 
sequential number beginning with 01 for the first patient. The UPN must not include patient 
initials or other identifying information. All data will be recorded with this identification 
number on the appropriate CRFs. 
 
5.3 
Confirmation of Patient Eligibility and Enrollment 
 
Patient eligibility will be confirmed using the information listed below and scanning and 
emailing it to the WUSM research coordinator at least two business days prior to 
enrolling the patient: 
 
1. Completed eligibility checklist, signed and dated by a member of the study team 
2. Copy of appropriate source documentation confirming patient eligibility 
 
Once the patient has been confirmed to be eligible for enrollment, the WUSM coordinator 
will forward verification of enrollment and the UPN via email. 
 
5.4 
Patient Enrollment Submissions 
 
Patient enrollment packets may be submitted Monday through Friday between 8am and 
5pm CT.  Exceptions will be evaluated and approved on a case-by-case basis. Patient 
eligibility and subsequent enrollment will be confirmed by the WUSM research 
coordinator or designee by email within one business day of submission. Verification of 
eligibility and registration must be kept in the patient chart. 
 
5.5 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (if applicable).   
 
5.6 
Strategies for Recruitment and Retention 
 
This trial will be open to all patients irrespective of gender, race, or socioeconomic status. 
Patients will be identified in both the inpatient (consults) and outpatient setting.   
 
 
6.0 
TREATMENT PLAN 
 


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Consenting and eligible patients will receive adaptive SCRT (25 Gy in 5 fractions), followed by 
standard of care total neoadjuvant chemotherapy followed by standard of care gastrectomy or 
esophagogastrectomy. The recommended SOC chemotherapy options are CAPOX, FOLFOX, or 
FLOT, but any SOC total neoadjuvant chemotherapy may be given at the discretion of the treating 
medical oncologist after consultation with the study chair. Patients who are not able to complete 
their full total neoadjuvant therapy regimen prior to surgery may complete chemotherapy 
postoperatively at the discretion of the treating physician. 
 
6.1 
Safety Cohort and Early Stopping Rules 
 
There will be a lead-in safety cohort of 5 patients, monitored for 30 days after completion 
of RT. If there is one treatment-related patient death, then the safety cohort will be 
expanded to 10 patients. If there are two or more treatment-related deaths, the radiation 
dose will be decreased to 20 Gy in 5 fractions. The trial will be terminated if there are more 
than three treatment-related deaths (equaling approximately 10% of the entire projected 
accrual). 
 
Treatment-related grade 5 toxicities should be reported to the institutional PI within 24 
hours and to the WUSM PI according to the timelines in Section 8.2. 
 
For the purposes of the early stopping rules, “treatment-related” refers to both adaptive 
SCRT and SOC total neoadjuvant chemotherapy. 
 
6.2 
Radiation Therapy Guidelines 
 
6.2.1 Dose, Fractionation, and Constraints 
 
When feasible it is strongly recommended that radiotherapy begin on a Monday. It 
is accepted that occasional logistical delays may occur during radiotherapy 
treatment due to machine downtime or other issues.  Radiotherapy as administered 
during this study may take up to 10 business days without being considered a 
protocol deviation. 
 
Radiotherapy will consist of five fractions, delivered once daily, to a total dose of 
25 Gy at 5 Gy per fraction. Radiation must be delivered with daily adaptive 
planning and MR gating or CBCT breath hold treatment. The stomach and OARs 
must be redrawn each day for the adaptive plan. Plans should be adapted to meet 
OAR constraints or improve coverage as needed for each day’s unique anatomy.  
 
Coverage:  
PTV V95% = 100% 
 
Luminal GI structures: 
30 Gy < 0.5 cc (hard constraint).  
25 Gy < 0.5 cc (soft constraint). 
 


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Kidneys V18 < 200cc. 
Spinal cord V28 < 0.03cc. 
 
6.2.2 Treatment Planning Procedures 
 
Image-based treatment planning and intensity modulated radiotherapy (IMRT) is 
permitted.  Proton therapy is not permitted. Dose volume histogram (DVH) 
information for the target volumes, small bowel, and uninvolved colon (defined to 
be large bowel outside the clinical target volumes) is mandatory.  This is to assist 
in interpreting outcome, including morbidity.   
 
6.2.3 Simulation Procedures/Patient Positioning 
 
Patients should be simulated in supine position. It is recommended to have the left 
arm raised and right arm down.  Both arms down is acceptable as long as dose 
constraints can be met (avoiding beams through arms). Simulation scan should be 
obtained on expiratory breath hold. 
 
6.2.4 Clinical Target Volume (CTV) and Planning Target Volume (PTV) 
Definitions 
 
The CTV_primary will include the stomach GTV (as per PET/CT and endoscopy 
report) plus a 1-3 cm proximal-distal expansion along the length of the bowel 
structure (i.e. stomach, esophagus, or duodenum as applicable) This range is 
provided to allow more coverage near the GE junction (akin to esophageal 
expansions) but to prevent irradiating the entire stomach. Expansion may extend 
into esophagus and/or duodenum per tumor location. A 1-1.5 cm radial expansion 
is generated for CTV primary, cropped to GI luminal structure. Clinically 
suspicious locoregional lymph nodes as identified by EUS or imaging that are 
visible on 0.35 T MR may be included with a 1.0 cm expansion to CTV_node (or 
included in CTV_elective)). Both the CTV_primary and CTV_node must be 
evaluated for change and re-contoured daily at the machine if significantly changed 
per reviewing MD assessment. If the LN is not visible then the gross node CTV 
volume should not be changed.   
 
 CTV is generated with a 1-1.5 cm brush, creating a semicircle volume 
encompassing the proximal 1-1.5 cm of celiac SMA vessel, with the aorta at its 
posterior border and the anterior border demarcated by bowel or pancreas. Ideally, 
CTV_elective should not change if treatment imaging is acquired in the same 
position and phase of breathing as the simulation scan.  
 
PTV is generated by a uniform 1 cm expansion about the CTV. Reducing PTV 
margins to modify OAR dose(s) is not permitted.  
 
For daily adaptive treatments, patient should be aligned to CTV_elective. GTV is 
rigidly deformed and redrawn to match daily anatomy of stomach using diagnostic 


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imaging and prior fraction treatment plan. CTV_primary is created as above.  
 
6.2.5 Normal Tissue Contours 
 
Small bowel, large bowel, duodenum, kidneys, and spinal cord should be 
contoured.  Since absolute rather than relative bowel volumes are to be tracked, it 
is not necessary to contour the entire large and small bowel.  Only those loops 
within 1.5 cm superior and inferior or within 3 cm axial distance of the PTV must 
be contoured for daily adaptation. All bowel within 1.5 cm superior and inferior to 
the PTV should be contoured for initial planning. Gating boundary should be set at 
5 mm. 
 
6.2.6 Retrospective Plan Review 
 
Deidentified DICOM datasets will be sent through encrypted transfer to 
Washington University for central review of contours and treatment plans. Initial 
radiation treatment plans will be overlaid on each daily anatomy and the change in 
dose to PTV and OARs will be determined.  
 
6.3 
Chemotherapy Guidelines 
 
Chemotherapy will be given as per standard of care and should begin 2 to 4 weeks after 
completion of radiotherapy.  Recommended total neoadjuvant chemotherapy regimens are: 
• CAPOX (capecitabine/oxaliplatin) 
• FOLFOX (oxaliplatin, leucovorin, and 5-FU) 
• FLOT (docetaxel, oxaliplatin, leucovorin, and 5-FU) 
 
However, the treating medical oncologist may prescribe other SOC total neoadjuvant 
chemotherapy regimen upon discussion with the WUSM PI.  Additionally, if one regimen 
is not tolerated, subjects can move between regimens for a goal of 4 months of 
chemotherapy treatment total prior to surgery. 
 
Patients who are unable to complete their total neoadjuvant therapy regimen may complete 
the chemotherapy postoperatively, at the discretion of the treating physician. Postoperative 
chemotherapy should start within 3 months of surgery. Patients who are medically 
inoperable will continue to receive chemotherapy until the entire regimen is complete.  
 
A maximum (cumulative) delay of treatment of 4 weeks (or single delay of 3 weeks) is 
allowed per protocol due to factors/AEs listed in Section 7.0 (i.e., chemotherapy should be 
completed within a 5-month period).  Cumulative delays in excess of 4 weeks, or single 
delays in excess of 3 weeks, will need to be discussed with the Principal Investigator in 
regard to proceeding to surgical resection.  Such cases will need to be individualized 
depending on the clinical scenario.  
 


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Please note that chemotherapy administration and AE assessment should be performed 
under the supervision of a medical oncologist.  Dosing is to follow standard of care 
recommendations per institutional guidelines. 
 
Interval imaging during chemotherapy, if obtained, is at the discretion of the treating 
physician. 
 
6.4 
Surgery 
 
Exclusion of metastatic disease will be performed per institutional standard (exploratory 
laparoscopy or CT imaging).  
 
Surgical resection is dependent on the location of the tumor. Prior to initiation of radiation 
and chemotherapy, tumor may be tattooed with ink (e.g. carbon black) so that the original 
tumor extent is identifiable post-radiation and chemotherapy. Tumors should be resected 
to negative margins as per frozen sections. Subtotal gastrectomy is appropriate for distal 
tumors, with total gastrectomy at the surgeon’s discretion. Total gastrectomy or 
esophagogastrectomy are appropriate for proximal tumors. The spleen should be preserved 
when feasible. D2 nodal dissection is mandatory. Clips may be placed to identify areas of 
tumor adhesion or high risk for residual disease with documentation in the operative report. 
 
Peritoneal washings should be obtained intraoperatively as part of surgical staging. 
 
In the event of negative frozen but positive permanent margin, further treatment will be at 
the discretion of the treating physician.  . 
 
6.5 
Patient Clinical Outcomes Data 
 
Clinical outcomes data (including but not limited to patient demographics (age, date of 
birth, weight, sex, height), tumor staging, treatment delivered, pathologic response, local 
failure and distant failure) will be recorded in OnCore. Each patient will be deidentified 
with a unique patient identification number. Only those individuals at the patient’s 
respective institution will have access to the patient’s personal health identifiers (e.g. 
name). 
 
6.6 
Definitions of Evaluability 
 
Endpoint 
In order to be evaluable for this 
endpoint, a patient must… 
Primary 
Rate of pCR 
Have received at least one fraction of 
radiation therapy and undergone 
surgical resection 
Secondary 
Proportion of patients able to complete a full 
course of total neoadjuvant chemotherapy 
Have received at least one fraction of 
radiation therapy 


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Local control rate at 1 year post RT 
Have received at least one fraction of 
radiation therapy and undergone at 
least one disease assessment 
Rate of grade 3 or greater toxicity 
Have received at least one fraction of 
radiation therapy 
Overall survival at 1 year post RT 
Have received at least one fraction of 
radiation therapy 
Disease-free survival at 1 year post RT 
Have received at least one fraction of 
radiation therapy and undergone at 
least one disease assessment 
Exploratory 
Average percent difference in coverage of 
PTV by 95% isodose line 
Have received at least one fraction of 
radiation therapy 
Average percentage difference in dose to 
nearby OARs due to variation in OAR 
position 
Have received at least one fraction of 
radiation therapy 
Percentage of patients in each TCGA 
molecular subtype after radiation and 
chemotherapy 
Have completed radiation therapy and 
neoadjuvant chemotherapy 
Specific biomarkers 
Have had specimens collected for 
biomarkers 
ctDNA 
Have had specimens collected for 
biomarkers 
 
Note that inevaluable patients will not be replaced. 
  
6.7 
Concomitant Therapy and Supportive Care Guidelines 
 
Although addition of trastuzumab is not considered standard of care in the management of 
locally advanced gastric cancer, if the treating physician feels that adding trastuzumab 
would be in the patient’s best interests, it will be allowed. 
 
6.8 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 21 days prior to the first dose of study treatment.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 3 months following the last dose of study treatment.  
 
If a patient is suspected to be pregnant, all study treatment should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 


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If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up.  
 
6.9 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, radiation therapy will continue 
for 5 fractions, neoadjuvant chemotherapy will continue for up to 4 months, and surgery 
will take place after that.  Treatment will be discontinued if one of the following criteria 
applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
6.10 
Duration of Follow-up 
 
Patients will be followed for local recurrence, distant recurrence, and toxicity for 12 months 
after surgery (or date of definitive end of treatment for patients who do not have surgery).  
Follow-up visits will be include the following: 
 
• 3-month follow-up: H&P, ECOG PS.  
• 6-month follow-up: CT C/A/P, blood for ctDNA. 
• 12-month follow-up: CT C/A/P  
 
6.11 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled 


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visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 1 month and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
7.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
7.1 
Dosing Adjustments for Radiation Therapy 
 
Radiotherapy for this trial may take place over a maximum of 10 business days before it is 
considered a protocol deviation.  There are no dose adjustments (reductions, omissions) 
associated with radiotherapy. 
 
7.2 
Dosing Adjustments for Chemotherapy 
 
Dose reductions and holds for chemotherapy may be made at the discretion of the treating 
physician.  All chemotherapy is being given as per standard of care, and dosing is not 
dictated by this protocol.  Please refer to the package insert of each drug for recommended 
dosing adjustments. 
 
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. Please refer to Appendix B for definitions and Appendix C for a grid of reporting 
timelines. All investigators treating patients on this study are responsible for ensuring that serious 
adverse events (as defined in Appendix B) are reported to the WUSM PI within an adequate 
timeframe for the event to be assessed by the WUSM PI for reporting to HRPO and QASMC. 
 
Adverse events will be tracked from baseline through 12 months after surgery (or, for patients who 
do not undergo surgery, 12 months after definitive end of treatment). All adverse events must be 
recorded on the toxicity tracking case report form (CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 


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• Adverse events that are thought to be at least possibly related to a non-protocol treatment 
received after the patient comes off SCRT or neoadjuvant chemotherapy 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University School of Medicine study team may be found 
in Section 8.1.  Reporting requirements for secondary site study teams participating in WUSM-
coordinated research may be found in Section 8.2. 
 
8.1 
WU PI Reporting Requirements 
 
8.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
8.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The WUSM PI (or designee) is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  
(Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu. Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
For events that occur at secondary sites, the WUSM PI (or designee) is required to 
notify the QASMC within 10 days of WUSM notification via email to 
qasmc@wustl.edu.  Submission to QASMC must include either the myIRB form 
and supporting documentation or (if not submitted to myIRB) the date of 
occurrence, description of the event, whether the event is described in the currently 
IRB approved materials, the event outcome, determination of relatedness, whether 
currently enrolled participants will be notified, and whether the informed consent 
document and/or any study procedures will be modified as a result of this event. 
 
8.1.3 Reporting to Secondary Sites 
 
The WUSM PI (or designee) will notify the research team at each secondary site of 


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all unanticipated problems involving risks to participants or others that have 
occurred at other sites within 10 working days of the occurrence of the event or 
notification of the PI (or designee) of the event.  This includes events that take place 
both at Washington University and at other secondary sites, if applicable.  Refer to 
Section 16.0 (Multicenter Management) for more information 
 
8.2 
Secondary Site Reporting Requirements 
 
The research team at each secondary site is required to promptly notify the WUSM PI and 
designee of all serious adverse events (refer to Appendix B, Section D) within 1 working 
day of the occurrence of the event or notification of the secondary site’s PI of the event.  
This notification may take place via email if there is not yet enough information for a 
formal written report (using FDA Form 3500A (MedWatch) and Washington University’s 
cover sheet (Appendix D)) form if required or an institutional SAE reporting form if not).  
A formal written report (using FDA Form 3500A) must be sent to the WUSM PI and 
designee within 4 calendar days (for fatal or life-threatening suspected adverse reactions) 
or 11 calendar days (for serious unexpected adverse reactions) of the occurrence of the 
event or notification of the secondary site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.   
 
WUSM research team pre-approval of all protocol exceptions must be obtained prior to 
implementing the change.  Local IRB approval must be obtained as per local guidelines.  
WUSM IRB approval is not required for protocol exceptions occurring at secondary sites. 
 
8.3 
Sub-Investigator Reporting Requirements 
 
All investigators treating patients on this study are responsible for ensuring that serious 
adverse events (as defined in Appendix B) are reported to the WUSM PI within 24 hours 
of learning of the event in order for the event to be assessed by the WUSM PI for reporting 
to HRPO and QASMC. 
 
8.4 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 8.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
9.0 
CORRELATIVE STUDIES 
 


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9.1 
Tissue for Research 
 
Patients with pCR will have normal gastric tissue collected at the time of surgery.  Fresh 
tissue will be formalin-fixed and paraffin-embedded (FFPE) per institutional standards. 
 
RNA and whole exome sequencing will be used for formalin-fixed, paraffin-embedded, 
post-treatment gastric adenocarcinoma tissue samples to determine the post-treatment 
patient distribution amongst the TCGA molecular subgroups. Blocks will be reviewed by 
institutional pathologists, H&E slide prepared to identify the block with highest tumor 
volume and grade (ideally tumor samples with ≥60% tumor nuclei and ≤20% necrosis will 
be processed for nucleic acid extraction38) and then the corresponding block sent for 
biomarker analysis. Normal tissue adjacent to tumor will also be obtained for differential 
expression analysis. FFPE tissue will be packaged in insulated Styrofoam packaging and 
shipped to and sequencing performed at the Washington University Genome Technology 
Access Center. Cold packs and dry ice are not necessary for FFPE tissue samples.  Shipping 
address is: 
Genome Technology Access Center 
Cortex, Suite 209 
4444 Forest Park 
St. Louis, MO 63108  
 
9.1.1 TCGA Molecular Subtype Analysis 
 
Whole transcriptome sequencing (RNA-seq) data will be aligned to Human 
Genome Reference Consortium Human Build 38 (GRCh38) using HISAT263 with 
Ensembl genes for Homo sapiens version 90 and TCONs. Novel transcripts will be 
assembled and all gene expression levels (Fragments Per Kilobase per Million 
fragments, or FPKM) will be calculated using Cufflinks64. Read counts will be 
calculated using featureCounts65. Whole exome sequencing data will be aligned to 
GRCh38 using BWA66. Single nucleotide variants will be called using GATK 6 
and VarScan267. Small indels and structural variations will be discovered using 
Pindel68. Copy number variations will be analyzed using GISTIC269. RNA-seq data 
will also be aligned to reference Epstein-Barr Virus (EBV) genes using BLAT70. 
Samples will be classified into subtypes using the methods as described 
previously38. Pearson's chi-squared test (χ2) will be applied to TCGA molecular 
subtypes to evaluate the difference in post-treatment data compared to TCGA data. 
 
9.1.2 Differential Biomarker Expression Analysis 
 
Whole transcriptome sequencing data will be pre-processed excluding genes with 
consistent low expression levels (e.g. <1 FPKM or <200 reads) across all samples71. 
MicroRNA and non-coding small RNA expression will be calculated72.  The 
Bioconductor packages including DEseq74 and edgeR75 will be applied to the above 
raw read counts in the unit of genes or pathways. Raw read counts are modeled on 
the negative binomial (NB) distribution in both packages. This is recommended for 
proper RNA-seq DE analysis since it will handle the well-known over-dispersion 


Amendment 5 // Protocol Version 9: 16 April 2024 
 
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problem by adjusting relevant variables and solving the multiple testing issue. The 
ratio of means (e.g. log fold-change > 1.5) will be used as the effect size measure 
as indicated previously76, and adjusted false discovery rate (FDR) will be applied 
to reduce type I errors from a list of differentially expressed genes. All biomarkers 
discovered will be examined for their predictive and prognostic utility using 
Kaplan–Meier estimator. Further experiments will include larger discovery and 
validation patient cohorts using these biomarker panels to verify their association 
with clinical outcomes in Korean and Western gastric cancer patients77. 
 
9.2 
Blood for ctDNA 
 
Twenty mL of blood will be collected into EDTA tubes at the following time points: 
• Prior to the start of radiation 
• After the completion of radiation therapy and prior to starting chemotherapy (2-4 
weeks after radiation completion) 
• At the completion of chemotherapy and prior to surgery (2-4 weeks after 
chemotherapy completion) 
• 6 months after surgery 
 
Use BD Vacutainer purple top 10mL K2-EDTA tubes for blood collection (Becton 
Dickinson catalog # 366643). Under no circumstances should blood collected in heparin 
tubes be used, as heparin greatly inhibits the downstream reactions. Process the blood as 
soon as possible after drawing (within 2 hours, upper limit 6 hours per Parpart-Li et al, 
CCR, 2016). If there is a delay between phlebotomy and processing, keep tubes in 
refrigerator at ~4°C. If not processed immediately, note the time delay prior to processing. 
  
Plasma and Plasma Depleted Whole Blood (PWDB) Banking  
1. ~20 ml of whole blood will be collected in K2-EDTA tubes (purple) and placed on 
ice. 
2. Pool whole blood to measure collected volume. 
3. Split whole blood into two tubes and spin at 1800 x g for 10 minutes at 15-200 C. 
4. Remove tubes from centrifuge carefully and place on ice. 
5. Remove supernatant (plasma) to fresh tube(s). 
6. Spin supernatant a second time, 1800 x g for 5 minutes at 15-200 C.  
7. Remove cleared plasma supernatant and aliquot into 2 ml vials. (If there is a cell 
pellet after 2nd spin, suspend these cells in remaining plasma and add this mixture 
to PDWB, see step 9). 
8. Move frozen Plasma vials to a storage box @ -80o C. 
9. During second plasma spin, gently mix remaining PDWB cells from step 5 above.  
10. Remove 2 ~1.8 ml PDWB aliquots, and store @ -80o C. 
11. Ship plasma and PDWB on dry ice. 
  
CAPP-SEq analysis will be as previously described, with barcoded adapters for library 
preparation, targeted DNA hybrid capture, and next-generation sequencing followed by 
bioinformatic correction of stereotypic errors.  
 


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All biospecimens will be marked according to individual country regulations prior to 
shipment to Washington University.  For local specimens, take directly to the Fields lab 
for processing.  For specimens from participating sites, ship processed specimens to the 
Fields lab at the address below: 
Washington University School of Medicine 
Department of Surgery 
425 South Euclid Avenue 
Fields Lab 
Clinical Science Research Building, Room 3306 
St. Louis, MO 63110 
 
 
10.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
MRgRT Treatment Summary 
Form 
End of radiation 
SOC Chemo Treatment Form End of each cycle of SOC chemotherapy 
Surgery Form 
Research Tissue Form 
Time of surgery 
Research Blood Form 
Prior to starting treatment, end of radiation, end of neoadjuvant 
chemotherapy, 6-month follow-up 
Toxicity Form 
Continuous until 12 months after surgery/date of definitive end 
of treatment 
Follow Up Form 
3 months, 6 months, and 12 months after surgery 
Local Control Form 
12 months after start of radiation 
Progression Form 
Time of progression 
Death Form 
Time of death 
MedWatch Form 
See Section 8.0 for reporting requirements 
 
Secondary sites are expected to enter data within 10 business days. Any queries generated by 
WUSM must be responded to within 10 days of receipt by the participating site. The WUSM 
research team will conduct a regular review of data status at all secondary sites, with appropriate 
corrective action to be requested as needed. 
 
De-identified patient clinical data will be submitted by all non-Washington University sites on the 
OnCore website. No patient identifiers will be included for non-Washington University patients 
with the exception of dates. Unique patient identification numbers will be assigned to each patient 
and the corresponding patient identifiers (protected health information) will be known only to the 
investigators within each respective institution. 


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10.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 8.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
11.0 
MEASUREMENT OF EFFECT 
 
Effect will be measured by the rate of pCR (primary and nodal) found at the time of surgical 
resection. Partial pathologic response will be defined as < 10% viable tumor remaining.  Residual 
disease will be documented in the form of % treatment response and % viable tumor. No 
radiographic response to treatment will be recorded or assessed. 
 
 
12.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  The DSMB will consist of no fewer than 3 members including 2 
clinical investigators and a biostatistician.  DSMB members must be employed by Washington 
University, Barnes-Jewish Hospital, or St. Louis Children’s Hospital (unless an external ad hoc 
member is necessary due to a conflict of interest).  Like investigators, DSMB members are subject 
to the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB must also 
be disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to 
be prepared by the study team will be submitted directly to the Quality Assurance and Safety 
Monitoring Committee (QASMC) (bypassing the independent DSMB). The first report is required 
either 30 days after the enrollment of the 5th participant (if sooner than 6 months after study 
activation) or 6 months after study activation (provided at least one patient has been enrolled; if 
zero patients have been enrolled at the 6-month mark, the first report will be required one year 
after accrual opens provided at least one patient has been enrolled). 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician. Following review by the DSMB, the report and the DSMB’s recommendations will be 
submitted to the QASM Committee.  The DSMB must review this study at least every six months 


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beginning six months after enrollment of the first patient at a secondary site, no more than one 
month prior to the due date of the DSM report to QASMC.  This report will include: 
• Study demographic information (local protocol number, protocol title, list of 
primary study team members, study sites, primary and secondary sponsors, date of 
most recent QA audit, and study status and history (including activation and 
suspension dates) 
• Accrual information, including study-wide target accrual and actual accrual, 
anticipated and/or actual accrual end date, and accrual by year by site 
• Subject status information presented in both cumulative format (total number of 
subjects who consented, enrolled, screen failed, started intervention, discontinued 
intervention, went off study, expired) and current format (number of subjects in 
screening, on intervention, in follow-up, or off study at time of report) 
• Protocol objectives and the number of participants who are evaluable for each 
objective 
• History of study (including summaries of substantive amendments, accrual 
suspensions and reasons, protocol exceptions, errors, and breaches of 
confidentiality) 
• Summary of exceptions, noncompliance reports, and unanticipated problems 
reported to the IRB 
• Early stopping rules and data describing whether the stopping rules have been met 
• Separate SAE and worst grade toxicity tables, each separated by site 
• Participant-level response and survival data 
• Summary of specimen collection (percentage of participants who have had 
specimens collected at each required time point) 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety of participants or the 
ethics of the study   
 
Further DSMB responsibilities are described in the DSMC charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 8.0). 
  
Refer to the Quality Assurance and Safety Monitoring Committee Policies and Procedures and the 
Siteman Cancer Center Independent Data Safety Monitoring Board (DSMB) Policies and 
Procedures documents for full details on the responsibilities of the DSMB.  This is located on the 
QASMC 
website 
at 
https://siteman.wustl.edu/research/resources-for-researchers/quality-
assurance-and-safety-monitoring/.  
 
 
13.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC)) will monitor each participating site to ensure that all protocol 


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requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the WUSM study team designee, who will obtain the audit materials 
from the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
• Subject screening and enrollment 
• Reporting of adverse events 
• Maintenance of HIPAA compliance 
• Completeness of regulatory documentation 
• Completeness of participant documentation 
• Acquisition of informed consent 
• IRB documentation 
• Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/research/resources-for-researchers/quality-assurance-and-safety-
monitoring/.  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Statistical Hypotheses and Sample Size Determination 
 
Chemotherapy alone has a pCR rate of 6-16%10. PCR is defined as a pathologic complete 
response (no tumor on gastrectomy specimen). We hypothesized that preoperative 
radiation followed by chemotherapy would result in a pCR rate of 20%, and with 36 
patients, our confidence interval for this estimate will fall between 9% and 37%. 
 
14.2 
Analysis of the Primary Endpoint 
 
The pCR rate will be described as percent with 95% confidence interval.  Because only 
patients who undergo surgery are considered evaluable for the primary endpoint, the 
denominator used to describe the pCR rate will be the number evaluable.  This will be 
described clearly when study results are reported. 
 
14.3 
Analysis of Secondary Endpoints  
 
Secondary endpoints include the following: 


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• The proportion of patients that can complete total neoadjuvant chemotherapy. 
• The local control rate at 1 year will be described as percent with 95% confidence 
interval. Local control is defined as no local recurrence, calculated from RT start. 
• The rate of grade 3 or higher toxicity will also be described as percent with 95% 
confidence interval. 
• Kaplan-Meier estimates will be used to describe disease-free survival (no cancer 
evident or death) and overall survival (survival from start of RT) at 1 year. 
 
14.4 
Baseline Descriptive Statistics 
 
Baseline demographic characteristics will be summarized: Continuous factors will be 
presented as median with range; categorical factors will be presented as counts and 
percentages. 
 
 
15.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the WUSM Regulatory Coordinator (or designee) prior to 
IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show which 
version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
• Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 


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Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 
 
 
 
 


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16.0 
REFERENCES 
 
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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 


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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, 
or welfare of participants or others or the scientific validity of the study. 
 
 


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APPENDIX C: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Unanticipated problem 
involving risk to participants or 
others 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report 
within 1 working day. 
Report via email after IRB 
acknowledgment 
Major deviation 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report 
within 1 working day. 
 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working days.   
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants 
or others OR noncompliance, report 
within 10 working days.  If the event 
results in the death of a participant 
enrolled at WU/BJH/SLCH, report 
within 1 working day.  Otherwise, report 
at the time of continuing review. 
 
Breach of confidentiality 
Within 10 working days. 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
 


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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
working day.  Otherwise, report at the time of 
continuing review. 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
Serious AND unexpected 
suspected adverse reaction 
Report no later than 11 calendar days 
after it is determined that the information 
qualifies for reporting. 
Report all applicable events 
to local IRB according to 
local institutional guidelines. 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
Report no later than 4 calendar days after 
initial receipt of the information. 
Unanticipated problem 
involving risk to participants 
or others 
Report no later than 4 calendar days after 
initial receipt of the information. 
Adverse event or SAE that 
does not require expedited 
reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 
 


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APPENDIX D: Washington University Unanticipated Problem Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
WUSM PI:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Admission Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
1. Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
2. Is this event unexpected? 
 
 yes  
 
 no 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date 
 
 


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APPENDIX E: Study-Specific DSM Tables 
 
Protocol Objectives and Subject Evaluability 
Objective 
# of patients evaluable for this 
endpoint to date 
Primary 
To quantify the pCR rate in gastric cancer patients 
treated with preoperative radiation followed by total 
neoadjuvant chemotherapy. 
  
Secondary 
To quantify the proportion of patients able to complete a 
full course of total neoadjuvant chemotherapy 
 
To quantify the local control rate of gastric cancer 
patients treated with preoperative radiation followed by 
chemotherapy 
 
To quantify the toxicity of gastric cancer patients treated 
with preoperative radiation followed by chemotherapy 
 
To quantify the overall survival in gastric cancer patients 
treated with preoperative radiation followed by 
chemotherapy 
 
To quantify the disease-free survival in gastric cancer 
patients treated with preoperative radiation followed by 
chemotherapy 
 
Exploratory 
To quantify the deviation in dose to the tumor due to 
variation in stomach position 
 
To quantify the deviation in dose to the nearby OARs 
due to variation in OAR position 
 
To determine the distribution of TCGA molecular 
subtypes in gastric adenocarcinoma after radiation and 
chemotherapy 
 
To identify differentially expressed post-treatment 
biomarkers  
 
To correlate circulating tumor DNA (ctDNA) levels with 
clinical outcomes 
 
 
 
Interim Analysis and Early Stopping Rules 
Does the study design include an interim toxicity analysis? 
No 
Does the study design include an interim futility analysis? 
No 
Are there early stopping rules that outline circumstances under which the study must be 
suspended or closed? 
Yes 
If yes, please insert text describing early stopping rules from the protocol: 


Amendment 5 // Protocol Version 9: 16 April 2024 
 
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There will be a lead-in safety cohort of 5 patients, monitored for 30 days after completion of 
RT. If there is one treatment-related patient death, then the safety cohort will be expanded to 10 
patients. If there are two or more treatment-related deaths, the radiation dose will be decreased 
to 20 Gy in 5 fractions. The trial will be terminated if there are more than three treatment-related 
deaths (equaling approximately 10% of the entire projected accrual). 
If yes, please provide data describing whether the stopping rules have been met (by 
indicating whether there have been any treatment-related grade 5 toxicities in the safety 
lead-in cohort): 
 
 
 
Response 
UPN 
On tx 
date 
# fx SCRT 
complete 
# cycles chemo 
complete 
Pathologic 
response 
Date of 
progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Discontinuation and Survival 
UPN 
Off tx 
date 
Reason off tx 
Vital status 
If dead, cause 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary of Specimen Collections 
Type of specimen 
Time point 
# of patients 
eligible for 
collection at this 
time point 
% of patients who 
have reached this 
time point and had 
the specimen collected 
Tissue 
Surgery 
 
 
Blood for ctDNA 
Prior to start of RT 
 
 
After completion of 
RT but before 
starting chemo  
 
 
After completion of 
chemo but before 
surgery 
 
 
6 months after 
surgery