A Trial of Palliative Lattice Stereotactic Body Radiotherapy (SBRT)
Phase: NA
Conditions: Cancer, Palliative Radiotherapy
Sponsor: Washington University School of Medicine

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Protocol Version: 15 June 2020 
 
 
 
A Trial of Palliative Lattice Stereotactic Body Radiotherapy (SBRT) 
 
Washington University School of Medicine 
Division of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224 
St. Louis, MO  63110 
 
Protocol #: 201910071 
Version Date: 15 June 2020 
 
 
Principal Investigator: 
Matthew Spraker, M.D., Ph.D. 
Phone: (314) 362-8567 
E-mail:  mspraker@wustl.edu    
 
Sub-Investigator:     
James Kavanaugh, M.S. 
Sai Duriseti, M.D., Ph.D. 
 
Sub-Investigators 
 
 
 
Modality 
Clifford Robinson, M.D. 
 
 
Radiation Oncology 
Jeff Michalski, M.D.  
 
 
Radiation Oncology 
Dennis Hallahan, M.D. 
 
 
Radiation Oncology 
Wade Thorstad, M.D.  
 
 
Radiation Oncology 
Julie Schwarz, M.D., Ph.D.  
 
Radiation Oncology  
Perry Grigsby, M.D.  
 
 
Radiation Oncology 
Hyun Kim, M.D. 
 
 
 
Radiation Oncology 
Chris Abraham, M.D.  
 
 
Radiation Oncology 
Dinesh Thotala, Ph.D. 
 
 
Radiation Oncology 
Brian Van Tine, M.D., Ph.D.  
 
Medical Oncology 
Sreekrishna Goddu, Ph.D. 
 
 
Physics 
Nels Knutson, Ph.D.  
 
 
Physics 
Sasa Mutic Ph.D. 
 
 
 
Physics 
Yu Tao, M.D., M.S.                                        Biostatistics 
Yi Huang, M.S. 
 
 
 
Biostatistics 
 
NCT#: 
NCT04133415  
Funded by: 
Radiation Oncology Department 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 

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Protocol Version: 15 June 2020 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
A Trial of Palliative Lattice Stereotactic Body Radiotherapy (SBRT) 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
14 October 2019 
Amendment #1 Version 
 
 
 
 
 
 
04 December 2019 
Amendment #2 Version 
 
 
 
 
 
 
09 December 2019 
Amendment #3 Version 
 
 
 
 
 
 
07 February 2020 
Amendment #4 Version 
 
 
 
 
 
 
23 April 2020 
Amendment #5 Version 
 
 
 
 
 
 
15 June 2020 
 
 
 
 

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Protocol Version: 15 June 2020 
STATEMENT OF COMPLIANCE 
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)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 

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Protocol Version: 15 June 2020 
Glossary of Abbreviations  
 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
ATC 
Advanced Technology Consortium  
BJH 
Barnes Jewish Hospital 
CBC 
Complete blood count 
CD4+ 
Cluster of differentiation 4+ 
CFR 
Code of Federal Regulations 
CMP 
Comprehensive metabolic panel 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CYP3A4 
Cytochrome P450 3A4 
DHHS 
Department of Health and Human Services 
DNA 
deoxyribonucleic acid 
DOB 
Date of birth 
DSM 
Data and Safety Monitoring  
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
GTV 
Gross Tumor Volume 
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
ICH 
International Council for Harmonisation 
IGRT 
Image-guided radiation therapy 
IMRT 
Intensity modulated radiotherapy 
IL 
Interleukins  
IRB 
Institutional Review Board 
MRI 
Magnetic resonance imaging 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NRS 
Numeric Rating Scale  
NSCLC 
Non-small cell lung cancer 
OAR 
Organs at risk  
OHRP 
Office of Human Research Protections  
PD-L1 
Programmed death ligand 1 

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Protocol Version: 15 June 2020 
PI 
Principal investigator 
PRO-CTCAE 
Patient Reported Outcomes-Common Terminology Criteria for Adverse Events 
PTV 
Planning Target Volume  
QASMC 
Quality Assurance and Safety Monitoring Committee 
QoL 
Quality of Life  
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SBRT 
Stereotactic body radiation 
SFRT 
Spatially fractionated radiotherapy 
Lattice SBRT 
Spatially-fractionated stereotactic body radiation 
SIB 
Simultaneous integrated boost 
SLCH 
St. Louis Children’s Hospital  
TEAE 
Treatment emergent severe adverse events 
TNF 
Tumor necrosis factor 
TPCF 
Tissue Procurement Core Facility  
UPN 
Unique patient number 
VMAT 
Volumetric modulated arc therapy 
WU 
Washington University 
 
 

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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 8 
Synopsis ...................................................................................................................................... 8 
SCHEMA ........................................................................................................................................ 9 
SCHEDULE OF ACTIVITIES ................................................................................................. 10 
1.0 
INTRODUCTION ............................................................................................................. 11 
1.1 
Metastatic or Unresectable Tumors ................................................................................ 11 
1.2 
Radiotherapy for Tumors Needing Palliation ................................................................ 11 
1.3 
Spatially Fractionated Radiotherapy (SFRT) ................................................................. 11 
1.4 
Correlative Studies Background..................................................................................... 12 
1.5 
Rationale for treatment approach ................................................................................... 12 
1.6 
Study Design .................................................................................................................. 12 
1.7 
Risk/Benefit Assessment ................................................................................................ 13 
2.0 
OBJECTIVES AND ENDPOINTS ................................................................................... 14 
3.0 
STUDY POPULATION .................................................................................................... 15 
3.1 
Inclusion Criteria ............................................................................................................ 15 
3.2 
Exclusion Criteria ........................................................................................................... 15 
3.3 
Inclusion of Women and Minorities ............................................................................... 16 
4.0 
REGISTRATION PROCEDURES ................................................................................... 16 
4.1 
Confirmation of Patient Eligibility ................................................................................. 16 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 16 
4.3 
Assignment of UPN ....................................................................................................... 16 
4.4 
Screen Failures ............................................................................................................... 16 
4.5 
Strategies for Recruitment and Retention ...................................................................... 17 
5.0 
TREATMENT PLAN ........................................................................................................ 17 
5.1 
Study Intervention Description ...................................................................................... 17 
5.2 
Pre-Radiation Evaluation ............................................................................................... 18 
5.3 
Radiation Therapy .......................................................................................................... 18 
5.4 
Patient-Reported Quality of Life Outcome and Toxicity Measures .............................. 22 
5.5 
Acquisition of Blood for Research ................................................................................. 22 
5.6 
Definitions of Evaluability ............................................................................................. 23 
5.7 
Concomitant Therapy and Supportive Care Guidelines ................................................. 23 
5.8 
Women of Childbearing Potential .................................................................................. 23 
5.9 
Duration of Therapy ....................................................................................................... 23 
5.10 Follow-up Specifications................................................................................................ 24 
5.11 Lost to Follow-Up .......................................................................................................... 24 
6.0 
RADIATION THERAPY DOSE/DELAYS MODIFICATIONS ..................................... 25 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 25 
7.1 
WU PI Reporting Requirements .................................................................................... 25 
7.2 
Exceptions to Expedited Reporting ................................................................................ 26 
8.0 
CORRELATIVE STUDIES .............................................................................................. 26 
8.1 
Blood Sample Collection and Processing ...................................................................... 26 
9.0 
DATA SUBMISSION SCHEDULE ................................................................................. 27 
9.1 
Adverse Event Collection in the Case Report Forms ..................................................... 27 
10.0 DATA AND SAFETY MONITORING ............................................................................ 28 
11.0 STATISTICAL CONSIDERATIONS............................................................................... 28 

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11.1 Study Design .................................................................................................................. 28 
11.2 Study Endpoints ............................................................................................................. 29 
11.3 Data Analysis ................................................................................................................. 29 
11.4 Power Analysis and Sample Size ................................................................................... 29 
11.5 Accrual ........................................................................................................................... 29 
11.6 Continuous Toxicity Monitoring using Pocock-type boundary ..................................... 29 
12.0 REFERENCES .................................................................................................................. 31 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 35 
APPENDIX B: Definitions for Adverse Event Reporting ............................................................ 36 
APPENDIX C: Reporting Timelines ............................................................................................ 38 
APPENDIX D: PRO-CTCAE Inventories.................................................................................... 40 
 
 

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Protocol Version: 15 June 2020 
 
PROTOCOL SUMMARY 
 
Synopsis 
 
Title: 
A Trial of Palliative Lattice Stereotactic Body Radiotherapy (SBRT) 
Study Description: 
Lattice SBRT will be used to deliver palliative radiotherapy to large (≥4.5 
cm) tumors. The safety and efficacy of this approach will be assessed for 
this novel treatment technique. 
Objectives: 
Primary Objective: To evaluate the safety of 5-fraction palliative Lattice 
SBRT in patients with non-hematologic malignancies with large lesions 
who are planning to undergo palliative radiotherapy (≥4.5 cm). 
 
Exploratory Objectives: 
1. To assess pain response to Lattice SBRT  
2. To assess patient-reported toxicity outcomes  
3. To assess patient reported quality of life outcomes  
4. To evaluate blood for immune- and tumor damage-associated 
response with Lattice SBRT 
Endpoints: 
Primary: Rate treatment-related, non-hematologic CTCAE version 5.0 ≥ 
Grade 3 toxicity 
 
Exploratory: Pain assessment, PROMIS Global, Physical Function, Pain 
Interference, Anxiety, and Depression, peripheral blood immune-related 
biomarkers. 
Study Population: 
Ten patients will be enrolled, all ≥ 18 years of age with ECOG ≤ 2. All 
genders and races will be included.  
Phase: 
Unphased 
Description of Sites / 
Facilities Enrolling: 
This is a single-institutional study 
Description of Study 
Intervention: 
5-fraction Lattice SBRT delivered to 20 Gy with a simultaneous 
integrated boost (SIB) to 66.7 Gy. 
Study Duration: 
6 months plus 2 weeks for treatment and 90 days follow up 
Participant Duration: 
2 weeks of treatment plus 90 days follow up. 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Plan 
Pre-treatment imaging and blood sample collection. 
SF- SBRT to 20 Gy with a SIB to 66.7 Gy in 5 
fractions. 
Immediate post-treatment blood sample collection 
Eligible Patients 
Patients ≥ 18 years of age with histologically confirmed cancer with a 
lesion ≥ 4.5 cm in any dimension and planning to undergo palliative 
radiotherapy  
Follow Up 
Post-treatment blood sample collection at 14 and 30 
days and imaging at 90 days. Continued disease, 
symptom, and toxicity monitoring for 90 days. 

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SCHEDULE OF ACTIVITIES 
 
Screening 
Pre-Tx / 
Baseline 
Fx 1 
Fx 2 
Fx 3 
Fx 4 
Fx 5 
EOT 
(2 weeks 
post) 5 
30 Day 
F/U6 
90 Day 
F/U6 
Informed consent 
X 
Demographics 
X 
Physical exam (incl. height 
and weight) 
X 
 
Once during these 5 fractions3 
X 
X 
X 
ECOG PS 
X 
Medical history  
X 
Pregnancy test4 
X 
 
 
 
 
 
 
 
 
 
Hematology (CBC, CMP) 
X 
CT or MRI of the chest, 
abdomen, and pelvis 
 
X7 
 
 
 
 
 
 
 
X8 
Peripheral blood collection 
X 
X 
X 
X 
Questionnaires 
X2 
X 
X 
X 
Lattice SBRT1 
X 
X 
X 
X 
X 
AE review and evaluation 
X3--------------------------------------------------------------------X 
X 
X 
X 
Footnotes: 
1. 
Treatment given every other day 
2. 
Completed within at least 2 weeks prior to treatment  
3. 
Every patient will be required to have 1 on-treatment visit per standard of care clinical practice  
4. 
For women of child bearing potential only and within 20 days of study entry  
5. 
+/- 1 week 
6. 
+/- 2 weeks 
7. 
Within the past 3 months 
8. 
Within 3 months after treatment; if there’s more than one scan, use the later scan 

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Protocol Version: 15 June 2020 
1.0 
INTRODUCTION 
 
1.1 
Metastatic or Unresectable Tumors 
 
In 2018, it is estimated that the US cancer prevalence was about 14.5 million Americans, 
and this is expected to balloon to approximately 19 million Americans by 2024 
(American Cancer Society 2019). Metastatic or unresectable disease is the cause of 
cancer-related morbidity and mortality for about 90% of cancer patients (Chaffer and 
Weinberg 2011). Clinical presentation of disease can vary widely depending on the site 
of the tumor, but pain is frequently a presenting symptom (Hamilton et al. 2015). 
 
1.2 
Radiotherapy for Tumors Needing Palliation  
 
While radiotherapy paradigms evolve, symptomatic palliation is at the forefront of 
treatment intent (Spencer et al. 2018; Jones and Simone II 2014). As such, appropriate 
modality, dose, and fractionation continue to be investigated. Ongoing studies suggest 
hypofractionated approaches are favorable for this population with regimens  based on 
principles of cancer radiobiology, such as the Spanos Regimen and the QUAD SHOT, 
having variable success in specific disease sites (Carrascosa et al. 2007; Corry et al. 
2005). 
 
Recent data demonstrates that SBRT offers improvements over conventionally 
fractionated radiotherapy for palliative treatment (Sprave et al. 2018; Nguyen et al. 
2019). Three issues limit the utility of SBRT. First, dose escalation can be difficult given 
the proximity to surrounding OARs (Hartsell et al. 2005; Shiue et al. 2018). Second, it 
may be unsafe to treat large tumors with SBRT. Retrospective data and secondary 
analyses from SBRT trials for NSCLC suggest that 5 cm should be the upper limit for 
which SBRT may be employed (Allibhai et al. 2013; Videtic et al. 2017). Third, SBRT 
may not be as effective for larger lesions as it is for smaller lesions. Prior studies support 
this limitation. (Ricco et al. 2017; Masucci 2018) 
 
1.3 
Spatially Fractionated Radiotherapy (SFRT) 
 
SFRT may address these limitations of traditional SBRT. SFRT relies on beam 
collimation to create high-dose “peaks,” organized throughout a target volume with 
intervening low-dose “valleys” (Billena and Khan 2019). SFRT as a 2-dimensional 
technique is being evaluated in soft tissue sarcoma in a prospective setting (M. 
Mohiuddin et al. 2009; Mohammed Mohiuddin et al. 2014). In these studies, a single 
dose of 2-dimensional SFRT was used either alone or in combination with further 
conventionally fractionated radiation with or without chemotherapy with1-2 year LC 
greater than 90% and limited Grade 2-3 skin toxicities.  
 
Lattice radiotherapy is a form of SFRT that uses a 3-dimensional beam arrangement to 
target high-dose spherical volumes which allows for a more flexible beam arrangement, 
better normal tissue optimization, and lower exit beam skin dose (X et al. 2010). 
Classically, SFRT had been planned to achieve a dose fall off to 20-30% of the “peak” 

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dose (Meigooni et al. 2006). Tested approaches for Lattice designate spheres 1-2 cm 
spaced 2-3 cm apart (center to center) (Amendola et al. 2018; E et al. 2010). Prior studies 
show that Lattice SFRT can be delivered using IMRT or VMAT (Gholami et al. 2016; 
Billena and Khan 2019). 
 
1.4 
Correlative Studies Background 
 
In animal models, extreme hypo-fractionation was found to induce infiltration of T-cells 
(Lugade et al. 2005). Also, SBRT has been shown to alter levels of soluble PD-L1, IFN 
α/β/γ, TNFα, and various interleukins (Trovo et al. 2016; Ellsworth et al. 2017; Walle et 
al. 2018; Song et al. 2019). 
 
It is hypothesized that SFRT spares interspersed small volumes of normal tissue allowing 
it to tolerate higher doses of radiotherapy while immune-mediated bystander effects 
allow for cell kill of areas of tumor receiving a lower dose. This hypothesis is supported 
by the finding SFRT is associated with increased serum TNFα and that higher levels of 
TNFα are associated with complete tumor response (Sathishkumar et al. 2002). 
 
SFRT has been shown to elicit a local effect by the “bystander effect” (i.e. effects to 
tumor cells in the valleys) via secretion of cytokines, induction of cellular repair 
pathways, and induction of apoptosis (Sathishkumar et al. 2016; Najafi et al. 2014; Asur 
et al. 2012). 
 
While SBRT and SFRT are both felt to elicit robust immune responses, the immunogenic 
effects of Lattice SBRT have not been studied.  
 
1.5 
Rationale for treatment approach 
 
Standard palliative radiotherapy regimens may provide limited durability of response in 
large tumors. Thus, there is a clinical need for a new approach. A standard palliative 
radiotherapy regimen is 20 Gy in 5 fractions, and therefore it is reasonable to assume that 
this should be the minimum dose delivered for adequate tumor coverage in an Lattice 
SBRT plan. Assuming that this represents the 30% isodose (i.e. the “valley”), this would 
allow appropriate dose escalation in the “peak” to 66.7 Gy (i.e. the 100% isodose). The 
Lattice SBRT approach may improve symptom response, LC, and better prime the tumor 
microenvironment for immune response (Ko, Benjamin, and Formenti 2018; Walle et al. 
2018; Krombach et al. 2019) compared with canonical palliative radiotherapy doses with 
the added benefit of less toxicity than a traditional homogenous SBRT plan.  
 
1.6 
Study Design 
 
1.6.1 Overall Design 
 
This is a study evaluating the safety of Lattice SBRT for patients with large 
tumors (≥ 4.5 cm) planning to undergo palliative radiotherapy. Eligible patients 
will undergo radiotherapy using Lattice SBRT. Lattice SBRT will be prescribed 

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Protocol Version: 15 June 2020 
to 20 Gy in 5 fractions delivered every other day with a Lattice SIB to 66.7 Gy in 
5 fractions. Patients will be followed for 90 days after the completion of all 
therapy for treatment-related toxicity assessment.   
 
An exploratory study will analyze blood-based markers of treatment response, so 
blood will be drawn prior to and after completion of radiotherapy. 
 
1.6.2 Scientific Rationale for Study Design 
 
Tumor burden incurs significant morbidity in terms of symptomatology, including 
pain, dyspnea, hemoptysis, and mass effect on surrounding organs. Palliative 
hypofractionated radiotherapy is known to be a useful modality for control and/or 
amelioration of such symptoms. However, large tumors are difficult to treat with 
traditional palliative methods. Hypofractionated radiotherapy may offer 
insufficient control and SBRT may be associated with a high rate of toxicity. 
 
Dose escalation using SFRT my offer improved local control, symptom relief, and 
reduced toxicity compared with traditional radiotherapy methods. Also, SFRT has 
been associated with significant activation of systemic anti-tumor cytokines and 
chemokines. Since Lattice SBRT has not been tested, the goal of this study is to 
evaluate the safety of this approach. 
 
1.6.3 Justification for Dose 
 
One standard regimen for palliative radiotherapy is 20 Gy in 5 fractions. In SFRT, 
the traditional dose gradient between minimum tumor dose and maximum tumor 
dose is 30% to 100%, respectively. Using 20 Gy in 5 fractions as traditional 
coverage for lesions needing palliation (i.e. 30% “valley” tumor coverage), the 
“peak” 100% dose is 66.7 Gy in 5 fractions. 
 
1.7 
Risk/Benefit Assessment 
 
1.7.1 Known Potential Risks 
 
High-dose radiation has been known to cause toxicity to normal tissue. This is 
manifested variably depending on the area of the body treated. While the potential 
toxicities can be serious and include death, these toxicities are rare when high-
quality, high-dose radiation is delivered within established normal tissue dose 
constraints using appropriate immobilization, image guidance, and institutional 
experience. We have successfully tested many Lattice SBRT plans prescribed to 
66.7 Gy in 5 fractions using institutional quality assurance protocols similar to 
conventional SBRT. Therefore, we expect the toxicity risks associated with 
Lattice SBRT plans to be similar to conventional SBRT if the required established 
dose constraints are met.  
 

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Blood collection prior to and after radiotherapy poses a small risk of pain and 
bleeding. 
 
 
2.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for Endpoints 
Primary 
To evaluate the safety of 
palliative Lattice SBRT in 
patients with non-hematologic 
malignancies with large lesions 
in need of palliative 
radiotherapy (≥ 4.5 cm) 
Rate treatment-related, non-
hematologic CTCAE v5.0 Grade 
≥ 3  toxicity 
SBRT to large tumors is 
traditionally associated with high 
dose to OARs, with sequelae of 
radiation-induced toxicities. As 
these patients have no effective 
treatment options, evaluation of 
the safety of this method of 
dose-escalation with SBRT is 
warranted. CTCAE v5.0 is a 
widely accepted standardized 
measure of treatment-related 
toxicity. 
Exploratory 
To assess pain response to 
Lattice SBRT 
For patients that have pain, their 
pain level will be assessed with 
the pain Numeric Rating Scale 
(NRS) 
The NRS is an 11-point scale for 
patient self-reporting of pain. 
This is selected because it is a 
reliable and clinically 
meaningful measure of pain that 
is extensively used in research 
and clinical practice.  
To assess patient-reported 
toxicity outcomes 
For patients that do not have pain, 
patient-reported symptom 
response will be assessed with 
PRO-CTCAE 
PRO-CTCAE is a standardized 
inventory to collected patient 
reported symptomatic adverse 
events in clinical trials.  
To assess patient reported 
quality of life outcomes 
 
Patient reported quality of life 
and functional outcomes will be 
measured before treatment, after 
treatment, and at each follow up 
with the PROMIS Global, 
Physical Function, Pain 
Interference, Anxiety, and 
Depression system 
This patient reported outcome 
inventory was selected because it 
is a reliable and clinically 
meaningful measure of patient 
reported toxicities and functional 
outcomes. 
To evaluate blood for immune- 
and tumor damage-associated 
response with Lattice SBRT 
Whole blood will be collected at 
baseline and after Lattice SBRT 
for exploratory studies of immune 
and tumor damage associated-
response 
The response of immune-related 
markers will be assessed before 
and after Lattice SBRT to better 
understand the immunogenic 
effects of treatment on tumor. 
 
 
 
 

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Protocol Version: 15 June 2020 
3.0 
STUDY POPULATION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed cancer. 
 
2. Planning to undergo palliative radiotherapy to a lesion ≥ 4.5 cm as measured with 
radiographic imaging or with calipers by clinical exam. 
 
3. ECOG performance status ≤ 2 
 
4. At least 18 years of age. 
 
5. Radiotherapy is known to be teratogenic.  For this reason, women of childbearing 
potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control, abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she must inform her treating physician immediately.  Men 
treated or enrolled on this protocol must also agree to use adequate contraception 
prior to the study, for the duration of the study, and 6 months after completion of the 
study 
 
6. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Prior radiotherapy that overlaps with any planned site of protocol radiotherapy.  
 
2. Patients with tumors in need of urgent surgical intervention, such as life-threatening 
bleeding or those at high risk for pathologic fracture. 
 
3. Currently receiving any cytotoxic cancer therapy regimens or VEGF inhibitors that 
will overlap with the Lattice SBRT administration.  
a. Cytotoxic chemotherapy and VEGF inhibitors prior to radiotherapy or planned 
after radiotherapy delivery are allowed at the discretion of the treating radiation 
oncologist.  This includes continuing a treatment plan which was initiated prior to 
the start of radiotherapy.  A 2 week washout is recommended, but not required. 
 
4. Pregnant.  Women of childbearing potential must have a negative pregnancy test 
within 20 days of study entry. 
 
5. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or 
they have a history of AIDS-defining opportunistic infection within the 12 months 
prior to registration.  Concurrent treatment with effective ART according to DHHS 
treatment guidelines is recommended.  Recommend exclusion of specific ART agents 

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Protocol Version: 15 June 2020 
based on predicted drug-drug interactions (i.e. for sensitive CYP3A4 substrates, 
concurrent strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers 
(efavirenz) should be contraindicated). 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.   
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility  
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. The registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form  
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study. All 
data will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not entered in the study.  A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants, to meet the Consolidated 

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Protocol Version: 15 June 2020 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (if applicable).   
 
4.5 
Strategies for Recruitment and Retention 
 
Our institution sees a high volume of patients that are referred for palliative radiotherapy.  
 
The primary source of patients who are eligible for this study will be radiation 
oncologists within our department. The most likely service lines to see patients with large 
tumors in need of palliative radiotherapy are sarcoma, thorax (i.e. lung cancer), 
gastrointestinal, gynecologic, palliative, and head and neck. Dr. Spraker (service line 
chief of sarcoma) is the PI, and the other service line chiefs are enthusiastic about this 
trial and are listed as co-investigators: Dr. Clifford Robinson (Thorax), Dr. Hyun Kim 
(Gastrointestinal), Dr. Perry Grigsby (Gynecologic), Dr. Chris Abraham (Palliative), and 
Dr. Wade Thorstad (Head and Neck). Additionally, a full-time research coordinator will 
be assigned to this study who will be screening all patients who are referred to our 
department for palliative radiotherapy.   
 
With the current rate of patients in need of palliative radiotherapy presenting to our 
department, we anticipate approximately 125 patients per year will be eligible for this 
protocol. A conservative estimate is that 20% of these patients will consent to participate 
in this study. This yields an estimated accrual of 25 patients per year. We anticipate that 
we will enroll 10 patients of all genders, races, and ethnicities. Given the 
hypofractionated course of therapy, 90% of patients should be able to complete therapy. 
We anticipate that we will accrue approximately 1-2 patients per month, therefore 
completing accrual in 6 months. Patients will be accrued from the outpatient clinics and 
inpatient hospitals of one U.S. site. Potential participants will be identified by our 
multidisciplinary team physicians and discussed in tumor board.  
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Study Intervention Description 
 
Consenting and eligible patients will undergo Lattice SBRT prescribed to a dose of 20 Gy 
in 5 fractions with a simultaneous integrated boost of 66.7 Gy in 5 fractions. As long as 
radiotherapy fields do not overlap, treatment of up to 4 other tumor sites are allowed. 
Lattice SBRT is required for all tumor sites ≥ 4.5 cm. Lattice SBRT fractions will be 
delivered every other day. For sites < 4.5 cm, other planning techniques may be used (i.e. 
3D conformal or SBRT). Following radiotherapy, patients will be evaluated for toxicity 
at 14, 30, and 90 days. 
 
Peripheral blood will be collected from patients before treatment, immediately after 
radiotherapy completion (Fraction 5), within 7-14 days after radiotherapy, and 30 days 
after radiotherapy.   

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Protocol Version: 15 June 2020 
 
5.2 
Pre-Radiation Evaluation 
 
• History and physical exam by team radiation oncologist 
• CBC & CMP 
• CT or MRI of the chest, abdomen, and pelvis 
• Completion of baseline NRS pain score (if applicable), PRO-CTCAE (if 
applicable), PROMIS Global, Physical Function, Pain Interference, Anxiety, and 
Depression questionnaires 
• Peripheral blood collection. 
 
5.3 
Radiation Therapy 
 
Lattice SBRT must be used for at least one lesion 4.5 cm or greater. The prescription 
dose for Lattice SBRT is 20 Gy in 5 fractions with a SIB to 66.7 Gy in 5 fractions. For 
Lattice SBRT, patients must be treated with intensity modulated radiotherapy (IMRT) or 
volumetric modulated arc therapy (VMAT).  
 
For Lattice SBRT, each lesion should be treated no more frequently than every other day, 
but treatment of each lesion may be staggered so that the patient has radiotherapy daily. 
No more than 3 lesions should be treated on the same day. 
 
For other lesions, a standard palliative regimen of 5 fractions or less is encouraged but 
not required. 
 
Multiple Lattice radiotherapy plans delivered during the trial period may not overlap. 
Reirradiation of prior irradiated sites is not allowed. 
 
5.3.1 Localization, Simulation, and Immobilization 
 
Simulation and treatment position will be determined by the treating radiation 
oncologist and team. Patients should be optimally positioned for stereotactic body 
radiation therapy with alpha cradles, aquaplast masks, or other methods of 
immobilization. The use of devices to alter dose distributions, such as bolus or 
lead shields, are allowed. Use of techniques to control and/or accommodate tumor 
motion may also be employed in constructing the planning target volume (PTV). 
 
A treatment planning CT scan or MRI in the treatment position will be required to 
define the PTV. The extent of the CT scan will be determined at the discretion of 
the treating physician. A CT scan slice thickness of ≤ 5 mm should be employed.  
 
5.3.2 Treatment Planning/Target Volumes 
 
The definitions for the GTV, PTV and normal structures used in this protocol 
generally conform to the 1993 ICRU report #50 titled Prescribing, Recording and 
Reporting Photon Beam Therapy.  

Page 19 of 41 
Protocol Version: 15 June 2020 
 
5.3.2.1 Target Volumes and Normal Structures  
 
Target Volumes 
Gross Tumor Volume (GTV): Contour using all available clinical and 
radiographic information. Fusion of other diagnostic imaging to delineate 
the GTV is allowed. Construction of an iGTV using 4DCT imaging is 
allowed. For boney lesions of the spine, the entire involved vertebral body 
may be included in the GTV.  
 
Planning Target Volume 2000 cGy (PTV_2000): Represents a geometric 
expansion of the GTV (or iGTV) of up to 1.0 cm. The PTV should be 
reduced as not to extend beyond the patient (i.e. in to air) and may be 
reduced as to not extend into skin (i.e. external contour contracted by 3-5 
mm). 
 
Planning Target Volume 6670 cGy (PTV_6670): Spheres with diameter 
1.5 cm should be placed 6 cm apart as measured from center to center 
inside the GTV. The spheres should be placed to maximize the number of 
whole spheres within the GTV. There should be 3 cm between axial slices 
in which spheres are placed. Vertices will be offset such as to create an 
octahedron between 3 slices on which spheres are placed. See the figure 
below for a geometric explanation. Crop all sphere volume extending 
outside of the GTV. 
 

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Protocol Version: 15 June 2020 
 
Geometric representation of sphere placement. Yellow dots represent the 
center of each sphere. Short dashes represent in-plane distances, dotted 
lines represent out-of-plane distances. Note that superior/inferior axial 
planes have spheres offset by 3 cm in-plane. To the right are axial slices 
representing yellow sphere placement in each plane. A blue diamond is 
represented to indicate vertices in the reference axial plane, and the 
center of vertices in planes 3 cm superior and inferior to this. 
 
Normal structures: Relevant normal structures and their dose constraints 
are described in the table below. Each normal structure should be 
contoured in its entirety.  
 
5.3.2.2 Radiation Treatment Planning 
 
CT-based planning with tissue inhomogeneity correction is required. Daily 
IGRT is required. Motion management strategies such as breath holding, 
respiratory gating, fluoroscopy, and MR-guided daily adaptive therapy are 
allowed.  
5.3.2.3 Planning Objectives and Normal Tissue Constraints 
 

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Protocol Version: 15 June 2020 
The normal tissues in the table below are to be contoured in their entirety 
when present on the CT simulation scan.  
 
The following organs and doses are guidelines for the radiation treatment 
plan. Organ at risk tolerance levels cannot be exceeded. Under 
coverage of PTV targets in order to meet OAR constraints is allowed. 
 
• PTV_2000: at least 95% should be covered by 20 Gy. Keeping 
Dmax within the PTV_2000 and outside the PTV_6670 to less than 
24 Gy is recommended but not required. 
• PTV_6670: at least 95% should be covered by 66.7 Gy. A Dmin of 
at least 60 Gy within vPTV is recommended. 
 
Serial Tissue 
Max point* dose 
(Gy) 
Optic pathway 
25 
Cochlea 
22 
Brainstem (excluding medulla) 
31 
Spinal cord and medulla 
28 
Cauda equina 
31.5 
Sacral plexus 
32 
Esophagus 
35 
Brachial plexus 
32.5 
Heart/pericardium 
38 
Great vessels 
53 
Trachea and large bronchus 
40 
Bronchi 
33 
Skin 
38.5 
Stomach 
35 
Bile duct 
41 
Duodenum 
26 
Jejunum/ileum 
32 
Colon 
40 
Rectum 
55 
Ureter 
45 
Bladder wall 
38 
*A point is defined as volume ≤ 0.035 cc) 
 
 
Parallel Tissue 
Critical Dose 
(Gy) 
Critical 
Volume 
Lungs - GTV 
12.5 
< 1500 cc 
13.5 
< 1000 cc 
< 37% 
Liver 
21 
< 700 cc 

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Protocol Version: 15 June 2020 
Renal cortex (bilateral) 
28 
< 200 cc 
Femoral Heads (Right & Left) 
30 
<10 cc 
 
5.3.3 Dose Specifications 
 
For Lattice SBRT, the daily prescription dose will be 20 Gy to be delivered to the 
PTV_2000 with a SIB of 66.7 Gy to be delivered to the PTV_6670 over 5 
fractions (4 Gy and 13.34 Gy to the PTV_2000 and PTV_6670 per day, 
respectively). All doses will be prescribed to the periphery of the PTVs. In 
general, the prescription isodose line (generally 93-98%) chosen should 
encompass at least 95% of the PTV. Under coverage of the PTV to meet dose 
constraints is allowed.  
 
The maximum point dose, minimum point dose, and the mean dose to the PTV 
will also be reported. 
 
5.3.4 Technical Factors 
 
The guidelines for VMAT in this trial will conform to the policies set by the 
Advanced Technology Consortium (ATC) and the National Cancer Institute 
(NCI).  Each of the target volumes and normal structures listed below must be 
delineated on each slice from the 3D planning CT in which that structure exists.  
 
5.3.5 Radiation Quality Assurance 
 
Radiation quality assurance will be evaluated by a Medical Physics team. Prior to 
treatment, plan quality will be assessed with an ion chamber and film-based 
dosimeters. 
 
5.4 
Patient-Reported Quality of Life Outcome and Toxicity Measures 
 
Symptom response and patient-reported quality of life will be measured using the pain 
numeric rating scale, PRO-CTCAE (abridged as indicated in Appendix D), PROMIS 
Global, Physical Function, Pain Interference, Anxiety, and Depression questionnaire at 
the following time points: 
 
1. Within 2 weeks prior to the start of radiotherapy 
2. Within 2 weeks after completion of radiotherapy 
3. At 30 days after radiotherapy   
4. At 90 days after radiotherapy 
 
The patient reported outcomes measures will be conducted using a computer-assisted 
interview program and may be done in person before/after a routine office visit or over 
the phone at the preference of the study participant. Patient reported outcomes may also 
be collected online. 
 
5.5 
Acquisition of Blood for Research 

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Protocol Version: 15 June 2020 
 
Refer to Section 8.0. 
 
5.6 
Definitions of Evaluability 
 
All patients enrolled on the study are evaluable for toxicity if they have received at least 
one fraction of radiation.  Patients are evaluated from first receiving study treatment until 
90 days after the conclusion of treatment or death. 
 
5.7 
Concomitant Therapy and Supportive Care Guidelines 
 
Patients may not receive any concurrent cytotoxic chemotherapy or VEGF inhibitors with 
radiation. The interval from last receipt of cytotoxic chemotherapy or VEGF inhibitors to 
the initiation (or re-initiation) of subsequent therapy will be at physician discretion. 
Supportive care will be consistent with standards for palliative radiotherapy, directed by 
the treating physician.  
 
5.8 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum/urine pregnancy test within 20 days prior to the first dose of 
radiation. 
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the 
study and for 6 months following the last dose of radiation.  
 
If a patient is suspected to be pregnant, radiation should be immediately discontinued.  In 
addition a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume therapy. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy 
or within 6 months after the last dose of radiation, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.9 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation 
documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for a 
maximum of 2 weeks or until one of the following criteria applies: 

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Protocol Version: 15 June 2020 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
5.10 
Follow-up Specifications 
 
5.10.1 Duration of Follow Up 
 
Patients will be followed at 14, 30, and 90 days after completion of radiotherapy. 
Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event.  Patients may be followed in-
person during visits, medical records review, phone calls, office visits, and 
assessment of any other clinically relevant materials after completion of therapy. 
 
5.11 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 4 weeks 
and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a 
required study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 1-2 weeks and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to 
and/or should continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address).  These contact attempts should be documented in the 
participant’s medical record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 

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Protocol Version: 15 June 2020 
 
6.0 
RADIATION THERAPY DOSE/DELAYS MODIFICATIONS 
 
The planned course of radiation therapy is five fractions delivered every other day to each lesion. 
For plans unable to meet dose constraints to OARs, under coverage of the PTV in order to meet 
the constraints is recommended. Patients with delayed treatment starts of any duration may be 
treated using existing or new plans at physician discretion. Continuance of treatment for delays 
while on-treatment will be at the discretion of the treating physician.  
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix B for definitions and Appendix C for a grid of 
reporting timelines. 
 
Adverse events will be tracked from start of treatment through 90 days following the completion 
of radiotherapy.  All adverse events must be recorded on the toxicity tracking case report form 
(CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
• AEs that do not fall under the following categories 
o Gastrointestinal 
o Hepatobiliary 
o Immune system 
o Metabolic 
o Nervous system 
o Renal and urinary 
o Respiratory 
o Skin disorders 
• AEs that are grade 1 
 
Refer to the data submission schedule in Section 9.0 for instructions on the collection of AEs in 
the EDC. 
 
7.1 
WU PI Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing 
the change. 
 

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Protocol Version: 15 June 2020 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problems involving 
risks to participants or others occurring at WU or any BJH or SLCH institution 
that has been reported to and acknowledged by HRPO.  (Unanticipated problems 
reported to HRPO and withdrawn during the review process need not be reported 
to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB 
form and any supporting documentation sent with the form. 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
8.0 
CORRELATIVE STUDIES 
 
8.1 
Blood Sample Collection and Processing 
 
Patients will be have up to 50 mL of anticoagulated blood collected in up to 5 EDTA 
purple top tubes at the following time points: 
• Baseline 
• immediately after radiotherapy completion (Fraction 5) 
• 14 days after radiotherapy 
• 30-days follow-up 
 
All samples will be marked with the patient’s study number, initials, and date of sampling 
with the use of an indelible marker. 
 
Blood and tissue samples will be stored in Dr. Aadel Chaudhuri’s lab in the Cancer 
Biology Division of the Department of Radiation Oncology.  
 
8.1.1 Plasma and Whole Blood 
 
Each sample will be labeled with a unique de-identified specimen ID number, and 
stored in Dr. Chaudhuri’s lab until analysis. Specifically, blood samples (up to 50 
mL) will be collected in 5 EDTA (10 mL each) purple top tubes at baseline, post-

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Protocol Version: 15 June 2020 
treatment (i.e. immediately following fraction 5), 14 days after treatment, and at 
30 days follow-up. EDTA whole blood samples will be spun at 1200 g and 
processed for platelet depleted plasma and peripheral white blood cells. Nucleated 
white blood cells will be isolated using Ficoll or Lymphoprep extraction using 
Sepmate tubes, washed in phosphate buffered saline, then divided into 
approximately 10 x 106 cells/aliquot, and cryopreserved at -80° C for 24-72 hours, 
then moved for longer term storage in a LN2 tank. All plasma and aliquots of 
platelet-depleted whole blood will also be stored at -80° C.  
 
All samples should be sent to: 
 
Aadel Chaudhuri, M.D., Ph.D. 
Peter Harris, Ph.D. (Lab Manager) 
4511 Forest Park Avenue 
Phone: 314-273-9040, 269-598-2212 (cell)  
 
9.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Specimen Collection Form 
Screening, immediately after radiotherapy completion 
(Fraction 5), 14 days after radiotherapy, and 30 days after 
radiotherapy  
Questionnaires  
Baseline, after radiation at 2 weeks, 1 month, and 3 months 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
After radiation at 2 weeks, 1 month, and 3 months 
Death Form 
At time of death (if applicable) 
 
9.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac 
arrest), report as a grade 5 event under that AE.  Participant death must also be recorded 
on the Death Form. 
 
 

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Protocol Version: 15 June 2020 
10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, 
the Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the 
Washington University Quality Assurance and Safety Monitoring Committee (QASMC) semi-
annually beginning six months after accrual has opened (if at least one patient has been enrolled) 
or one year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy (phase I studies only if efficacy is objective of the protocol) 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
• Summary of toxicities  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC 
according to institutional guidelines. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design  
 
This is a single arm study where 20 eligible patients with non-hematologic malignancies 
patients with large tumors (≥ 4.5 cm) will undergo radiotherapy using Lattice SBRT. 
Lattice SBRT will be prescribed to 20 Gy in 5 fractions delivered every other day with a 
LATTICE simultaneous integrated boost (SIB) to 66.7 Gy in 5 fractions. Patients will be 

Page 29 of 41 
Protocol Version: 15 June 2020 
followed for 90 days after the completion of all therapy for treatment-related toxicity 
assessment.  An exploratory study will analyze blood-based markers of treatment 
response, so blood will be drawn prior to and after completion of radiotherapy. 
 
11.2 
Study Endpoints  
 
The primary endpoint is treatment related severe adverse event rate defined as the 
percentage of patients with grade 3 or higher non-hematological toxicities as scored by 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5. 
 
The exploratory endpoints include blood-based markers of treatment response, pain 
response to Lattice SBRT, patient reported quality of life (QoL) outcomes using the in-
field response, PROMIS Global, Physical Function, Pain Interference, Anxiety, and 
Depression questionnaire, before and after treatment with Lattice SBRT.  
 
11.3 
Data Analysis  
 
Demographic and clinical characteristics will be summarized using descriptive statistics. 
Paired t-test and/or paired-sample Wilcoxon Signed Rank test will be used to compare 
the QoL scores between before and after treatment with Lattice SBRT.  
 
11.4 
Power Analysis and Sample Size  
 
Approximately 20 evaluable patients will be enrolled. The proposed sample size was 
chosen to allow assessment of safety. With an expected ≥ grade 3 non-hematological 
toxicity rate around 30%, there is a 99.53% probability of observing at least one toxicities 
in the 20 patients.   
 
11.5 
Accrual  
 
The rate of accrual for the study is expected to be about 1 patient per month. It is 
estimated 20 eligible patients will be enrolled in 10-12 months.  
 
11.6 
Continuous Toxicity Monitoring using Pocock-type boundary 
 
The toxicities will be reviewed and monitored on a continuous basis. Early stopping of 
this trial will be based on the excessive Lattice SBRT treatment emergent severe adverse 
events (TEAE) of grade 3 or higher non-hematological rate. We assume the TEAE rate is 
expected ~30% and a toxicity rate of 40% or more is not desired. Sequential boundaries 
will be used to monitor dose-limiting toxicity rate after three patients are enrolled and 
evaluable for toxicity. The accrual will be halted if excessive numbers of TEAE are seen, 
that is, if the number of TEAE is equal to or exceeds bn out of n patients with full follow-
up (see table below). This is a Pocock-type stopping boundary that yields the probability 
of crossing the boundary at most 0.3 when the rate of TEAE is equal to the acceptable 
rate of 0.3 (Ivanova, Qaqish, and Schell 2005).  
 
number of patients  4 5 6 7 8 9 10 11 12 13 14 15 

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Protocol Version: 15 June 2020 
Boundary (bn) 
4 5 5 6 6 6 7 
7 
8 
8 
9 
9 
 
Thus, based on the continuous monitoring algorithm for toxicity using Pocock-type 
boundary, the study will halt if excessive Lattice SBRT -related adverse events occur in 
the 4 of the first 4 patients, or 6 of the first 8, or 7 of the first 11, or 9 of the 20 patients 
has completed the trial. 
 
The operating characteristics including early stopping probability, expected number of 
TEAEs and associated with the calculated boundaries are listed below. 
 
TEAE 
rate 
Early 
stopping 
(hitting the 
boundary) 
probability 
Expected 
number of 
TEAEs 
Standard 
deviation 
on number 
of TEAEs 
Expected 
number of 
patients 
enrolled  
Standard 
deviation of 
number of 
patinets 
enrolled  
Expected 
TEAE rate 
Standard 
deviation 
on TEAE 
rate 
0.30 
0.0447 
4.41 
1.65 
14.71 
1.50 
0.31 
0.15 
0.40 
0.1707 
5.58 
1.54 
13.96 
2.65 
0.43 
0.18 
0.50 
0.4101 
6.24 
1.38 
12.49 
3.67 
0.55 
0.19 
0.60 
0.6957 
6.24 
1.40 
10.40 
4.06 
0.67 
0.18 
0.70 
0.9052 
5.72 
1.38 
8.18 
3.61 
0.77 
0.16 
0.80 
0.9878 
5.05 
1.11 
6.31 
2.60 
0.85 
0.14 
0.90 
0.9998 
4.46 
0.72 
4.96 
1.53 
0.93 
0.10 
1.00 
1.0000 
4.00 
0.00 
4.00 
0.00 
1.00 
0.00 
 
 
 

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Protocol Version: 15 June 2020 
 
12.0 
REFERENCES 
 
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Hamilton, William, Jacqueline Barrett, Sally Stapley, Debbie Sharp, and Peter Rose. 2015. 
“Clinical Features of Metastatic Cancer in Primary Care: A Case–Control Study Using 
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dimensional-high-dose-lattice-radiotherapy-lrt. 
 
 
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development services. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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

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

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

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

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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
every 6 months. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 

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APPENDIX D: PRO-CTCAE Inventories 
 
All patients will complete the following PRO-CTCAE inventories: 
• Rash 
• Numbness/tingling 
• Dizziness 
• Concentration 
• Memory 
• General pain 
• Fatigue 
• Insomnia 
• Anxious 
• Discouraged 
• Sad 
 
Patients with GI cancers (including esophagus, lower GI, and retroperitoneal sarcoma) will 
complete the following additional PRO-CTCAE inventories: 
• Decreased appetite 
• Nausea 
• Vomiting 
• Heartburn 
• Gas 
• Bloating 
• Hiccups 
• Constipation 
• Diarrhea 
• Abdominal pain 
• Fecal incontinence 
 
Patients with thoracic cancers (including esophagus, lung, and chest wall) will complete the 
following additional PRO-CTCAE inventories: 
• Decreased appetite 
• Nausea 
• Vomiting 
• Heartburn 
• Gas 
• Bloating 
• Hiccups 
• Shortness of breath 
• Wheezing 
• Voice changes 
• Hoarseness 
 

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Patients with pelvic cancers (including prostate, gynecologic, sarcomas, rectum, anus) will 
complete the following additional PRO-CTCAE inventories: 
• Vaginal discharge 
• Vaginal dryness 
• Painful urination 
• Urinary urgency 
• Urinary frequency 
• Change in urine color 
• Urinary incontinence 
• Erection 
• Ejaculation 
• Libido 
• Delayed orgasm 
• Unable to have orgasm 
• Pain with intercourse 
 
Patients with head and neck cancers will complete the following additional PRO-CTCAE 
inventories: 
• Dry mouth 
• Swallowing 
• Mouth sores 
• Cheilitis 
• Voice changes 
• Hoarseness