Pre-Operative Immuno-Modulatory SBRT (POIMS Trial): A Pilot Trial in Early Stage NSCLC
Phase: NA
Conditions: Non-small Cell Lung Cancer
Sponsor: University of Kansas Medical Center

Official Study Title: 
Pre-Operative Immuno-Modulatory SBRT (POIMS Trial): A Pilot Trial in Early Stage NSCLC 
NCT Number: [not yet assigned] 
Document Description: Protocol Version 1.0 
Document Date: October 14, 2020 
 

 
 
 
Investigator Initiated Trial 
 
 
Pre-Operative Immuno-Modulatory SBRT (POIMS Trial): A pilot trial in early stage NSCLC 
 
SPONSOR/INVESTIGATOR 
 
Shalina Gupta-Burt, MD 
 
Assistant Professor 
Department of Radiation Oncology 
University of Kansas School of Medicine 
3901 Rainbow Blvd 
Mail Station 4033 
Kansas City KS   66160 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This material is the property of The University of Kansas Cancer Center. Do not disclose or use except as 
authorized in writing by the Sponsor/Investigator. 
The information contained in this document is property of The University of Kansas Cancer Center (or under its control), and therefore 
provided to you in confidence as an investigator, potential investigator or consultant for review by you, your staff and an applicable 
Independent Ethics Committee/Institutional Review Board. It is understood that this information will not be disclosed to others without 
written authorization from the Sponsor/Investigator except to the extent necessary to obtain informed consent from those persons to 
whom the trial treatment may be administered. 
 
 
Protocol Number: IIT-2020-POIMS-Lung 
Agent: Stereotactic Body Radiation Therapy (SBRT) 
  
Protocol Version: 1.0 dated 10-14-2020 
Funder: Varian   

The University of Kansas Cancer Center 
 
IIT-2020-POIMS-Lung 
Sponsor-Investigator:  Shalina Gupta-Burt, MD 
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Protocol Version 1.0 dated 10-14-2020 
CONFIDENTIAL 
 
LIST OF COLLABORATORS 
 
Co-Investigators: 
 
Alykhan Nagji, MD, Assistant Professor, Cardiovascular & Thoracic Surgery, The University of Kansas Medical 
Center 
Nirmal Veeramachaneni, MD, Assistant Professor, Cardiovascular & Thoracic Surgery, The University of Kansas 
Medical Center 
Gregory Gan, MD, PhD, Assistant Professor, Radiation Oncology, The University of Kansas Medical Center 
Shane Stecklein, MD,PhD, Assistant Professor, Radiation Oncology, The University of Kansas Medical Center 
David Akhavan, MD, PhD, Assistant Professor, Radiation Oncology, The University of Kansas Medical Center 
 
Rashna Madan MBBS, Professor, Department of Pathology and Laboratory Medicine, The University of Kansas 
Medical Center 
Subhrajit Saha, PhD, Associate Professor, Radiation Oncology, The University of Kansas Medical Center 
Habeeb Saleh, PhD, Chief, Medical Physics, Radiation Oncology, The University of Kansas Medical Center 
Shahid Awan, PhD, Medical Physicist, Radiation Oncology, The University of Kansas Medical Center 
Ying Cao, Statistician, Department of Radiation Oncology, The University of Kansas Medical Center 
 
Steven Soper, PhD, Professor, Chemistry, Biomedical Engineering (Liquid Biopsy Core Facility) The University of 
Kansas 
Malgorzata Witek, PhD, Associate Research Professor, Chemistry, Biomedical Engineering (Liquid Biopsy Core 
Facility) The University of Kansas 
Andrew Godwin, PhD, Professor, Pathology & Laboratory Medicine, Director, Biospecimen Repository Core 
Facility [BRCF] and Director, Clinical Molecular Oncology Laboratory [CMOL]) The University of Kansas Medical 
Center 
Amanda Schroder, Clinical Trials Coordinator, Radiation Oncology, The University of Kansas Medical Center 
Michele Park, (Biospecimen Repository Core Facility [BRCF]) 
LaToya Berry, (Clinical Pharmacology Shared Resource [CPSR]) 
 
Participating Sites: 
 
The University of Kansas Cancer Center 
 
 
 
 
 
 
 
 
 
 

The University of Kansas Cancer Center 
 
IIT-2020-POIMS-Lung 
Sponsor-Investigator:  Shalina Gupta-Burt, MD 
Page 3 of 49 
 
Protocol Version 1.0 dated 10-14-2020 
CONFIDENTIAL 
 
STATEMENT OF COMPLIANCE / PROTOCOL AGREEMENT 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice 
(ICH GCP) and the following:  
 
• 
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)  
 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the funding agency and documented approval from the Institutional Review Board (IRB), 
except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study 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.  
 
Protocol Number IIT-2020-POIMS-Lung 
Protocol Title Pre-Operative Immuno-Modulatory SBRT (POIMS Trial): A pilot trial in 
early stage NSCLC 
Sponsor/Investigator Shalina Gupta-Burt, MD 
 
 
Signature of Principal Investigator                                                                                        Date 
Printed Principal Investigator Name  
Institution Name 
 
 
 
 
 
 
 

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IIT-2020-POIMS-Lung 
Sponsor-Investigator:  Shalina Gupta-Burt, MD 
Page 4 of 49 
 
Protocol Version 1.0 dated 10-14-2020 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
LIST OF COLLABORATORS ................................................................................................................... 2 
STATEMENT OF COMPLIANCE / PROTOCOL AGREEMENT ........................................................ 3 
TABLE OF CONTENTS ............................................................................................................................ 4 
SCHEMATIC OF STUDY DESIGN ......................................................................................................... 6 
PROTOCOL SUMMARY .......................................................................................................................... 7 
1 
INTRODUCTION ............................................................................................................................ 9 
1.1 
Background ............................................................................................................................ 9 
1.2 
Rationale ................................................................................................................................ 9 
1.3 
Risk/Benefit Assessment ................................................................................................... 10 
 
Known Potential Risks ..................................................................................... 10 
 
Known Potential Benefits ................................................................................. 10 
 
Assessment of Potential Risks and Benefits ................................................ 11 
1.4 
Measures to Minimize Bias:  Randomization and Blinding .......................................... 11 
2 
HYPOTHESIS ............................................................................................................................... 11 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................. 11 
3.1 
Primary Objective ................................................................................................................ 11 
3.2 
Secondary Objectives ........................................................................................................ 12 
3.3 
Primary Endpoints .............................................................................................................. 12 
3.4 
Secondary Endpoints ......................................................................................................... 12 
4 
STUDY DESIGN ........................................................................................................................... 13 
4.1 
Overall Design ..................................................................................................................... 13 
4.2 
Justification for Dose .......................................................................................................... 13 
4.3 
End of Study Definition ...................................................................................................... 13 
5 
PARTICIPANT SELECTION ....................................................................................................... 13 
5.1 
Inclusion Criteria ................................................................................................................. 13 
5.2 
Exclusion Criteria ................................................................................................................ 15 
6 
CHILD-BEARING POTENTIAL / PREGNANCY ...................................................................... 16 
6.1 
Screen Failures ................................................................................................................... 16 
6.2 
Participant Replacement .................................................................................................... 16 
7 
PARTICIPANT REGISTRATION PROCEDURES .................................................................. 17 
7.1 
General Guidelines ............................................................................................................. 17 
7.2 
Registration Process .......................................................................................................... 17 
8 
study intervention PLAN .............................................................................................................. 17 
8.1 
Radiation Treatment Regimen .......................................................................................... 17 
8.2 
Sample Procurement .......................................................................................................... 21 
 
Pre-SBRT Biopsy Sample ............................................................................... 21 
 
Surgical Sample ................................................................................................ 21 
9 
STUDY PROCEDURES AND SCHEDULE .............................................................................. 21 
9.1 
Screening/Enrollment/Baseline......................................................................................... 21 
 
Procedures During Study Intervention ........................................................... 22 
 
Follow-Up Visits ................................................................................................. 23 
9.2 
Lost to Follow Up ................................................................................................................ 24 
9.3 
SCHEDULE OF EVENTS TABLE .................................................................................... 25 
9.4 
Supportive Care Guidelines .............................................................................................. 27 
 
Prohibited or Restricted Concomitant Medications ........................................... 27 
 
Diet 
27 

The University of Kansas Cancer Center 
 
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Sponsor-Investigator:  Shalina Gupta-Burt, MD 
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Protocol Version 1.0 dated 10-14-2020 
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9.5 
Participant Discontinuation/Withdrawal from the Study ................................................ 27 
10 
TRANSLATIONAL STUDIES ...................................................................................................... 28 
11 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ............................................................ 29 
11.1 
Adverse Event Monitoring ................................................................................................. 30 
11.2 
Adverse Event Reporting ................................................................................................... 30 
11.3 
Serious Adverse Event Reporting .................................................................................... 30 
 
Pregnancy Reporting ........................................................................................ 30 
12 
STATISTICAL CONSIDERATIONS ........................................................................................... 31 
12.1 
Description of Statistical Methods .................................................................................... 31 
12.2 
Study Stopping Rules ......................................................................................................... 31 
13 
REGULATORY REQUIREMENTS AND DATA REPORTING .............................................. 31 
13.1 
Institutional Review Board/Ethics Committee Approval ................................................ 31 
13.2 
Investigators Protocol Agreement .................................................................................... 32 
13.3 
Remaining Samples ........................................................................................................... 32 
13.4 
Confidentiality ...................................................................................................................... 32 
13.5 
Publication ............................................................................................................................ 32 
13.6 
Compliance with Trial Registration and Results Posting Requirements .................... 33 
13.7 
Required Site Documentation ........................................................................................... 33 
13.8 
Data Management .............................................................................................................. 33 
13.9 
Data Monitoring ................................................................................................................... 33 
14 
DSMC OVERSIGHT..................................................................................................................... 34 
14.1 
Serious Adverse Events..................................................................................................... 34 
14.2 
Review of Serious Adverse Event Rates ........................................................................ 35 
14.3 
Study Safety and Progress ................................................................................................ 35 
14.4 
The University of Kansas Cancer Center Quality Assurance Auditing ....................... 35 
15 
DATA HANDLING AND RECORD KEEPING .......................................................................... 35 
15.1 
Data Collection and Management Responsibilities ....................................................... 35 
15.2 
Protocol Deviations ............................................................................................................. 36 
15.3 
Study Closure ...................................................................................................................... 36 
15.4 
Study Records Retention ................................................................................................... 36 
16 
APPENDICES ............................................................................................................................... 37 
Appendix A:  ECOG Performance Status ......................................................................................... 37 
Appendix B:  Reportable Events ........................................................................................................ 38 
Adverse Event (AE) Definition ........................................................................................................ 38 
Serious Adverse Event (SAE) Definition ....................................................................................... 38 
Unanticipated Problem 
39 
Suspected Adverse Reaction .......................................................................................................... 39 
Expectedness and Attribution ......................................................................................................... 39 
Expectedness 
39 
Attribution 
40 
Adverse Event Monitoring 40 
Appendix C:  Clavien-Dindo Classification for Surgical Complications ........................................ 42 
Appendix D:  Examples of Grading Using Clavien-Dindo Classification ..................................... 43 
Appendix E:  Wound Healing Assessment - GTSD Training Manual- Pages 246-248 ............. 44 
17 
LITERATURE REFERENCES .................................................................................................... 47 
 
 
 
 

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Protocol Version 1.0 dated 10-14-2020 
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SCHEMATIC OF STUDY DESIGN 
 
Pre-Operative Immuno-Modulatory SBRT 
(POIMS Trial) 
A pilot trial in early stage NSCLC 
 
 
Diagnostic 
Biopsy 
Blood and 
Serum samples
SBRT 5-7 days 
preop 
800cGy x 3 
fractions 
10 patients
Surgery 
Blood and 
Serum samples
Tumor/Normal 
Tissue samples
Post-op Follow-
up 
Blood and 
Serum samples

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Sponsor-Investigator:  Shalina Gupta-Burt, MD 
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Protocol Version 1.0 dated 10-14-2020 
CONFIDENTIAL 
 
PROTOCOL SUMMARY 
 
Title 
Pre-Operative Immuno-Modulatory SBRT (POIMS Trial): A pilot trial in 
early stage NSCLC 
Protocol Number 
IIT-2020-POIMS-Lung 
Phase 
Pilot 
Design 
Single arm pilot trial 
Study Duration 
Approximately 5 years 
 
• 
Enrollment Period – approximately 18 months 
• 
Follow up period for adverse events to 36 months after surgery  
• 
Follow up period for post-operative surgical complication / wound 
healing events- 3-6 months after surgery  
• 
Follow-up period for disease outcome–36 months after surgery   
Study Center 
University of Kansas Cancer Center 
Objectives 
Primary:  
Assess the impact of non-ablative SBRT (800 cGy X 3 fractions) on 
immunomodulation in NSCLC tumor cells 
Secondary: 
Assess the impact of non-ablative SBRT (800 cGy X 3 fractions) prior to 
surgical resection on peri- and post-operative surgical complication rate, 
wound healing, and disease outcomes. 
Number of Participants 
10 
Diagnosis and Main 
Inclusion Criteria 
Inclusion Criteria: 
• 
Stage I-II NSCLC 
• 
Adequate diagnostic biopsy tissue to allow pre-SBRT tumor analysis 
• 
Candidate for oncologic surgery (lobectomy or sub lobar resection) for 
the lung cancer 
• 
Lesion located peripherally, ≥ 2 cm from bronchial margin, and 1 cm 
from visceral pleura, with location deemed acceptable by cardio-
thoracic surgeon for resection. 
• 
Adequate pulmonary function test results 
Exclusion Criteria: 
• 
Prior history of lung/chest wall surgery 
• 
Prior chest radiation 
• 
Prior immunotherapy 
• 
History of autoimmune disease 
• 
Currently using immunosuppressive drugs 
Study Product(s), Dose, 
Route, Regimen 
SBRT 800 cGy x 3 fractions 

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Duration of 
Administration 
Total:  4-5 days 
 
1-2 days - consultation and simulation  
 
3 treatment (study intervention) days 
 
Study intervention (SBRT) delivery will be scheduled for 3 consecutive 
days, but may be modified as needed by the treating radiation oncologist. 
Interim Monitoring 
The data safety monitoring committee (DSMC)  of The University of 
Kansas Cancer Center is responsible for monitoring participant safety for 
this trial. 
Statistical Methodology  
We will summarize peri- and post- operative surgical complication rates as 
well as tumor control outcomes using descriptive statistics. 
 
Peri- and post- operative surgical complication rates will be quantified 
using the Clavien-Dindo classification of surgical complications 1,2. 
 
Wound healing complication rates will be scaled as defined by the 
General Thoracic Surgery Database. 3  
Stopping Rules 
 
If a participant experiences one or more of the following events, possibly 
related to study intervention, study will be suspended pending DSMC 
review to determine if study should continue. 
 
a. Wound healing delay beyond standard timeframe as deemed by 
study Cardio-Vascular (CV) surgeons 
b. Peri operative/post-operative surgical complications  beyond 
acceptable institutional rates as determined by study CV surgeons 
c. Death from study intervention 
 
 
 

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1 
INTRODUCTION 
 
1.1 
Background 
 
Recent advances in immunotherapy has resulted in a new era for the treatment of NSCLC. Radiotherapy is 
commonly used in early stage, locally advanced and advanced stage of NSCLC treatment. More recently the 
utility of highly conformal, large fraction size radiation defined as SBRT has become standard of care for early 
stage and oligometastatic NSCLC. The interplay of XRT and immunotherapy, however, remains poorly defined in 
NSCLC.4 The immunomodulatory potential of XRT has been long recognized but not yet well defined for clinical 
utility and integration into combined immunotherapy and XRT regimens. The phenotypic changes in tumor cell 
surface marker expression (e.g. PD-L1), tumor and surrounding normal tissue microenvironment, and 
serum/blood immune profile changes due to XRT have not been well elucidated in this patient population. This 
has been challenging in patients with NSCLC who receive radiation due the difficulty in obtaining post XRT tumor 
tissue.5 Defining the independent effect of XRT, more specifically, SBRT on the immunoregulatory pathways is 
also complicated by the multitude of trials that combine various immunotherapy agents with XRT complicating 
the analysis. The impact of the immunomodulation by non-ablative lower dose SBRT prior to definitive surgery on 
immunoregulatory pathways needs to be defined.6,7 
 
Cell culture and animal data have demonstrated that cytotoxic doses of XRT may not elicit a clinically meaningful 
alteration in the immune profile. In contrast, several cell culture and animal model studies have indicated that 
fractionated low dose XRT may provide a more immunomodulatory effect.8,9,10 In addition, there is a lack of 
consensus regarding the superiority of single fraction versus multi-fraction SBRT yielding greater 
immunomodulation.11,12 Studies using an animal model have concluded a fractionated regimen induces a greater 
abscopal effect than single dose radiation. Furthermore, they showed a regimen of 800 cGy X 3 fractions yielded 
the most significant changes in the immune profile compared to 2000 cGy X 1 or 600 cGy X 5.13 Clinical trials 
combining radiation with a multitude of immunotherapeutic agents are difficult to interpret due to variations in 
the trial design, including the specification of the irradiated site, dose/fractionation regimens, scheduling and 
sequencing differences, selection of the immunotherapeutic agent, and vast disparity in patient/disease selection 
criteria. The in vivo phenotypic changes in tumor cell surface marker expression, tumor and normal tissue 
microenvironment and gene expression profiles, serum/blood immune profile changes, and circulating tumor cell 
immunophenotypic and gene expression alterations of non-ablative low dose radiation fractionated SBRT in 
patients with early stage NSCLC has not been elucidated. Based on published literature, we believe that this 
proposed trial, using non-ablative SBRT prior to surgery, will be safe. Recent work from the Netherlands reported 
the results of a systemic review of seven retrospective case series on salvage surgery after local recurrence in 
patients who had definitive treatment with SBRT. They noted acceptable morbidity and mortality in appropriately 
selected patients.14 A recent prospective trial of ablative SBRT performed 10 weeks before surgery noted no 
perioperative mortality and reported Grade 3 or 4 toxicity in 7 of 40 patients.15 
 
1.2 
Rationale 
 
The current proposal is structured as a pilot trial to evaluate the impact of non-ablative SBRT (800 cGy X 3 
fractions) as an immunomodulatory mechanism in patients with early stage NSCLC who are surgical candidates. 
Tumor, normal tissue and blood specimens will be analyzed for immunomodulatory changes including 
phenotypic changes in tumor cell surface marker expression, tumor and normal tissue microenvironment and 
gene expression profiles, serum/blood immune profile changes, and circulating tumor cell immunophenotypic 
and gene expression alterations. 
 

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Published literature showed that cytotoxic doses of XRT may not elicit a clinically meaningful alteration in the 
immune profile. Further, studies using an animal model have concluded a fractionated regimen induces a greater 
abscopal effect than single dose radiation. Furthermore, they showed a regimen of 800 cGy X 3 fractions yielded 
the most significant changes in the immune profile compared to 2000 cGy X 1 or 600 cGy X 5.16 
 
The immune response within the tumor milieu is a complex dynamic process with an interplay among 
lymphocyte subsets, antigen presenting cells/dendritic cells, macrophages, and tumor cells. The interactions 
between the various components is orchestrated by a variety of extracellular and intracellular signaling pathways 
involving ligand and cell surface expression, cytokine release, and activation or inhibition of a variety of T cell 
subsets. In order to comprehensively define the immunomodulatory effect of three fractions of 800 cGy on the 
primary tumor, we will analyze the following: tumor cell surface phenotype, tumor microenvironment immune 
profile and gene expression profile, T cell repertoire changes in tumor tissue and peripheral blood, and circulating 
tumor cell phenotype and gene expression profiles. Each of these components has been shown to be impacted 
by radiation in either a cell culture or animal model systems. By characterizing, quantitating and defining these 
changes related to three fractions of 800 cGy, it will directly provide important insights to inform rational uses of 
XRT and immunotherapy in the future. 
 
 
1.3 
Risk/Benefit Assessment 
 
 
KNOWN POTENTIAL RISKS  
 
Immediate Risks 
Wound healing problems, increase in peri-operative bleeding, bronchopleural fistula, 
prolonged air leak, conversion to open procedure, and/or infection. 
Other Risks 
Inconvenience to participant due to additional study-related visits (in addition to 
standard of care visits): 1 screening/enrollment visit, 1 simulation visit and 3 SBRT 
treatments. 
 
 
KNOWN POTENTIAL BENEFITS  
 
Long-Range Potential Benefits Improved disease free survival 
 
 
 

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Assessment of Potential Risks and Benefits 
 
Rationale for necessity of 
exposing participants to risks 
Potential for improved disease free survival 
Improve understanding of radiation-mediated immuno modulation of 
cancer cells in the tumor microenvironment  
Justification why benefits 
outweigh risks 
This study can lead to an improvement in cancer control and will 
improve our understanding of radiation-related cancer biology.  
 
The delivered radiation dose (800 x 3) is known to be safe and well-
tolerated, and in fact is significantly below the most common SBRT 
dose regimen used for NSCLC (1800-2000 x 3). Therefore, the 
investigators believe the risks to the patients are minimized.  
 
Therefore, the potential benefit of this study is judged to outweigh risk and the risk/benefit ratio is in favor of 
benefit. 
 
1.4 
Measures to Minimize Bias:  Randomization and Blinding 
 
This study is not randomized or blinded. Consecutive participants will be enrolled to avoid bias. 
 
2 
HYPOTHESIS  
 
Primary:  Non-ablative SBRT (800 cGy X 3 fractions) given 5-7 days preoperatively in selected patients with stage 
I-II NSCLC will result in alterations in the tumor immunoprofile, tumor microenvironment, gene expression 
profiles and peripheral blood immune repertoire.  
 
Secondary:  This regimen will be well tolerated, associated with minimal toxicity, and will not impact on wound 
healing. 
 
It should be noted that this is designed as a pilot trial, so statistical analysis will be descriptive and formal 
hypothesis-testing will not be performed 
 
3 
OBJECTIVES AND ENDPOINTS 
 
3.1 
Primary Objective 
 
Assess the impact of non-ablative SBRT (800 cGy X 3 fractions) on immunomodulation in NSCLC tumor cells 
through analysis of targeted cell surface, tumor immune microenvironment, gene expression profile, radiation 
mediated changes in T-cell repertoire in tumor issue and peripheral blood and circulating tumor cell surface 
expression. 
 
 

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3.2 
Secondary Objectives 
 
• 
Assess the impact of non-ablative SBRT (800 cGy X 3 fractions) prior to surgical resection on peri- and 
post-operative complication rate, and wound healing. 
 
o Surgical complications wil be assessed using the Clavien-Dindo Classification system. The Clavien-
Dindo classification system has been validated and established as an “objective, reproducible” 
grading classification.17  
o This classification system uses a grading based on the extent of intervention needed to manage a 
specific complication. See appendices C and D for examples. 
 
o Wound healing will be assessed and charted by the study cardio-vascular (CV) surgeons using the 
General Thoracic Surgery Database with particular references to pages 246-248. See Appendix E. 
 
• 
Describe loco-regional control, metastasis-free survival, disease-free and overall survival in patients 
treated on this trial with pre-operative SBRT followed by surgery 
 
3.3 
Primary Endpoints 
 
What is being measured 
Measurement time frame 
Measurement Tool 
The impact of non-ablative SBRT on 
Immunomodulation in tumor cells 
 
Pre and post study intervention 
biopsy tissue comparison of 
immunomodulatory parameters 
including but not limited to PDL1, 
PDL2, HCA2, IDO, HC10, B2m, 
Calreticulin, MHC-1, Fas, ICAM 
 
From time of consent and collection of 
archival tumor tissue to time of surgery 
with collection of post-study 
intervention tumor tissue. 
 
Techniques anticipated 
include but are not limited to: 
Immunohistochemistry, 
Targeted Nanostring 
(PanCancer ImmunoOncology 
360; PanCancer Progression 
Panel), CTC Isolation, Tumor 
tissue and peripheral blood T-
cell repertoire  
 
3.4 
Secondary Endpoints 
 
What is being measured 
Measurement time frame 
Measurement Tool 
The impact of pre-surgical non-
ablative SBRT on peri- and 
post-operative surgical 
complication rate 
From Day  of post-SBRT surgery 
through  6 month (± 2 months) 
post-operative follow up visit 
 
Medical Record Review 
Clavien-Dindo Classification system  
The impact of pre-surgical non-
ablative SBRT on wound 
healing 
 From Day  of post-SBRT surgery 
through 6 month (± 2 months) post-
operative follow up visit 
 
Medical record review 
General Thoracic Surgery Database. 
 
Loco-regional control, 
metastasis-free survival, 
disease free and overall 
survival 
From Day of enrollment  through 
36 month follow up visit 
Medical record review 
  
 
 

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4 
STUDY DESIGN 
 
4.1 
Overall Design 
 
This is a single arm pilot study.  Participants with medically operable NSCLC  will receive SBRT 800 cGy X 3 
fractions delivered 5-7 days prior to planned surgery. 
 
4.2 
Justification for Dose 
 
Published literature shows that cytotoxic doses of XRT (e.g. 1800-2000 cGy x3)  may not elicit a clinically 
meaningful alteration in the immune profile. In addition, studies using an animal model have concluded a 
fractionated regimen induces a greater abscopal effect than single dose radiation. Furthermore, these studies 
showed a regimen of 800 cGy X 3 fractions yielded the most significant changes in the immune profile compared 
to 2000 cGy X 1 or 600 cGy X 5.18 
 
Based on these prior data, we chose 800 cGy x 3 for this trial. 
 
4.3 
End of Study Definition 
 
End of study is defined as the time of completion of 36 month follow-up after enrollment of all patients still 
eligible for follow-up (excluding death and drop-out prior to 36 months). 
 
5 
PARTICIPANT SELECTION 
 
Patients with Stage 1-2 Non-Small Stage Lung Cancer and who are candidates for oncological surgical resection 
may be eligible for this trial if they meet all entry criteria.  
 
5.1 
Inclusion Criteria 
 
PARTICIPANT MRN 
 
PARTICIPANT INITIALS 
Verified 
Criteria 
 
5.1.1 Ability of participant OR Legally Authorized Representative (LAR) to understand this study, and 
participant or LAR willingness to sign a written informed consent  
 
5.1.2 Males and females age ≥ 18 years 
 
5.1.3 ECOG Performance Status 0 - 1 (Appendix A.) 
 
5.1.4 Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to 
initiating study intervention. 
 
5.1.5 Histological confirmation of Stage I or II NSCLC 
 
5.1.6  Candidate for oncologic surgery (lobectomy or sub lobar resection)  

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PARTICIPANT MRN 
 
PARTICIPANT INITIALS 
Verified 
Criteria 
 
5.1.7 Adequate diagnostic biopsy tissue to allow for pre-SBRT tumor analysis 
 
5.1.7 Lesion must be located peripherally, > 2 cm from bronchial margin and 1 cm from visceral 
pleura with location deemed acceptable by cardiothoracic surgeon for resection. 
 
5.1.8 
Pulmonary function: 
Baseline PFTs including adequate FEV1 deemed by cardiothoracic surgeon to be acceptable for 
oncologic surgery, with a predicted post-operative FEV1 of 40% or greater and DLCO of 40% or 
greater. 
Adequate organ function, defined as follows: 
Result 
Date 
 
 
White blood cell (WBC) count ≥ 3.0 ×103 cells/mm3 
 
 
 
 
Hemoglobin ≥10 g/dL 
 
 
 
 
Absolute Neutrophil Count > 1.5 K/UL 
  
 
 
Platelets > 150 K/UL 
  
 
 
Serum creatinine clearance > 50 mL/min 
 
 
 
 
Total bilirubin ≤ 2.0 x ULN 
 
 
 
 
Aspartate aminotransferase and alanine aminotransferase ≤ 
2.5 x ULN  
 
 
 
 
Women of child-bearing potential and men with partners of child-bearing potential must agree 
to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing 
Potential/Pregnancy section for the duration of study participation and for 6 months following 
completion of therapy.  
 
 
 
 

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5.2 
Exclusion Criteria 
 
Participants meeting any of the exclusion criteria listed below at screening will be excluded from study 
participation. 
 
PARTICIPANT MRN 
 
PARTICIPANT INITIALS  
No 
Criteria 
 
5.2.1 Simultaneously enrolled in any therapeutic clinical trial  
 
5.2.2 Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with 
study requirements  
 
5.2.3 Is pregnant or breastfeeding 
 
5.2.4 Prior history of lung/chest wall surgery 
 
5.2.5 Prior history of  radiation treatment to the chest 
 
5.2.6 History of autoimmune disease 
 
5.2.7 Current use of immunosuppressive drugs 
 
5.2.8 Prior history of immunotherapy 
 
5.2.9 Prior history of metastatic cancer or concurrent active secondary malignancy 
 
Eligibility Confirmed 
Print Name 
Signature 
Date 
Clinical Research 
Coordinator  
 
 
 
Double Check 
 
 
 
Treating Physician 
 
 
 
 
Once eligibility has been confirmed, use the link below to register your participant. 
Please allow up to 24 business hours for the registration process. 
 
 
 
 

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6 
CHILD-BEARING POTENTIAL / PREGNANCY 
 
Because the effect of the study intervention is considered possibly teratogenic and has potential risks to the 
fetus, pregnant females will not be included in the study. However, no female of childbearing potential will be 
excluded from the study.   
 
An effective form of contraception of the woman’s choice will be required during study participation. Participants 
should not get pregnant, breastfeed, donate sperm or father a child while participating in this study and for 6 
months after the last dose of the study medication.  
 
Women of childbearing potential and male participants 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. If a 
woman becomes pregnant or suspects she is pregnant while participating in this study or if her male partner is a 
participant in this study, the treating physician should be informed immediately.  
 
Child-bearing potential is defined as any female (regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) who meets the following criteria: 
• 
Has either not undergone a hysterectomy or bilateral oophorectomy or has not been naturally 
postmenopausal for at least 12 consecutive months.  
 
Participants must agree to use one of the following acceptable forms of birth control.   
• 
Sexual Abstinence 
• 
One barrier method (cervical cap with spermicide plus make condom; diaphragm with spermicide plus 
male condom) PLUS hormonal method (oral contraceptives, implants, or injections) or an intrauterine 
device (e.g., Copper-T). 
 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her 
treating physician immediately.  
 
If the partner of a man becomes pregnant or suspects she is pregnant while he is participating in this study, he 
should inform his treating physician immediately.  
 
Men of child-bearing potential must not father a child or donate sperm while receiving investigational product 
and for 6 months after their last study intervention. 
 
6.1 
Screen Failures 
 
Patients who screen fail cannot be re-screened at a later date. 
 
Screen failures will be offered standard of care treatment per institutional guidelines and physician discretion. 
They will not be counted towards enrollment and will not be included in analysis of the data. 
 
6.2 
Participant Replacement 
 
Participants will not be replaced once they have successfully completed surgery. 
 
 

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7 
PARTICIPANT REGISTRATION PROCEDURES 
 
7.1 
General Guidelines 
 
Eligible participants will be registered through The University of Kansas Cancer Center Clinical Research Office 
central registration process and registration must occur prior to the initiation of therapy.  Any participant not 
registered to the protocol before initiating study intervention will be considered ineligible and study intervention 
will be denied.  
 
Issues that would cause study intervention delays should be discussed with the Sponsor/Investigator. If a 
participant does not receive protocol therapy following registration, notify The University of Kansas Cancer 
Center Clinical Site Management team via email at KUCC-CTO-IIT@kumc.edu and update participant’s status in 
the CRIS system. 
 
7.2 
Registration Process  
 
The University of Kansas Cancer Center participant registration is accessible for registration Monday through 
Friday, 8:00 AM to 5:00 PM Central Time. Please allow up to 24 hours for completion of registration. 
 
The registration procedures are as follows: 
1. Obtain written informed consent prior to the performance of any study related procedures or 
assessments.  Tests required at screening and performed as part of customary care prior to signing 
consent, are allowed IF those tests were performed within the timeframe listed in Participant Selection 
section.  
2. Complete appropriate baseline demographic information in CRIS.  Print, complete and obtain appropriate 
signatures for the inclusion/exclusion criteria to document eligibility.  Maintain completed documents in 
participant’s research record. Participants must meet all eligibility criteria to be eligible for registration.   
3. Use the hyperlink at the bottom of the eligibility criteria or in the CRIS system, complete information and 
submit to initiate the registration process.   
4. Email confirmation of registration will be sent to the person initiating the registration.  Registration 
confirmation should be maintained as part of the participant’s research record.  
 
8 
STUDY INTERVENTION PLAN 
 
8.1 
Radiation Treatment Regimen 
 
Study 
Intervention 
Dose 
Schedule 
Cycle Length 
SBRT 
800 cGy x 3 fractions 
Daily 
5-7 days prior to planned 
surgery 
 
RADIATION THERAPY 
 
Modalities:   
Stereotactic Body Radiation Therapy has now been formally defined and described in a published guideline from 
the American College of Radiology and American Society for Therapeutic Radiology and Oncology.19,20 

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This protocol will follow that guideline. 
 
Dose Fractionation  
Patients will receive 2400 cGy in 3 fractions of 800 cGy/fraction to the prescription line at the edge of the PTV 
(see section below with title Prescription Dose Constraints for Treatment Planning for more prescription details). 
Treatment delivery will be scheduled for 3 consecutive days, but may be modified as needed by the treating 
radiation oncologist. 
 
A minimum of 18 hours between fractions is required.  
 
Technical Factors  
 
• 
Physical Factors 
Only photon (x-ray) beams produced by linear accelerators, with photon energies of 6-15 MV will 
be allowed. 
 
• 
Dose Verification at Treatment 
Patient specific QA will be performed for each patient prior to first fraction.   Additionally, in-vivo 
dosimeter measurements (e.g., TLD/NanoDots/Mosfet)) may be obtained for surface dose 
verification for accessible beams as per institutional preference.  
 
Localization, Simulation, and Immobilization  
 
• 
Patient Positioning  
Patients will be positioned in a reproducible position. A variety of immobilization systems may be 
used. 
 
• 
Inhibition of Effects of Internal Organ Motion  
Special considerations must be made to account for the effect of internal organ motion (e.g., 
breathing) on target positioning and reproducibility. Acceptable maneuvers include reliable 
abdominal compression, accelerator beam gating with the respiratory cycle, tumor tracking, and 
active breath-holding techniques.  
 
Localization.   
 
• 
IGRT will be required with CBCT images obtained prior to each fraction and verified by treating physician 
prior to treatment delivery. 
 
Treatment Planning/Target Volumes  
 
• 
Computed tomography will be the primary image platform for targeting and treatment planning. The 
target lesion will be outlined by the treating physician and will be designated as the gross tumor volume 
(GTV), which will also be designated the clinical target volume (CTV)(i.e. GTV=CTV). 4DCT data sets will be 
used to generate internal tumor volume (ITV). The PTV will include the ITV plus an additional 0.5 cm 
margin uniformly applied to the ITV. Per physician discretion, these volumes can be adjusted based on 
each patient’s clinical situation and anatomy. 
 
 

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Dosimetry  
• 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for each case 
to deliver highly conformal prescription dose distributions. Non-opposing, noncoplanar beams are 
preferable. For purposes of dose planning and calculation of monitor units for actual treatment, this 
protocol will require tissue density heterogeneity corrections.  
 
Prescription Dose Constraints for Treatment Planning  
The prescription isodose surface will be chosen such that 95% of the target volume (PTV) is conformally 
covered by the prescription isodose. Dose homogeneity within the GTV of +/- 5% is highly recommended. 
 
Organs At Risk (OAR) visible in the planning CT will be contoured.  Dose constraints are defined below. 
Dose Constraints 
 
1. Modification as defined in the chart below of the Dose Constraints as defined by RTOG 9501 
Arm 2 12 Gy X 4 is the basis of dose limitations of the organs at risk to be used this protocol.21 
 
2. The risk of end-organ damage as defined in the table is anticipated to be less than 1%. 
 
Organ at Risk 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
Endpoint (≥ Grade 3) 
Spinal Cord 
<0.35 cc 
<1.2 cc 
10.4 Gy (5.2 Gy/fx) 
6.8 Gy (3.4 Gy/fx) 
13 Gy (6.5 Gy/fx) 
Myelitis 
Esophagus 
<5 cc 
9.4 Gy (4.7 Gy/fx) 
15 Gy (7.5/fx) 
Stenosis/fistula 
Brachial Plexus 
<3 cc 
11.8 Gy (5.9 Gy/fx) 
13.6 Gy(6.8Gy/fx) 
Neuropathy 
Heart/Pericardium <15 cc 
14 Gy (7 Gy/fx) 
17 Gy (8.5 Gy/fx) 
Pericarditis 
Great vessels 
<10 cc 
21.5 Gy (10.75 Gy/fx) 
24.5 Gy (12.25 Gy/fx) Aneurysm 
Trachea and Large 
Bronchus 
<4 cc 
7.8 Gy (3.9 Gy/fx) 
17.4 Gy (8.7 Gy/fx) 
Stenosis/fistula 
Rib 
<1 cc 
16 Gy (8 Gy/fx) 
20 Gy (10Gy/fx) 
Pain or fracture 
Skin 
<10 cc 
16.6 Gy (8.3 Gy/fx) 
18 Gy (9 Gy) 
Ulceration 
Stomach 
<10 cc 
8.8 Gy (4.4 Gyfx) 
18.6 Gy (6.8 Gy) 
Ulceration/fistula 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume Dose 
Max (Gy) 
 
Endpoint (≥ Grade 3) 
Lung (Right & Left) 1500 cc 
5.8 Gy (2.9 Gy/fx) 
 
Basic Lung Function 
Lung (Right & Left) 1000 cc 
6.2 Gy (3.1 Cy//fx 
 
Pneumonitis 
 
Quality assurance  
Patient safety will be ensured with effective treatment delivery with a robust quality assurance protocol as 
defined below.  
• 
Prior to treatment each patient will be discussed by quality assurance team as defined by a study 
investigator, treating radiation oncologist, study physicist and dosimetrist.  
 
• 
The treating radiation oncologist will confirm prior to the first fraction delivery that the radiation 
treatment plans must meet target dose levels for dose homogeneity.. 
 
• 
Prior to plan approval, the organ at risk dose volume histogram must be verified by the treating radiation 
oncologist and physicist. Dose constraints as defined shall not be exceeded.  
 

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• 
Image-guided radiation treatment (I GRT/SBRT) with cone beam CT will be used to verify patient 
positioning prior to each treatment. And will require approval by the treating radiation oncologist prior 
to treatment delivery.  
 
Possible side effects of SBRT as listed below. 
 
The likelihood of the defined organ risk/toxicity is anticipated to be less than 1%, as the dose constraints  
defined in this protocol are well below the RTOG-0915 defined dose constraints for SBRT of the lung. 
 
Organ at Risk 
Possible Side Effect 
Volume  
Volume Max (Gy) 
Dose threshold as defined for end 
organ damage in RTOG 0915 
Spinal Cord 
Myelitis 
< 0.35 cc 
< 1.2 cc 
20.8 Gy (5.2 Gy/fx) 
13.6 Gy (3.4 Gy/fx) 
Esophagus 
Stenosis/fistula 
< 5 cc 
18.8 Gy (4.7 Gy/fx) 
Brachial Plexus 
Neuropathy 
< 3 cc 
23.6 Gy (5.9 Gy/fx) 
Heart/Pericardium 
Pericarditis 
< 15 cc 
28 Gy (7 Gy/fx) 
Great vessels 
Aneurysm 
< 10 cc 
43 Gy (10.75 Gy/fx) 
Trachea and Large 
Bronchus 
Stenosis/fistula 
< 4 cc 
15.6 Gy (3.9 Gy/fx) 
Rib 
Pain or fracture 
< 1 cc 
32 Gy (8 Gy/fx) 
Skin 
Ulceration 
< 10 cc 
33.2 Gy (8.3 Gy/fx) 
Stomach 
Ulceration/fistula 
< 10 cc 
17.6 Gy (4.4 Gy/fx) 
Parallel Tissue 
Possible Side Effect 
Critical Volume (cc) 
Critical Volume Dose Max (Gy) 
Lung (Right & Left) 
Basic Lung Function 
1500 cc 
11.6 Gy (2.9 Gy/fx) 
Lung (Right & Left) 
Pneumonitis 
1000 cc 
12.4 Gy (3.1 Gy/fx) 
 
Surgery  
• 
Surgery will occur 5 to 7 days post completion of the last fractionation of radiation treatment. Surgery 
will consist of a lobectomy or sub lobar resection. The technique will be at the discretion of the study 
cardiothoracic surgeon, and may employ either an open approach, video assisted thoracoscopic or 
robotic-assisted approach. Surgical sampling of the at risk hilar and mediastinal nodes may be performed 
at the time of resection but is not a requirement of the study. 
• 
In the event adjuvant systemic therapy is elected, follow up studies as defined in this protocol may be 
modified as clinical necessity requires.  Participants will be continued for secondary objectives and will be 
reported using descriptive statistical analysis. 
 
Pathology Processing    
• 
After resection, the tumor will be oriented by the surgeon and submitted to the pathology lab. In the 
pathology lab it will undergo gross examination in a standard manner. The specimen  will be submitted 
for microscopic examination. Samples for translational research use will be processed and transferred to 
the appropriate laboratory as defined in the study laboratory manual.  
 
 
 

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8.2 
Sample Procurement 
 
 
Pre-SBRT Biopsy Sample 
 
Pre-SBRT biopsy samples will be obtained at time of diagnostic biopsy and will consist of a minimum of two core 
biopsies.  
 
• 
Required collection of archival tumor biopsy tissue (either from initial diagnosis of lung cancer done 
prior to any study intervention or from any subsequent biopsy), for translational studies.  
A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at 
least 15 slides containing unstained, freshly cut, serial sections should be submitted along with 
an associated pathology report prior to study enrollment.  If only 10 to 14 slides are available, the 
specimen may still be used, after Principal Investigator confirmation has been obtained.   
 
• 
Required fresh tumor biopsy for translational studies.  
If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, if participant 
consents, then fresh tumor tissue can be obtained from a biopsy performed after screening.   
 
If participant does not consent, they cannot participate in this study. 
 
Refer to Lab Manual for additional information on tumor specimens collected at screening. 
 
 
Surgical Sample 
 
Post-assessment by pathologist and verification that adequate tissue has been obtained for clinical use, the 
remainder of the tumor tissue will be processed for translational studies as defined in study laboratory manual. 
 
9 
STUDY PROCEDURES AND SCHEDULE 
 
9.1 
Screening/Enrollment/Baseline 
 
SCREENING VISIT  
• 
Informed Consent 
• 
Cancer history 
• 
Demographics - including date of birth, gender, race, and zip code 
• 
Review participant eligibility criteria to ensure participant qualification for study entry 
• 
Physical exam to include vital signs, weight and height at baseline – which helps in the evaluation for 
surgical candidacy 
• 
Baseline medical history to aid in assessment of possible adverse events 
• 
ECOG Performance Status 
• 
Pulmonary function test 
• 
CBC with differential ( ± 3 Days) 
• 
CMP (Serum chemistries) ( ± 3 Days) Serum chemistries to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), 
glucose, total bilirubin, magnesium, lactate dehydrogenase (LDH), phosphate 
• 
Urinalysis( ± 3 Days) 

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• 
Urine pregnancy test (women only) ( ± 7 Days) 
• 
Imaging (Chest) – CT preferred.  
o IV and oral contrast will be used for all imaging unless contraindicated. In the event the 
participant is intolerant to the contrast agent, an alternative imaging modality may be used. If CT 
contraindicated – MRI will be allowed (IV contrast will be used unless contraindicated). The same 
type of imaging used at screening must continue to be used throughout the study.  Studies will 
be evaluated using RECIST Version 1.1.22 
 
• 
Required collection of archival tumor biopsy tissue (either from initial diagnosis of lung cancer done 
prior to any study intervention or from any subsequent biopsy), for translational studies.  
A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at 
least 15 slides containing unstained, freshly cut, serial sections should be submitted along with 
an associated pathology report prior to study enrollment.  If only 10 to 14 slides are available, the 
specimen may still be used, after Principal Investigator confirmation has been obtained.   
 
• 
Required fresh tumor biopsy for translational studies.  
If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, if participant 
consents, then fresh tumor tissue can be obtained from a biopsy performed after screening.   
 
If participant does not consent, they cannot participate in this study. 
 
Refer to Lab Manual for additional information on tumor specimens collected at screening. 
 
At any time after enrollment and before surgery 
Pre-operative anesthesia clinic clearance for surgery is required and may include 
• 
EKG 
• 
Stress Test 
• 
Cardiac Clearance 
 
 
Procedures During Study Intervention 
 
Day 0 - Simulation 
• 
Radiation Simulation 
• 
Adverse event assessment 
 
Day 1 – Prior to 1st fraction 
• 
Blood collection for translational studies 
 
Day 1 – 1st Fraction 
• 
Radiation – Fraction 1 
• 
Adverse event assessment 
 
 
Day 2 – 2nd Fraction 
• 
Radiation – Fraction 2  
• 
Adverse event assessment 
 
Day 3 – 3rd Fraction 

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• 
Radiation – Fraction 3  
• 
Adverse event assessment 
 
NOTE:  There is a 5-7 day rest period after radiation and before surgery. 
 
Day of Surgery (Occurs during days 8-10) 
 
• 
ECOG  
• 
CBC with Differential ( ± 3 Days) 
• 
CMP (Serum Chemistries) ( ± 3 Days) 
• 
Physical exam 
• 
Adverse event assessment 
• 
Peri-operative surgical complication assessment 
• 
Blood collection for translational studies BEFORE surgery 
• 
Surgical specimen collection 
 
 
Follow-Up Visits  
 
POST OPERATIVE FOLLOW UP 
 
24 Hours post-op 
• 
Physical exam 
• 
Adverse event assessment 
• 
Post-operative surgical complication assessment 
• 
CBC with Differential ( ± 3 Days) 
• 
Basic Metabolic Panel (BMP) ( ± 3 Days) 
• 
Post-operative chest x-ray (within 24 hours of surgery) 
 
Day of Discharge (post-op) 
• 
Physical exam 
• 
Adverse event assessment  
• 
Post-operative surgical complication assessment 
• 
Wound healing assessment 
• 
Blood collection for translational studies 
 
• 
1-3 weeks post-op Physical exam 
• 
Adverse event assessment  
• 
Post-operative surgical complication assessment 
• 
Wound healing assessment 
• 
Chest X-Ray (CXR) 
 
 
 

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6 Months (post-op) (± 2 months) 
  
• 
Imaging (Chest) – CT preferred.  
o IV and oral contrast will be used for all imaging unless contraindicated. In the event the 
participant is intolerant to the contrast agent, an alternative imaging modality may be 
used. If CT contraindicated – MRI will be allowed (IV contrast will be used unless 
contraindicated). The same type of imaging used at screening must continue to be used 
throughout the study.  Studies will be evaluated using RECIST Version 1.1. 
• 
Physical exam 
• 
Adverse event assessment 
• 
Post-operative surgical complication assessment 
• 
Wound healing assessment 
• 
Check pregnancy status  
 
Every 6 months (± 2 months) after initial 6-month follow up 
Last study follow up at month 36 after enrollment 
 
• 
Imaging (Chest) – CT preferred.  
o IV AND oral contrast will be used for all imaging unless contraindicated. In the event the 
participant is intolerant to the contrast agent, an alternative imaging modality may be 
used. If CT contraindicated.  The same type of imaging used at screening must continue 
to be used throughout the study.  Studies will be evaluated using RECIST Version 1.1 
• 
Physical exam 
• 
Adverse event assessment 
 
9.2 
Lost to Follow Up 
 
Institution policy will be followed for participants considered lost to follow up.   
 
 

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9.3 
SCHEDULE OF EVENTS TABLE 
 
Screening Period 
Screening 
& 
Baseline 
 
Day 0 
Day 1 
Day 2 
Day 3 
Days  
8 – 10 
Post-Operative Follow Up 
Simu-
lation 
1st 
Fraction 
2nd 
Fraction 
3rd 
Fraction 
Surgery 
24 
Hours  
Day of 
Discharge 1-3weeks  
6 months 
 
Every 6 months 
after surgery 
(Last follow up at 36 
months)    
 
Simulation 
 
X 
 
 
 
 
 
 
 
 
 
SBRT 
 
 
X 
X 
X 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Cancer History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status (PS) 
X 
 
 
 
 
X 
 
 
 
 
 
Pre-Op Anesthesia 
Clearance 
To be completed before surgery 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Assessment 
X 
(Med Hx 
Review) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peri- / Post-
Operative Surgical 
Complication 
Assessment 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Wound Healing 
Assessment 
 
 
 
 
 
 
 
X 
X 
X 
 
CBC with Diff 
X 
 
 
 
 
X 
Before 
Surgery 
X 
 
 
 
 
CMP (Serum 
Chemistries) 
X 
 
 
 
 
X 
Before 
Surgery 
 
 
 
 
 
BMP 
 
 
 
 
 
 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy ( URINE) 
Test  
X 
 
 
 
 
 
 
 
 
 
 

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Screening Period 
Screening 
& 
Baseline 
 
Day 0 
Day 1 
Day 2 
Day 3 
Days  
8 – 10 
Post-Operative Follow Up 
Simu-
lation 
1st 
Fraction 
2nd 
Fraction 
3rd 
Fraction 
Surgery 
24 
Hours  
Day of 
Discharge 1-3weeks  
6 months 
 
Every 6 months 
after surgery 
(Last follow up at 36 
months)    
 
Pregnancy Status 
Check 
 
 
 
 
 
 
 
 
 
X 
 
CT Imaging of chest  
X 
 
 
 
 
 
 
 
 
X 
X 
Chest X-Ray 
 
 
 
 
 
 
 
X 
 
X 
 
 
Blood Collection for 
Translational Studies 
X 
 
X 
Before 
SBRT 
 
 
X 
Before 
Surgery 
 
X 
 
 
 
Tumor Tissue 
Collection  
X 
(Archival) 
 
 
 
 
X 
(Surgical 
Specimen)
 
 
 
 
 
 
 

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9.4 
Supportive Care Guidelines 
 
Therapies required for standard supporting care following surgery is acceptable. 
 
 
Prohibited or Restricted Concomitant Medications 
 
We strongly encourage physicians to avoid use of immunosuppressive medications up to 1 month 
following surgery as this can affect surgical wound healing and may alter the immune 
microenvironment. 
 
 
Diet 
 
No dietary modifications required in this study. 
 
9.5 
Participant Discontinuation/Withdrawal from the Study 
 
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. 
Participants may be withdrawn from the study intervention if any of the following occur: 
• 
Intercurrent illness that prevents further administration of study intervention. 
• 
Unacceptable adverse event(s). 
• 
Participant decides to withdraw from the protocol therapy. 
• 
General or specific changes in the participant's condition render the participant unacceptable for 
further study intervention in the judgment of the treating investigator. 
• 
Major violation of the study protocol (i.e., unable to adhere to study schedule) that in the 
opinion of the treating investigator, puts the participant at undue risk.  
• 
Discontinuation of the study by The University of Kansas Cancer Center. 
• 
Confirmed pregnancy. 
• 
Completed follow up as per protocol 
• 
Lost to follow-up. 
• 
Death 
Participants will be removed from the protocol therapy when any of these criteria apply.  The reason for 
removal from protocol therapy, and the date the participant was removed, must be documented in the 
electronic case report form (eCRF). Alternative care options will be discussed with the participant.  
Safety monitoring and follow-up assessments should continue as appropriate according to the study 
schedule, unless the participant has withdrawn consent for study participation. Participants removed 
from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization 
of the adverse event. 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in CRIS. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately notify 
the Sponsor/Investigator. 
 

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10 TRANSLATIONAL STUDIES 
 
1. Targeted Cell Surface Analysis 
Radiation can alter the cell surface expression of many immunomodulatory proteins. Upregulation of 
PDL1 and PDL2 has been demonstrated in multiple cell lines. Altered expression of MHC 1 on tumor cells 
has also been reported. Changes in the composition of the immune regulatory cells within the tumor 
micro-environment in response to changes in tumor cell phenotype has also been demonstrated. 
Utilizing paired pre-XRT (biopsy) and post XRT (surgical specimen) tumor tissues and normal tissue 
samples from the resection sample, we will use immunohistochemistry to assess cell surface markers 
and immune parameters. Tumor panels will include PDL1, PDL2, HCA2, IDO, HC10, B2m, Calreticulin, 
MHC-1, Fas, ICAM. T-cell panels will include CD3, CD8, FoxP3, TBet, Ki67, GranzymeB; and CD3, CD8, 
PD1, 1263 Tim3, Lag3, GranzymeB.    
 
2.  Tumor Immune Microenvironment 
Using the “biopsy-XRT-resection” approach, we will be able to gain insight into the composition of the 
tumor immune microenvironment before SBRT and understand how SBRT influences the 
microenvironment and expression of immunotherapy targets. Prior rodent studies have delineated how 
radiation dose and fractionation can alter the STING pathway.23,24,25 The consequence of this is  
recruitment and activation of dendritic cells which can prime CD8+ T cells and mediate a systemic 
cytotoxic tumor response.26 Similarly, other groups have utilized murine models to delineate how 
radiation can increase the CD8/CD4 ratio and broaden the T-cell repertoire Ko et al IJROBP 2019).27 We 
propose to examine changes in the tumor immune microenvironment focusing on transcriptomic 
changes as well as functional changes in the T-cell receptor repertoire.   
 
3. Gene Expression Profile 
We will use the NanoString nCounter® PanCancer ImmunoOncology (IO) 360™ Gene Expression Panel to 
perform quantitative highly multiplexed gene expression profiling. Total DNA and RNA will be collected 
from FFPE-embedded biopsy (pre-radiotherapy) and surgical (post-radiotherapy) specimens using the 
AllPrep DNA/RNA FFPE Kit (Qiagen). DNA will be cryopreserved for future translational genomic studies. 
RNA will be analyzed on the nCounter® PanCancer IO 360™ Gene Expression Panel using the 
instrumentation in the Clinical Molecular Oncology Laboratory (CMOL) overseen by Dr. Andrew Godwin 
at KU Cancer Center. This platform quantifies expression levels for 770 transcripts, including 40 
housekeeping genes for automated normalization, and provides a quantitative measure of immune-
related biological signatures, pathways, and processes, extrapolated relative levels of immune cell 
subtypes, and expression of immunotherapy targets within each sample. Paired analysis between pre-
radiotherapy and post-radiotherapy samples will enable us to detect radiotherapy induced changes in 
the tumor immune microenvironment and expression of immunotherapy targets. 
 
These studies will provide critical insight into the potential of radiotherapy as an immunogenic adjunct 
in NSCLC and identify novel therapeutic approaches to combine radiotherapy with immunotherapy. 
 
4.  Radiation-Mediated Changes in T-cell Repertoire in Tumor Tissue 
We will use the AmpliSeq™ for Illumina® Direct FFPE DNA to develop a highly multiplexed targeted 
resequencing panel followed by DNA sequencing in order to measure T cell diversity and clonal 
expansion by sequencing T cell receptor (TCR) beta chain rearrangements. Paired pre-RT core needle 
biopsy and post-RT resected tumors will be compared for unique immune cell receptor transcripts that 

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have infiltrated tumor tissue after radiation treatment. This project will lay the groundwork for future 
work to identify radiation treatment regimens that may be augmented with immune-therapeutics. 
 
5.  Radiation-Mediated Changes in T-cell Repertoire in Peripheral Blood 
We will process peripheral blood T cells in order to measure T cell diversity and clonal expansion by 
sequencing TCR beta chain rearrangements. We will simultaneously evaluate T cell profile by flow 
cytometry, assessing for markers of T cell exhaustion. 
 
6.  Tumor Tissue and Circulating Tumor Cell Analysis 
Circulating tumor cells (CTCs) have been widely used for diagnostic purposes as well as a biomarker to 
screen for treatment failure. Furthermore, CTCs have been shown to prognosticate both lung and 
head/neck squamous cell carcinoma patient disease-free survival and contribute to both loco-regional 
and distant metastasis.28,29,30,31  In our model system, we have previously demonstrated that 
radiotherapy can induce accelerated tumor repopulation in vivo and this is likely regulated by epithelial-
to-mesenchymal transition (EMT).32,33  Predictably, generation of “mesenchymal” CTCs require EMT and 
those CTCs with persistent EMT pathway activation have been correlated as a poor patient prognostic 
outcome particularly in head and neck cancer. 34,35 In addition, EMT gene expression in CTC’s from lung 
cancer patients who undergo curative surgical resection have been shown to be a poor prognostic 
feature.36 Furthermore, PD-L1 expression (and other immunomodulatory proteins) are known to be 
upregulated in pre-clinical models37,38  following radiotherapy and immune cell surface proteins (i.e. PD-
L1) has been shown to be expressed in CTCs.39 
 
We propose to examine CTC before and after SBRT. Both mesenchymal and nonmesenchymal 
(epithelial) expressing CTCs will be isolated from whole blood using specialized nanofabricated cell 
isolation chips (KU Lawrence collaboration, Sopek, Witek) designed for harvesting CTCs and demonstrate 
a 10-100x higher cell capture rate compared with commercial vendors.40 Endpoints include 
mesenchymal and epithelial CTC cell enumeration before and after SBRT; examination of PD-L1 cell 
surface expression in CTCs; as well as targeted transcriptomic analysis of collected CTCs using a modified 
Nanostring nCounter® PanCancer Progression Panel customized with supplemental user-defined genes 
focusing on p38-MAPK pathway. 
 
We hypothesize from this work that following SBRT there will be a higher proportion of mesenchymal 
CTCs over epithelial CTCs and these results will be confirmed using targeted transcriptomic analysis. We 
also anticipate that patients receiving SBRT will have upregulation of PDL1 cell surface expression and 
will be confirmed by immunofluorescence. We also hypothesize that genes in the p38-MAPK pathway 
will be upregulated following SBRT and promising genes candidates will be confirmed by 
immunohistochemistry looking at tumor tissue before and after SBRT. The goal of this work will be to: 1) 
explore the effect of SBRT on mesenchymal CTC generation; 2) examine the gene expression profile of 
CTCs with a focus on EMT; and 3) identify promising novel targets within the MAPK pathway that are up-
regulated following SBRT that maybe relevant and targetable for metastasis. 
 
11 ADVERSE EVENTS/SERIOUS ADVERSE EVENTS 
 
Although pregnancy is not always serious by regulatory definition, for the purposes of this protocol, this 
is considered to be an SAE and follow the SAE reporting timeline. 
 
Refer to Appendix B for additional Adverse Event/Serious Adverse Event information.   

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11.1 Adverse Event Monitoring 
 
Baseline adverse events are recorded and graded using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.041.  Additional serious adverse event and adverse event monitoring begins 
after initiation of study intervention and ends 36 months following surgery (i.e.; end of study). 
 
11.2 Adverse Event Reporting 
 
Information for adverse events, whether reported by the participant, directly observed or detected by 
physical examination, laboratory test or other means, will be collected, recorded, followed and reported 
in the CRIS system within 5 days of being reported.   
 
All adverse events experienced by participants will be collected. Medical conditions are collected as 
baseline adverse events and evaluated as above.  Additional adverse event monitoring begins after 
initiation of study intervention and ends 36  months following surgery.   
 
Participants who experience an ongoing adverse event related to study intervention beyond 36 months 
will continue to be contacted by a member of the study team until the event is resolved, stabilized, or 
determined to be irreversible by the Sponsor/Investigator.   
 
Study participants should also be instructed to report any new serious post-study event(s) that might 
reasonably be related to participation in this study. 
 
11.3 Serious Adverse Event Reporting 
 
SAEs regardless of expectedness or relationship will be reported to The University of Kansas Cancer 
Center IIT Regulatory Department within 24 hours of notification as follows:  
• 
Enter into CRIS 
• 
Submit a complete FDA 3500A MedWatch form and all supporting documents to The University 
of Kansas Cancer Center IIT Regulatory department at KUCC-CTO-IIT@kumc.edu.   
 
Follow-up source documentation is required within 5 days. 
Local policy will be followed for reporting SAEs to the IRB.   
 
 Pregnancy Reporting 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study she must 
inform the investigator immediately.  Reporting requirements are the same as for an SAE in above. The 
pregnancy must be followed for the final pregnancy outcome. 
 
If a female partner of a male participant becomes pregnant during the male participants participation, 
he must inform the investigator immediately.  Reporting requirements are the same as for an SAE 
above. Every effort should be made to follow the pregnancy for the final pregnancy outcome. 
 
 

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12 STATISTICAL CONSIDERATIONS  
 
12.1 Description of Statistical Methods 
 
We will summarize peri- and post- operative surgical complication rates as well as tumor control 
outcomes using descriptive statistics. 
 
Peri- and post- operative surgical complication rates will be quantified using the Clavien-Dindo 
classification of surgical complications.. 
 
Wound healing complication rates will be scaled as defined by the General Thoracic Surgery Database 
with particular references to pages 246-248. 
 
12.2 Study Stopping Rules  
 
If a participant experiences one or more of the following events, possibly related to study intervention, 
study will be suspended pending data safety monitoring committee (DSMC) review to determine if study 
should continue: 
 
a. Wound healing delay beyond standard timeframe as deemed by study Cardio-Vascular (CV) 
surgeons 
b. Peri operative/post-operative surgical complications  beyond acceptable institutional rates as 
determined by study CV surgeons 
c. Death  from study intervention 
 
13 REGULATORY REQUIREMENTS AND DATA REPORTING  
 
13.1 Institutional Review Board/Ethics Committee Approval 
 
Before trial initiation this protocol and informed consent form will be submitted for review and approval 
by the IRB of record for the clinical site. Any form of proposed advertising and advertising text for 
patient recruitment must be reviewed and approved by the IRB. In accordance with FDA 21 CFR 56 of 
the Code of Federal Regulations the Investigator will forward the Sponsor/Investigator a copy of the IRB 
approval letter for the initial approval, amendments, informed consent and any informed consent 
updates.  
 
The Investigator will be responsible for providing the Sponsor/Investigator a list of IRB members 
including profession and affiliation or a United States Department of Health and Human Services 
General Assurance number and expiration date. If neither of these is available, the IRB Chairperson must 
submit a statement indicating the members of the board responsible for the review meet the FDA and 
other appropriate regulatory requirements.  
 
Sub-sites will not be activated until the Sponsor/Investigator has received documentation of IRB 
approval. 
 

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13.2 Investigators Protocol Agreement 
 
 
The Investigator must sign the Protocol Agreement before the study is activated. The original will be 
forwarded to the Sponsor/Investigator and the Investigator must retain a copy. The completed 
Investigator’s Protocol Agreement signifies agreement to comply with all procedures outlined by this 
protocol by the Investigator. An Investigator’s Protocol Agreement must be signed when a protocol 
amendment is issued. 
 
13.3 Remaining Samples 
 
Any samples remaining after the trial specified analyses is completed will be stored by the 
Sponsor/Investigator at The University of Kansas Cancer Center if the participant consented for use of 
their remaining samples for future research purposes. This includes the original specimen collected from 
the participant (blood, tumor tissue) as well as derivatives created from the original specimen (DNA, 
RNA, blocks or slides).  
 
If a participant has not consented for their remaining samples to be used for future research purposes 
remaining samples and derivatives will be destroyed and documented in accordance with The University 
of Kansas Cancer Center policy. 
 
13.4 Confidentiality 
 
The Investigator and any other personnel involved in the trial shall not disclose or use for any purposes 
other than for the performance of this trial any data, records or other information disclosed to the 
Investigator or other trial personnel. Such information shall remain the confidential and proprietary 
property of the Sponsor/Investigator and shall be disclosed only to the Investigator or other designated 
trial personnel.  
 
Participant confidentiality will be ensured by using assigned site-specific participant ID numbers 
throughout the trial. 
 
13.5 Publication 
 
The Sponsor/Investigator holds the primary responsibility for publication. 
 
Data 
Funder and its co-development collaborator may use the data generated under the Research Agreement 
for all purposes, subject to Institutions right to publish. 
 
Publication 
The University of Kansas Cancer Center Sponsor/Investigator shall publish the results of the approved 
study, subject to reasonable delay to allow for filing of patent applications on any inventions (as 
applicable).  Sponsor/Investigator will provide the funder with the opportunity to review and comment 
on any publications, prior to submission. 
 

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13.6 Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the FDA Modernization Act (FDAMA) and the FDA Amendments Act (FDAA) the 
Sponsor/Investigator of the trial is solely responsible for determining if the trial and results meet the 
requirement for submission to the Clinical Trials Data Bank, http://www.clinicilaatrials.gov. Information 
posted will allow participants to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate trial 
location and trial site contact information. 
 
13.7 Required Site Documentation 
 
Before the study is initiated at any site the following documentation must be provided to The University 
of Kansas Cancer Center IIT Regulatory Department. 
• 
A copy of the official IRB approval letter for protocol and informed consent. 
• 
A copy of the IRB-approved consent form. 
• 
CVs and medical licensure for the Principal Investigator and all Sub-Investigators who 
will be involved with conduct of the study.  
• 
Appropriately completed and signed Form FDA 1572 with appropriate documentation. 
• 
COP and CLIA Laboratory certification numbers and institution laboratory normal values. 
• 
Executed clinical research contract. 
 
13.8 Data Management 
 
Web-based eCRFs will be used to collect participant data. All eCRFs and resulting data will be developed 
and maintained in a manner consistent with currently available regulations and guidance pertinent to 
the use of computerized systems in clinical trials. All users of the eCRF system will be trained prior to the 
use of the system. 
 
A Risk-Based Monitoring (RBM) approach will be used focusing on critical variables and triggered events 
and ensuring the eCRF accurately reflects data recorded in source documents.   
 
13.9 Data Monitoring  
 
Data monitoring procedures will be carried out by The University of Kansas Cancer Center Clinical Trials 
Office (CTO) Clinical Site Managers for all participating sites and will be performed on a regular basis to 
comply with Good Clinical Practice.  
 
The study will be monitored at appropriate intervals, no less than those assigned per The University of 
Kansas Cancer Center Protocol Review and Monitoring Committee (PRMC) risk level designation, to 
assure compliance to GCP and to assess the data quality and study integrity.  
 
Interim monitoring visits (IMV) will occur at regular intervals following enrollment/registration of the 
first study participant with the frequency and duration of each visit depending on recruitment status 
and participant enrollment/registration. 
 

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Review of the case report forms, cross-reference with source documents, review of trial related 
regulatory documents and logs will be monitored on an ongoing basis during monitoring sessions. The 
monitor will ensure that the trial is conducted according to protocol design and regulatory 
requirements.  
 
The monitor will complete a follow-up letter and provide to the Sponsor/Investigator. The letter will 
include a summary of what the site monitor reviewed and the site monitor’s statements concerning the 
significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or 
actions recommended to ensure compliance. The site will be expected to submit any Corrective and 
Preventative Action Plan (CAPA) in writing to the Sponsor/Investigator. A copy of the monitoring forms,  
follow up letter and CAPA will be kept in the site monitor’s trial file and will be followed up at the next 
monitoring session.  
 
The investigator and staff are expected to cooperate and provide all relevant study documentation in 
detail at each site visit on request for review. The study monitor will have direct access to source data 
for data verification. Data verification will be conducted by comparing the data entered into the CRFs 
with source data. 
 
14 DSMC OVERSIGHT  
 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of The University of Kansas Cancer 
Center will monitor every participant receiving study intervention on this protocol for safety, conduct 
and scientific progress of research protocols, and the validity and integrity of the data for clinical trials. 
This protocol will adhere to the policies of the currently approved University of Kansas Cancer Center 
Data and Safety Monitoring Plan which is in accordance with NCI and The University of Kansas Cancer 
Center -IRB policy and guidelines. The committee is led by a senior practicing oncologist and consists of 
The University of Kansas Cancer Center faculty and staff with expertise in oncology, research, pharmacy, 
research nursing and data management. The University of Kansas Cancer Center DSMC has the authority 
to require amendments, suspend, or terminate any research activities that fall within its jurisdiction, and 
can institute other appropriate actions as needed to protect participant safety. 
 
The DSMC is an autonomous committee. However, its actions are communicated to other committees 
engaged in oversight of clinical research at The University of Kansas Cancer Center. The PI is responsible 
for forwarding all DSMC letters, including those recommending continuation of the study, to the IRB and 
PRMC. DSMC recommendations for modifications to the trial are forwarded to the Deputy Director of 
The University of Kansas Cancer Center. The PI is notified of this recommendation and is expected to 
alert all collaborating investigators about the DSMC action. At this time the PI may appeal the 
Committee’s decision to the Deputy Director of The University of Kansas Cancer Center or their 
designee. The Deputy Director of The University of Kansas Cancer Center or their designee will notify the 
PI if he/she concurs with the DSMC’s recommendation, including suspension or closure. 
 
14.1 Serious Adverse Events 
 
Serious adverse events that require expedited reporting will be reviewed by the DSMC Chair or designee 
who will determine if immediate action is required.  If determined to be necessary by the DSMC, all 
participating sites will be notified of the event and any resulting action within one working day of this 
determination.  

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14.2 Review of Serious Adverse Event Rates 
 
Once per month, serious adverse event rates will be monitored by the DSMC Coordinator. If any study 
site has had 2 or more of the same SAE reported within one month, or more than 6 of the same SAE in 6 
months, the DSMC will review summaries of SAEs, and discuss events in detail with the PI. The DSMC 
chair or designee determines whether further action is required.  The Sponsor/Investigator, in 
collaboration with the DSMC Coordinator ensure that collaborating investigators and IRBs for all 
participating sites are notified of any resulting action. 
 
14.3 Study Safety and Progress 
 
An overall assessment of toxicities as described in the protocol is reviewed at DSMC meetings.  This 
review enables DSMC committee members to assess whether significant risks are occurring that would 
warrant study suspension/closure or protocol amendment. 
 
14.4 The University of Kansas Cancer Center Quality Assurance Auditing 
 
The study will be audited by The University of Kansas Cancer Center Quality Assurance Department at 
appropriate intervals, no less than those assigned per The University of Kansas Cancer Center Protocol 
Review and Monitoring Committee (PRMC) risk level designation, to assure compliance to GCP and 
Good Documentation Practices (GCP).  
 
The investigator and staff are expected to cooperate and provide all relevant study documentation in 
detail at each site visit on request for review. The study monitor will have direct access to source data 
for data verification. Data verification will be conducted by comparing the data entered into the CRFs 
with source data. 
 
15 DATA HANDLING AND RECORD KEEPING  
 
15.1 Data Collection and Management Responsibilities 
 
Electronic case report forms (eCRFs) will be completed for each participant enrolled and registered on 
this study.  All CRFs will be customized per this study, in order to emphasize completeness and accuracy. 
The investigatory and trained study staff will enter and edit the data via a secure network with secure 
identification and password requirements. A complete electronic audit trail will be maintained.  
 
Source documents serve as the evidence of the existence of the participant and the data collected for 
this trial. Source documents will be the responsibility of the Investigator and will be filed at the site and 
available as needed by the Sponsor/Investigator or assigned Clinical Site Manager.  
 
Data captured in the eCRF is to be transcribed from source documents and must be consistent with any 
discrepancies explained and document. The medical chart and any other clinical worksheets, procedural 
reports, etc. will be the source documentation of data captured into the study database.   
 

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15.2 Protocol Deviations 
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. All deviations will be entered into the CRIS 
system must be reported to the DSMC. All deviations will be reported to the IRB per local reporting 
policy.  
 
15.3 Study Closure  
 
Upon study closure, the Sponsor/Investigator and/or Institution will be required to certify that all safety 
reporting obligations were met. 
 
15.4 Study Records Retention 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information 
enables the study to be fully documented and the study data to be subsequently verified. Original 
source documents supporting entries in the case report forms include but are not limited to hospital 
records and clinic charts, laboratory and pharmacy records, ECG, signed ICFs, participant diaries and 
pathology reports. All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
 

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16 APPENDICES 
 
Appendix A:  ECOG Performance Status 
 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair.* 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
 

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Appendix B:  Reportable Events 
 
 
Adverse Event (AE) Definition 
 
Adverse event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation participant administered study intervention and that does 
not necessarily have a causal relationship to this intervention. An AE can therefore be any unfavorable 
and unintended sign (such as an abnormal laboratory finding), symptom or disease temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention.  
 
Progression of the cancer under study or events which are unequivocally due to disease progression 
should not be reported as an AE during the study unless the treating investigator considers it to be study 
intervention related.   
 
Serious Adverse Event (SAE) Definition 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event defined as a medical event or multiple medical events that may 
not be immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgement may jeopardize the participant or may require 
intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed above.   
• 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
intervention. 
 
Although pregnancy is not always serious by regulatory definition, for the purposes of this protocol, this 
event is considered to be an SAE and follow the SAE reporting timeline. 
 
Any component of the study endpoints that is considered related to study therapy should be reported as 
an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis is reported an SAE.) 
 
NOTE: The following hospitalizations are not considered SAE’s: 
• 
An Emergency room or other hospital department visit <24 hours that does not result in 
admission.  Unless considered an important medical or life-threatening event) 
• 
Elective surgery planned prior to signing consent. 
• 
Admissions as per protocol for a planned medical/surgical procedure. 
• 
Routine health assessment requiring admission for baseline/trending of health status. (e.g., 
routine colonoscopy) 

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• 
Medical /surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention. (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason) 
• 
Admission for administration of anticancer therapy in the absence of any other SAE. 
 
Unanticipated Problem 
 
An Unanticipated Problem is any incident, experience or outcome involving risk to participants or others 
in any human participant research that meets all of the following criteria:  
 
• 
Unexpected (in terms of nature, severity or frequency) given the research procedures described 
in the IRB-approved protocol and informed consent document and the characteristics of the 
population being studied. 
• 
Related or possibly related to participation in such research (i.e., there is a reasonable possibility 
the incident, experience or outcome may have been caused by the procedures involved in such 
research). 
• 
Suggests that the research placed participants or others at a greater risk of harm (including 
physical, psychological, economic or social harm) that was previously known or recognized.  
 
Suspected Adverse Reaction 
 
A Suspected Adverse Reaction (SAR) is any AE for which there is a reasonable possibility that it was 
caused by the study intervention.   
 
Reasonable possibility means there is evidence to suggest a causal relationship between the study 
intervention and the AE. Examples of reasonable possibility are:  
• 
A single occurrence of an event that is uncommon and know to be strongly associated with 
study intervention exposure.  
• 
One or more occurrences of an event that is not commonly associated with study intervention 
exposure but is otherwise uncommon in the population exposed to the study intervention. 
• 
An aggregate analysis of specific events observed in a clinical trial that indicates that those 
events occur more frequently in the study intervention group than in a concurrent or historical 
control group. 
 
Expectedness and Attribution 
 
Both AE’s and SAE’s are evaluated with regard to expectedness and attribution.   
 
Expectedness  
 
Expected events are those that have previously been identified as resulting from administration of the 
agent. For the purposes of this study an event is considered expected when it appears in the 
Investigator’s Brochure, the package insert or is included in the informed consent document as a 
potential risk.  

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An event is unexpected when it varies in nature, intensity or frequency from information provided in the 
Investigator’s Brochure, the package inserts or when it is not included in the informed consent 
document as a potential risk.  
 
Attribution 
 
Attribution is the relationship between an event and the study intervention. Attribution is assigned as 
follows:  
 
• 
Definite – The event is clearly related to the study intervention 
• 
Probable – The event is likely related to the study intervention 
• 
Possible – The event may be related to the study intervention 
• 
Unlikely – The AE is doubtfully related to the study intervention 
• 
Unrelated – The AE is clearly NOT related to the study intervention 
 
Adverse Event Monitoring 
 
Baseline adverse events are recorded and graded using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0.  Additional serious adverse event and adverse event monitoring begins after 
initiation of study intervention and ends 36 months following surgery or until the start of a new anti-
cancer therapy whichever is earlier.   
 
Adverse event data collection and reporting are a part of every clinical trial and are done to ensure the 
safety of participants enrolled in the studies as well as those who will enroll in future studies using 
similar agents.  
 
Adverse events should be evaluated to determine 
• 
Start and end dates 
• 
Severity or grade 
• 
Seriousness 
• 
Relationship to study intervention 
• 
Action taken (i.e., dose held, dose reduced, medical intervention) 
• 
Outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
 

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Participants experiencing an adverse event, regardless of its relationship to study intervention will be 
monitored until: 
• 
Adverse event resolves or the symptoms or signs that constitute the adverse event return to 
baseline.  
• 
Clinically significant abnormal laboratory values have returned to baseline. 
• 
The treating investigator has determined there is a satisfactory explanation other than the study 
intervention for the changes observed. 
• 
Death 
 
The following laboratory abnormalities should be documented and reported as adverse events. 
• 
Meets the definition of an SAE. 
• 
Requires medical intervention (i.e., dose modification and/or other intervention such as 
supportive medication administration, supplementation, physical therapy, diet change, fluid  
 
 
 

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Appendix C:  Clavien-Dindo Classification for Surgical Complications 
 
The Clavien-Dindo Classification of Surgical Complications  
 
Full Scale  
 
Contracted Form  
Grades  
Definition  
Grades 
Definition 
Grade  I:  
Any deviation from the normal postoperative course 
without the need for pharmacological treatment or 
surgical, endoscopic and radiological interventions.  
 
Grade I:  
Same as for Full
Scale  
Allowed therapeutic regimens are: drugs as 
antiemetics, antipyretics, analgesics, diuretics and 
electrolytes and physiotherapy. This grade also 
includes wound infections opened at the bedside.  
  
Grade  II:  
Requiring pharmacological treatment with drugs other 
than such allowed for grade I complications. 
Blood transfusions and total parenteral nutrition are 
also included.  
 
Grade II: 
Same as for Full
Scale  
  
Grade  III:  
Requiring surgical, endoscopic or radiological 
intervention  
 
Grade III:  
 
Grades IIIa & 
IIIb  
Grade III-a:  
intervention not under general anesthesia  
Grade III-b:  
intervention under general anesthesia  
  
Grade IV:  
Life-threatening complication (including CNS 
complications)‡ requiring IC/ICU-management  
 
Grade IV:  
Grades IVa & 
IVb  
Grade IV-a:  
single organ dysfunction (including dialysis)  
Grade IV-b:  
multi organ dysfunction  
  
Grade V:  
Death of a patient  
 
Grade V:  
Same as for Full
Scale  
Suffix 'd':  
If the patients suffers from a complication at the time 
of discharge, the suffix “d”  (for ‘disability’) is added to 
the respective grade of complication. This label 
indicates the need for a follow-up to fully evaluate the 
complication.  
 
 
 
‡ brain hemorrhage, ischemic stroke, subarrachnoidal bleeding, but excluding transient ischemic attacks (TIA);IC: 
Intermediate care; ICU: Intensive care unit. 
 
Dindo D., Demartines N., Clavien P.A.; Ann Surg. 2004; 244: 931-937 
 
 
 

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Appendix D:  Examples of Grading Using Clavien-Dindo Classification 
 
 
 
 

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Appendix E:  Wound Healing Assessment - GTSD Training Manual- Pages 246-248 
 
 
 
 
 

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