A Feasibility Study of Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) in One Fraction for Inoperable Primary or Metastatic Carcinoma (SMART ONE)
Phase: NA
Conditions: Metastatic Carcinoma
Sponsor: Baptist Health South Florida

Protocol Title: 
 
A Feasibility Study of Stereotactic MRI-guided Adaptive Radiation Therapy 
(SMART) in One Fraction for Inoperable Primary or Metastatic Carcinoma (SMART 
ONE) 
 
 
Protocol Version: 7.0 
Date: 30 AUG 2022 
Protocol Number: 2020-CHU-002  
 
 
Principal Investigator: 
 
Michael Chuong, M.D. 
Miami Cancer Institute (MCI), Baptist Health South Florida (BHSF) 
Department of Radiation Oncology 
8900 North Kendall Drive 
Miami, FL 33176 
Phone: (786) 596-2000 
Fax: (786) 814-4395 
Email: michaelchu@baptisthealth.net     
 
 
 
Coordinating Center: 
 
Miami Cancer Institute 
Office of Clinical Research 
8900 North Kendall Drive 
Miami, FL 33176 
Email: MCIMultiSiteResearch@baptisthealth.net 
 
 
Study Funding provided by: 
 
ViewRay 
 
 
 
 
 
 
 
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 2 of 43 
Confidential 
 
 
 
 
 
 
Co-Investigators: 
 
Rupesh Kotecha, M.D. 
Miami Cancer Institute (MCI), Baptist Health South Florida (BHSF) 
Department of Radiation Oncology 
Email: rupeshk@baptisthealth.net         
 
Adeel Kaiser, M.D. 
Miami Cancer Institute (MCI), Baptist Health South Florida (BHSF) 
Department of Radiation Oncology 
Email: adeelk@baptisthealth.net   
 
Kathryn Mittauer, Ph.D. 
Miami Cancer Institute (MCI), Baptist Health South Florida (BHSF) 
Department of Radiation Oncology 
Email: KathrynM@baptist.net 
 
Muni Rubens, Ph.D. 
Miami Cancer Institute (MCI), Baptist Health South Florida (BHSF) 
Office of Clinical Research 
Email: munir@baptisthealth.net    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 3 of 43 
Confidential 
 
 
 
 
Sponsor Investigator Signature Page 
 
 
 
 
Title (2020-CHU-002) A Feasibility Study of Stereotactic MRI-guided Adaptive Radiation 
Therapy (SMART) in One Fraction for Inoperable Primary or Metastatic Carcinoma 
(SMART ONE) 
 
 
 
This study protocol was subjected to critical review and has been approved by Miami 
Cancer Institute. The information it contains is consistent with the current/risk benefit 
evaluation of the study treatment as well as with the moral, ethical and scientific principles 
governing clinical research following the guidelines on Good Clinical Practice. 
 
 
 
 
 
 
 
_____________________________________________                     ______________ 
Michael Chuong, M.D.                                                                            Date 
Sponsor Investigator 
Miami Cancer Institute (MCI), Baptist Health South Florida (BHSF) 
Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 4 of 43 
Confidential 
 
 
 
Investigator’s Agreement 
 
 
 
 
I have read this study protocol, including appendices. By signing this protocol, I agree to 
conduct the clinical study, following approval by an Institutional Review Board (IRB), in 
accordance with the study protocol, the current International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP), Declaration of Helsinki 
(2013), and applicable regulatory requirements. I will ensure that all personnel involved 
in the study under my direction will be informed about the contents of this study protocol 
and will receive all necessary instructions for performing the study according to the study 
protocol. 
 
 
 
 
 
__________________________________________ 
Printed Name of Investigator 
 
 
 
__________________________________________ 
Signature of Investigator 
 
 
 
____________________ 
Date 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 5 of 43 
Confidential 
Protocol Summary 
 
 
Sponsor/Investigator: Michael Chuong M.D. Miami Cancer Institute 
Study Treatment: Single-fraction Stereotactic Ablative Body Radiation Therapy 
(SABR) 
Study Number: 2020-CHU-002 
Title: A Feasibility Study of Stereotactic MRI-guided Adaptive Radiation Therapy 
(SMART) in One Fraction for Inoperable Primary or Metastatic Carcinoma (SMART 
ONE) 
Study Center(s):  Multi-Site 
Investigators: Multi-site 
Study periods (years):  
Estimated last patient enrolled: Q3 2023  
Estimated date last patient last visit:  Q3 2024 
Hypothesis: 
Single-fraction SABR using daily MRI guidance with on-table adaptive replanning as 
needed is well-tolerated and able to be completed within a practical amount of time. 
Objectives 
Primary:  
To determine feasibility and tolerability of SABR delivered in one fraction. 
Feasibility will be achieved if all are true: 
•Successful completion of treatment to each lesion within 3 working days of 
intended treatment completion 
•Successful completion of treatment to each lesion within 90 minutes from the 
patient entering the treatment room until treatment completion 
•Image guidance verification of treatment delivery within 5 mm of the planned 
delivery 
Tolerability will be achieved if all are true: 
•No greater than 4 of 30 patients experience grade 3 or higher acute toxicity 
within 90 days of completing SABR 
•No grade 5 toxicity is attributed to SABR 
Secondary: 
•To assess 1-year local control  
•To assess 1-year overall survival  
•To assess acute and late toxicity  
•To assess patient-reported quality of life 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 6 of 43 
Confidential 
STUDY DESIGN 
This is a single arm, multi-site, feasibility study of single-fraction SMART for primary or 
metastatic carcinoma involving the lung, liver, adrenal gland, abdominal/pelvic lymph 
node, pancreas, and/or kidney. 
This study will consist of a Baseline period (Day-28 to Day-1), Enrollment, Treatment 
period (Day 1 up to Day 3), and After treatment visits occurring 6 weeks (optional), 3 
months, 6 months, 9 months, and 12 months after completion of Study Therapy. 
All patients deemed eligible will receive single-fraction SABR therapy using MRI as 
image-guidance. A total of 1-10 total lesions may be treated on the study and each 
lesion will be treated either sequentially or concurrently in one fraction.  
FACT-G Survey will be administered at baseline and every visit after completion of 
Study Therapy. 
Safety assessment performed will include collection of Adverse Events (AEs), vital 
signs, and physical exam, ECOG and laboratory assessments.  
CT scan of the Chest, Abdomen and Pelvis will be conducted at baseline, 6 weeks/ 
optional (± 1 week) after study therapy and every 3 months (± 1 week) until 12 months 
(± 1 week) after completion of SABR. 
All AEs will be collected upon initiation of treatment and for a minimum of 100 days 
after completion of study treatment or until resolution, whichever occurs later. Any 
pregnancy that occur at the time of study participation are to be reported. 
Number of Patients (planned): It is anticipated that approximately 30 patients will be 
enrolled and treated under this study protocol. 
Sites: Up to five (5) US sites 
Inclusion Criteria:  
Patient will be eligible for study entry if all of the following criteria are met: 
 
1. Subject must be ≥18 years of age at the time of study enrollment 
2. Subject must have Biopsy-confirmed primary or metastatic carcinoma with 
involvement of the lung, liver, adrenal gland, pancreas, kidney, and/or 
abdominal/pelvic lymph node that would receive SABR 
3. Any lesion that would receive SABR under this study protocol is no larger than 
5 cm in greatest dimension 
4. 1-10 total lesions that would receive SABR 
5. If multiple lesions are treated, they must be at least 3 cm apart  
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 
7. Life expectancy at least 6 months 
8. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control) prior to study entry 
and for the duration of study participation. Abstinence is acceptable if it’s the 
patient preferred method. Should a woman become pregnant or suspect she is 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 7 of 43 
Confidential 
pregnant while participating in this study, she must inform her treating physician 
immediately.  
9. Patients receiving hormonal therapy or immunotherapy such as immune 
checkpoint inhibitor that had begun at least 4 weeks prior to SABR will be 
allowed. 
Exclusion criteria: 
Patients will not be eligible for study entry if any of the following criteria are met: 
 
1. Subject has contraindication to having an MRI scan 
2. Subject has central or ultra-central lung tumor that would receive SABR on 
this study, defined as a lesion located within 2 cm of the trachea and proximal 
bronchial tree 
3. Subject has received cytotoxic chemotherapy or investigational agent within 
2 weeks of SBRT 
4. Subject has uncontrolled brain metastases, spinal cord compression, or 
leptomeningeal carcinomatosis 
5. Subject has any unresolved toxicity (Common Terminology Criteria for 
Adverse Events version 5.0 > grade 2) from previous anti-cancer therapy 
6. Any condition, therapy or lab abnormality in the opinion of the investigator that 
would interfere with patient safety, evaluation of study treatment or interpretation 
of study results   
7. Subject has received prior radiation therapy that directly overlaps any 
radiation therapy given in this study 
8. Subject has received radiation therapy that could lead to an unacceptably high 
risk of clinically significant normal tissue injury due to high cumulative normal 
tissue dose as determined by the investigator  
9. Female subject who are pregnant or breastfeeding 
10. Subject who has received vascular endothelial growth factor (VEGF) inhibitor 
such as bevacizumab within 4 weeks prior to study therapy or planned to receive 
it within 4 weeks after study therapy. 
Radiation Therapy 
1. Simulation: Both MRI and CT simulations scans must be performed in the 
treatment position.  MRI simulation scans should be performed on the MRIdian 
Linac. Use of dummy MRI coils is permitted.  
2. Supplemental Oxygen:  At the treating physician’s discretion, the patient may 
be simulated and treated with supplemental oxygen by nasal canula since this 
may improve the breath hold length and thus improve the treatment duty cycle 
efficiency.  The oxygen flow rate will be at the treating physician’s discretion 
although is suggested to be approximately 2-3 L/min.   

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 8 of 43 
Confidential 
3. Daily MR image guidance: The use of image guidance using MRI is mandatory.  
This will include a pre-treatment volumetric MRI using a TRUFI sequence that 
will be obtained prior to each delivered fraction. 
 
4. Target Volumes: 
• Gross Tumor Volume (GTV) will ,include visible tumor as seen on 
MRI/CT 
• Clinical Target Volume (CTV) is optional and will be used at the 
discretion of the treating physician 
• Planning Target Volume (PTV) will be created from a 3-5 mm uniform 
expansion from the GTV/CTV 
 
5. Prescription dose and fractionation 
Each lesion will be treated in one fraction. The prescription dose is dependent 
on the anatomic location of the lesion and based on previously published 
safety data. 
6. Treatment Planning Step-and-shoot intensity modulated radiation therapy 
(IMRT) using 6 MV FFF photons will be used. Ideally, ≥95% of the PTV and 
≥99% of the GTV/CTV should receive ≥100% of the prescribed dose. Hotspots 
of at least 120-130% of the prescription dose are permitted, and in fact are 
encouraged, if they are located within the GTV and not in organs at risk 
(OARs). For patients treated to multiple lesions, separate plans will be 
generated for each lesion if treated sequentially while one plan will be 
generated if all lesions are treated in the same session. The cumulative dose 
to OARs from all treatment plans should be assessed regardless of the number 
of lesions. 
 
7. Treatment delivery and on-table adaptive replanning  All patients will 
receive radiation therapy using photons on the MRIdian Linac system. For 
each delivered fraction, a volumetric MRI data set will be obtained using 
system integrated sequences. An estimated delivered dose will be calculated 
and saved using the software on the console (dose prediction). An adapted 
radiation therapy plan is created based on physician assessment of medical 
necessity. If required, adaptive replanning must be performed on the day of 
treatment delivery in order to achieve at least the same dose avoidance as the 
original plans. If multiple lesions are to be treated on this study, it is preferred 
that each one should be treated separately although it is permitted that multiple 
be treated concurrently.. During radiation dose delivery, continuous cine MR 
image acquisition in at least one principal plane is mandatory for soft tissue 
tracking and radiation beam gating.  
Treatment Response Evaluation 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 9 of 43 
Confidential 
Imaging Assessment Treatment response will be evaluated using the 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline, version 1.1. 
Statistical Methods  
 
Primary objective:  
The point estimate for feasibility will be reported as a binary variable with its 
95% confidence interval.  The point estimate for tolerability will be reported as 
a binary variable with its 95% confidence interval.  
  
Secondary objectives: 
1-year local control (LC) will be assessed according to RECIST 1.1 criteria and 
will be estimated using the Kaplan-Meier method along with the corresponding 
95% confidence interval from the time of study treatment. 
 
1-year overall survival (OS) will be estimated using the Kaplan-Meier method 
along with the corresponding 95% confidence interval from the time of study 
treatment. 
 
The proportion of patients who experience acute grade 3 or higher toxicity 
attributable to SABR will be determined along with the corresponding 95% 
confidence interval.  For patients receiving SABR to multiple lesions, acute 
toxicity will be determined from the date of the initiation of SABR.   
 
Patient-reported quality of life will be determined using the FACT-G survey 
instrument prior to and after SABR.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 10 of 43 
Confidential 
 
Table of Contents 
1. 
BACKGROUND ..................................................................................................... 13 
1.1 
Stereotactic ablative body radiation therapy (SABR) ....................................... 13 
1.2 
Single-fraction SABR ....................................................................................... 13 
1.3 
MR-guided radiation therapy ............................................................................ 14 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ........................................................... 15 
2.1 
Hypothesis ....................................................................................................... 15 
2.2 
Primary objective: ............................................................................................. 15 
2.3 
Secondary objectives ....................................................................................... 15 
3. 
STUDY DESIGN .................................................................................................... 16 
4. 
SITE AND INVESTIGATOR SELECTION .............................................................. 16 
5. 
PATIENT SELECTION ........................................................................................... 16 
5.1 
Inclusion criteria ............................................................................................... 16 
5.2 
Exclusion criteria .............................................................................................. 17 
5.3. Patient recruitment .............................................................................................. 17 
6. 
RADIATION THERAPY .......................................................................................... 18 
6.1 
Simulation ........................................................................................................ 18 
6.2 
Motion management ........................................................................................ 19 
6.3 
Daily MR image-guidance ................................................................................ 19 
6.4 
Target Volumes ................................................................................................ 19 
6.4.1. Gross Tumor Volume (GTV) ........................................................................ 19 
6.4.2 Clinical Target Volume (CTV) ........................................................................ 19 
6.4.3 Planning Target Volume (PTV) ..................................................................... 19 
6.5 
Prescription dose and fractionation .................................................................. 20 
6.6 
Organs at risk and constraints .......................................................................... 20 
6.7 
Treatment planning .......................................................................................... 22 
6.8 
Treatment delivery and on-table adaptive replanning ...................................... 23 
6.9 
Treatment plan storage .................................................................................... 25 
6.10 Additional radiation therapy .............................................................................. 25 
6.11 Systemic therapy .............................................................................................. 25 
6.12 Additional local therapy .................................................................................... 26 
7. 
STUDY PROCEDURES ......................................................................................... 26 
7.1 
Informed Consent ............................................................................................. 26 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 11 of 43 
Confidential 
7.2 
Screening and Enrollment Procedures ............................................................. 26 
8. 
PATIENT ASSESSMENTS .................................................................................... 27 
8.1 
Baseline assessments ..................................................................................... 27 
8.2 
During treatment .............................................................................................. 28 
8.3 
After treatment completion ............................................................................... 28 
8.4 
Study calendar ................................................... Error! Bookmark not defined. 
9. 
TREATMENT RESPONSE EVALUATION ............................................................. 30 
9.1 
Imaging assessment ........................................................................................ 30 
9.2 
Definitions for disease assessment .................................................................. 30 
9.3 
Definitions of Disease Response ..................................................................... 31 
9.4 
Evaluation of best overall response ................................................................. 31 
10. QUALITY OF LIFE ASSESSMENT ........................................................................ 32 
11. SAFETY ASSESSMENT ........................................................................................ 32 
11.1 Adverse event definition, assessment and reporting ........................................ 32 
11.2 Serious Adverse Event definition and reporting ............................................... 33 
11.3 Management of adverse events ....................................................................... 35 
11.4 Data Safety Monitoring Committee .................................................................. 35 
11.5 Early study closure ........................................................................................... 35 
11.6 Pregnancy ........................................................................................................ 35 
11.7 Overdose or misadministration of radiation ...................................................... 36 
12. PATIENT DISCONTINUATION AND REPLACEMENT ......................................... 36 
12.1 Patient discontinuation ..................................................................................... 36 
12.2 Patient replacement ......................................................................................... 36 
13. STATISTICAL METHODS ..................................................................................... 37 
13.1 Evaluation of study objectives .......................................................................... 37 
13.2 Primary objective: ............................................................................................. 37 
13.3 Secondary objectives ....................................................................................... 37 
13.4 Sample size determination ............................................................................... 38 
13.5 Accrual and study duration ............................................................................... 38 
14. ETHICAL AND REGULATORY REQUIREMENTS ................................................ 39 
14.1 Ethical conduct of the study ............................................................................. 39 
14.2 Informed consent ............................................................................................. 39 
15. DATA MANAGEMENT ........................................................................................... 39 
15.1 Monitoring, Auditing, and Quality Assurance.................................................... 40 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 12 of 43 
Confidential 
16. REFERENCES....................................................................................................... 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 13 of 43 
Confidential 
1. 
BACKGROUND  
 
1.1 
Stereotactic ablative body radiation therapy (SABR) 
Radiation therapy (RT) has historically been delivered using a fractionated approach, 
typically once daily over multiple weeks, based on classic radiobiological principles to 
optimize tumor cell kill and allow for normal tissue repair(1).  This approach has served 
as the foundation for the field of radiation oncology and can achieve effective palliation 
or cure when typically used in a multi-disciplinary manner with systemic therapy and/or 
surgery.   
 
Technological advances over the most recent decades have achieved increasingly 
conformal delivery of radiation dose such that there is better sparing of normal tissues, 
which in some cases may allow for an increase in dose delivered to the target(2-4).  
These advances include improvements in complex modulation of delivered dose, 
motion management for mobile tumors, and on-board imaging guidance capabilities(5, 
6).  A benefit of these improvements is the ability to deliver hypofractionated radiation 
therapy, or doses larger than approximately 2 Gy per fraction, in a fewer number of 
fractions.  Extreme hypofractionation can be delivered using stereotactic body radiation 
therapy (SBRT) in 5 or fewer fractions(7).  A unique radiological effect of delivering 
larger dose per fraction, such as >8 Gy, has been proposed(8). 
 
Important to note is that the term stereotactic body radiotherapy (SBRT) is not 
synonymous with ablative radiation dose as non-ablative dose can be delivered with this 
technique; ablative dose is generally agreed to be a biologically effective dose (BED10) 
of at least 100 Gy.  For example, SBRT for pancreas cancer is typically delivered with a 
non-ablative dose (i.e., 30-35 Gy in 3-5 fractions) due to the proximity of organs at risk 
including the small intestine, whereas SBRT for peripheral non-small cell lung cancer is 
commonly delivered a with ablative dose (i.e. 60 Gy in 5 fractions; BED10 = 132 Gy).  
Outcomes of ablative SBRT are generally superior to those of non-ablative SBRT as 
there are well-described dose response relationships that have been established for 
many cancers.  The term stereotactic ablative body radiation therapy (SABR) was 
developed to more clearly communicate that an ablative dose is prescribed(9).   
 
1.2 
Single-fraction SABR 
While SABR is delivered in as few as 1 but up to 5 daily fractions by definition, the vast 
majority of published outcomes data have used 3-5 fractions.  Nonetheless, there are 
published prospective and retrospective studies for single-fraction SABR as 
summarized in a recently published critical review by Ng and colleagues(10).  The most 
substantial supporting data for single-fraction SABR exists for early-stage peripheral 
non-small lung cancer (NSCLC) for which several randomized trials have been 
completed showing no significant difference in outcomes between singe- and multi-

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 14 of 43 
Confidential 
fraction regimens(11,12).  Despite these randomized data, the utilization of single-
fraction SABR for early-stage NSCLC has been scarce.  Safety and feasibility of single-
fraction SABR has been demonstrated for other anatomic sites including the liver (13), 
lymph nodes (14), adrenal gland(15), and the kidney(16).  Single-fraction SABR for 
locally advanced pancreas cancer has been prospectively evaluated (notably without 
intrafraction image guidance or daily adaptive replanning), and has been associated 
with increased gastrointestinal toxicity compared to fractionated SABR(17).   
 
A single-fraction regimen should be at least isotoxic and isoeffective as compared to 
multi-fraction SABR for such an approach to be considered a reasonable alternative.  
Assuming that both are true, then there are several advantages of completing treatment 
in one fraction including reduced cost(18), potentially reduced lymphopenia(19), and 
increased patient convenience.  One reason that clinicians may be hesitant to use 
single-fraction SBRT is concern about geographic miss, which stems from the lack of 
intrafraction evaluation of the tumor and internal anatomy using a linear accelerator 
using x-ray and/or CT-guidance(20).  Furthermore, generous margins may be placed on 
the gross tumor to decrease the risk of a geographic miss, thereby increasing normal 
organ dose and potentially increasing the risk of more severe toxicity(21).   
 
1.3 
MR-guided radiation therapy  
The recent develop of linear accelerators that use magnetic resonance (MR) instead of 
CT imaging for image guidance represents a tremendous advance in how radiation 
therapy is fundamentally delivered(22).  MR guidance offers several important 
advantages including: 1) superior soft tissue imaging, 2) continuous intrafraction 
visualization, 3) tissue tracking and automatic beam triggering, and 4) the ability to 
perform on-table (or online) adaptive replanning(23).  These technical capabilities have 
begun a transformation within the field of radiation oncology by facilitating better normal 
organ sparing, especially those in immediate proximity to the target, by permitting 
smaller margin expansions, treatment in breath hold, and daily on-table adaptive 
planning to account for intrafraction changes in internal and/or tumor anatomy(6).  In 
fact, this technology is particularly well-suited for the delivery of SABR, especially in one 
fraction.   
 
There is a growing body of literature describing favorable outcomes of MR-guided 
SABR for various cancers in diverse regions of the body, including the lung(24), 
breast(25), liver(26), pancreas(27), adrenal gland(28), kidney(29), lymph nodes(30), 
and prostate(31).   
 
The collective published experience of MR-guided SABR has nearly exclusively used 
multi-fraction SABR although a recent report of single-fraction MR-guided SABR for 
lung tumors to 34 Gy was recently reported from The Netherlands suggesting feasibility 
and tolerance(32).  However, treatment times were rather long although this can be 
explained by the decision of the investigators to perform on-table adaptive replanning 
prior to the start of treatment and then again half-way through; the clinical significance 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 15 of 43 
Confidential 
of this is unclear and the total treatment time would be significantly reduced if treatment 
was not interrupted to adapt the plan a second time.  Given the encouraging outcomes 
of single-fraction SABR delivered with CT-guidance, this study was designed to explore 
the feasibility and tolerability of single-fraction SABR using an MR-LINAC for various 
extracranial and extra-osseous tumors using on-table adaptive replanning, as needed. 
(33) 
 
2. 
HYPOTHESIS AND STUDY OBJECTIVES  
 
2.1 
Hypothesis 
Single-fraction SABR using daily MRI guidance with on-table adaptive replanning as 
needed is well-tolerated and able to be completed within a practical amount of time. 
 
2.2 
Primary objective 
• To determine feasibility and tolerability of SABR delivered in one fraction 
 
Feasibility will be achieved if all are true: 
 
• Successful completion of treatment to each lesion within 3 working days of 
intended treatment completion 
• Successful completion of treatment to each lesion within 90 minutes from the 
patient entering the treatment room until treatment completion 
• Image guidance verification of treatment delivery within 5 mm of the planned 
delivery 
• Tolerability will be achieved if all are true: 
• No greater than 4 of 30 patients experience grade 3 or higher acute toxicity 
within 90 days of completing SABR 
• No grade 5 toxicity is attributed to SABR 
 
2.3 
Secondary objectives 
• To assess 1-year local control  
• To assess 1-year overall survival  
• To assess acute and late toxicity  
• To assess patient-reported quality of life  
 
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 16 of 43 
Confidential 
3. 
STUDY DESIGN 
 
This is a multi-site single arm feasibility study of single-fraction SMART for primary or 
metastatic carcinoma involving the lung, liver, adrenal gland, abdominal/pelvic lymph 
node, pancreas, and/or kidney. This study will consist of a Screening period (within 28 
days from study therapy), Treatment period (Day 1 up to Day 3), and After treatment 
visits occurring at 6 weeks (optional), and every 3 months until 12 months after 
completion of study therapy.  
 
All patients deemed eligible will receive single-fraction SABR therapy using MRI as 
image-guidance. A total of 1-10 total lesions may be treated on the study and each 
lesion will be treated sequentially in one fraction. 
 
It is anticipated that approximately 30 patients will be enrolled and treated under this 
protocol at up to 5 sites in the US. 
 
4. 
SITE AND INVESTIGATOR SELECTION 
 
Investigators and sites will be selected and qualified by MCI for participation in this 
clinical investigation. Sites must have the facilities, specific technology, patient 
population and the ability to conduct research to fulfill the study requirements as 
determined by the sponsor investigator. The site must have written IRB approval for the 
study protocol and the informed consent form prior to enrolling any subjects. 
 
5. 
PATIENT SELECTION 
 
5.1 
Inclusion criteria 
1. ≥18 years of age at the time of study enrollment 
2. Biopsy-confirmed primary or metastatic carcinoma with involvement of the lung, 
liver, adrenal gland, pancreas, kidney, and/or abdominal/pelvic lymph node that 
would receive SABR 
3. Any lesion that would receive SABR is no larger than 5 cm in greatest dimension 
4. 1-10 total lesions that would receive SABR 
5. If multiple lesions are treated, they must be at least 3 cm apart   
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 
7. Life expectancy at least 6 months 
8. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control) prior to study entry 
and for the duration of study participation. Abstinence is acceptable if preferred 
by patient. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she must in form her treating physician immediately.  

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 17 of 43 
Confidential 
9. Patients receiving hormonal therapy or immunotherapy such as immune 
checkpoint inhibitor that had begun at least 4 weeks prior to SABR will be 
allowed. 
 
5.2 
Exclusion criteria 
1. Contraindication to having an MRI scan 
2. Central or ultra-central lung tumor that would receive SABR on this study, 
defined as a lesion located within 2 cm of the trachea and proximal bronchial tree 
3. Cytotoxic chemotherapy or investigational agent within 2 weeks of SBRT 
4. Presence of uncontrolled brain metastases, spinal cord compression, or 
leptomeningeal carcinomatosis 
5. Any unresolved toxicity (Common Terminology Criteria for Adverse Events 
version 5.0 > grade 2) from previous anti-cancer therapy 
6. Any condition, therapy or lab abnormality in the opinion of the investigator that 
would interfere with patient safety, evaluation of study treatment or interpretation 
of study results   
7. Prior radiation therapy that directly overlaps any radiation therapy given in this 
study 
8. Prior radiation therapy that could lead to an unacceptably high risk of clinically 
significant normal tissue injury due to high cumulative normal tissue dose as 
determined by the investigator  
9. Female patients who are pregnant or breastfeeding. 
10. Patients who have received vascular endothelial growth factor (VEGF) inhibitor 
such as bevacizumab within 4 weeks prior to study therapy or planned to receive 
it within 4 weeks after study therapy. 
 
5.3.  
Patient recruitment  
The patient’s treatment team, the study investigator, or treating institution’s research 
team will identify potential study participants.  The site principal investigator may screen 
records of patients for the limited purpose of identifying patients who would be eligible 
for study enrollment and limited contact information may be recorded to contact the 
patient regarding study enrollment.  However, it is expected that the patient’s treatment 
team or investigator working in consultation with the treatment team will conduct the 
initial discussion of possible study enrollment with the patient.  This recruitment process 
presents no greater than minimal risk to the privacy of screened patients.   A (partial) 
limited waiver of authorization is requested for reviewing medical records to identify 
potential research participants, conversing with patients about possible enrollment, and 
handing of personal health information. 
 
Both men and women in addition to individuals of all races and ethnic groups are 
eligible for this trial. 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 18 of 43 
Confidential 
6. 
RADIATION THERAPY 
 
6.1 
Simulation 
Fiducial markers are not needed for MRI-guided RT and therefore the placement of 
fiducial markers is not required prior to simulation. 
 
Patients may be positioned in the supine position for simulation and treatment, although 
prone positioning may be considered using a belly board to displace the small bowel 
away from target lesion(s) in the abdomen and pelvis.  There is not a requirement to 
use an immobilization device otherwise given the use of continuous infraction 
visualization with MRI. 
 
At the treating physician’s discretion, the patient may be simulated and treated with 
supplemental oxygen by nasal canula since this may improve the breath hold length 
and thus improve the treatment duty cycle efficiency.  The oxygen flow rate will be at the 
treating physician’s discretion although is suggested to be approximately 2-3 L/min.   
 
Both MRI and CT simulations scans must be performed in the treatment position.  It is 
preferred that MRI simulation be done prior to CT simulation with the CT scan 
deformably registered to the treatment planning MRI. MRI simulation scans should be 
performed on the MRIdian Linac.  Use of dummy MRI coils is permitted.  IV or oral 
contrast are not required for MRI simulation although Eovist may be used to better 
visualize hepatic lesions.  While contrast may be used for CT simulation, it is not 
required as the MRI simulation scan is expected to be the primary scan used for 
contouring and treatment planning.  Planning CT scan slice thickness should be 3 mm 
or less.   
 
A 4D-CT simulation scan should be acquired at least for lesions in the chest and upper 
abdomen to assess the extent of tumor motion. 
 
For patients with targets in the upper abdomen (e.g., pancreas, adrenal gland) it is 
recommended that patients have nothing by mouth (NPO) at least 2 hours prior to 
simulation or treatment.  For patients with targets in the pelvis, reproducible bladder and 
rectal filling should be attempted, as per the discretion of the treating physician. 
 
Arm position will be dependent on the location of the target lesion(s).  To improve 
patient comfort and reproducibility it is preferred that both arms be positioned down at 
the sides, as close to the body as possible, if appropriate, based on the location of the 
target lesion(s) the discretion of the treating physician.  Positioning both arms down may 
significantly limit beam angles for treating some lesions, especially those that are very 
lateral, and therefore positioning the ipsilateral arm above the head while keeping the 
contralateral arm down to the side should be considered.  Both arms may be positioned 
above the head, as needed.    
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 19 of 43 
Confidential 
For patients receiving SABR to multiple lesions in different anatomic locations, several 
MRI and CT simulation scans may be required especially if the arm positioning will be 
different for treatment of various lesions.  For example, while both arms may be placed 
down at the sides for treating a para-aortic lymph node, at least one arm may need to 
be raised above the head for treating a lateral lung lesion.   
 
6.2 
Motion management 
Motion management must be employed for moving targets. Breath hold treatment, 
which is strongly preferred, may be either in inspiration or expiration at the discretion of 
the treating physician, based on patient tolerance, reproducibility, and proximity of the 
target to OARs.  Patients who will be treated in breath hold should be able to 
reproducibly hold their breath such that a high quality 17-25 second volumetric MRI 
scan can be obtained with minimal motion artifact.   
 
Patients may be treated using free breathing gating and it is strongly recommended that 
an MRI-compatible abdominal compression device be used to limit diaphragmatic 
excursion and tumor motion.  
 
6.3 
Daily MR image-guidance 
The use of image-guidance using MRI is mandatory.  This will include a pre-treatment 
volumetric MRI using a TRUFI sequence that will be obtained prior to each delivered 
fraction.  Alignment should be to soft tissue including the target lesion. 
 
6.4 
Target Volumes 
6.4.1. Gross Tumor Volume (GTV) 
 
This will include visible tumor as seen on MRI/CT.   
 
6.4.2 Clinical Target Volume (CTV) 
 
The use of a CTV is optional and at the discretion of the treating physician.   
 
It is suggested that the CTV should be an expansion of 2-5 mm from the GTV, edited 
out of anatomic barriers to microscopic tumor spread.   
 
6.4.3 Planning Target Volume (PTV) 
 
It is preferred that a 3 mm uniform expansion from the GTV/CTV define the PTV.  
However, a 5 mm uniform expansion will also be permitted.   

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 20 of 43 
Confidential 
 
6.5 
Prescription dose and fractionation 
Each lesion will be treated in one fraction.   
 
The prescription dose is dependent on the anatomic location of the lesion and based on 
previously published safety data.   
 
• Lung (30-34 Gy. BED10 = 120-149.6 Gy) 
• Liver (35-40 Gy; BED10 = 157.5-200 Gy) 
• Pancreas (25 Gy; BED10 = 93.6 Gy) 
• Kidney (25 Gy; BED10 = 93.6 Gy) 
• Adrenal gland (25 Gy; BED10 = 93.6 Gy) 
• Abdominal/pelvic lymph node (25 Gy; BED10 = 93.6 Gy) 
 
If a CTV is used, then it will be prescribed the same dose as the GTV. 
 
6.6 
Organs at risk and constraints 
THORACIC  
Structure 
Contouring 
Constraint 
Spinal cord 
Spinal canal extending ≥2 cm 
cranial and caudal to the PTV 
≤0.03 cc 
≤0.35 cc 
≤1.2 cc 
14 Gy 
10 Gy 
7 Gy 
Skin 
Outer 5 mm of the body surface 
extending ≥2 cm cranial and 
caudal to the PTV 
≤0.03 cc 
≤10 cc 
26 Gy 
23 Gy 
Lungs (right and left) 
Combined right and left lungs 
minus GTV 
≤1500 cc 
≤1000 cc 
7 Gy 
7.4 Gy 
Proximal trachea 
Trachea extending ≥2 cm cranial to 
the PTV or ≥5 cm cranial to the 
carina (whichever is most cranial) 
extending caudally to the cranial 
aspect of the proximal bronchial 
tree 
≤0.03 cc 
4 cc 
20.2 Gy 
10.5 Gy 
Proximal bronchial tree 
Distal 2 cm of the trachea, carina, 
right/left main stem bronchi, 
right/left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, lingular bronchus, 
right/left lower lobe bronchi; lobar 
bronchi contour will not extend into 
the segmental bifurcation 
≤0.03 cc 
4 cc 
20.2 Gy 
10.5 Gy 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 21 of 43 
Confidential 
Heart 
Superiorly at the level of the 
bifurcation of the pulmonary artery 
inferiorly to the apex of the heart, 
including the pericardium 
≤15 cc 
≤0.03 cc 
16 Gy 
22 Gy 
Great vessels 
Aorta and vena cava (not the 
pulmonary artery/vein) extending 
³2 cm cranial and caudal to the 
PTV 
£10 cc 
≤0.03 cc 
31 Gy 
37 Gy 
Chest wall 
2 cm radial expansion of the 
ipsilateral lung excluding 
mediastinal soft tissue, anterior 
vertebral body, and any extension 
outside of the external body 
contour; extended 2 cm cranial and 
caudal of the PTV 
≤0.03 cc 
≤5 cc 
≤1 cc 
30 Gy 
27 Gy 
22 Gy 
Ribs 
Bone and marrow of the ribs as 
seen on bone windows within 5 cm 
of the PTV to not include the 
intercostal spaces 
≤0.03 cc 
≤1 cc 
30 Gy 
22 Gy 
Brachial plexus 
Subclavian and axillary vessels 
starting proximally at the 
bifurcation of the brachiocephalic 
trunk into the jugular/subclavian 
veins (or carotid/subclavian 
arteries) and following along the 
route of the subclavian vein to the 
axillary vein ending after the 
neurovascular structures cross the 
second rib 
≤0.03 cc 
≤3 cc 
17.5 Gy 
14 Gy 
Esophagus 
All muscular layers extending ≥2 
cm cranial and caudal to the PTV 
≤0.03 cc 
≤10 cc 
12.4 Gy 
11.2 Gy 
Stomach 
From the gastroesophageal 
junction to the pylorus 
≤0.03 cc 
≤10 cc 
12.4 Gy 
11.2 Gy 
 
 
ABDOMEN/PELVIS  
Structure 
Contour 
Volume 
Dose 
Liver - GTV 
Entire liver minus GTV 
≤700 cc 
9.1 Gy 
Spinal cord 
Spinal canal extended ≥2 cm 
cranial and caudal to the PTV 
≤0.03 cc 
≤0.35 cc 
≤1.2 cc 
14 Gy 
10 Gy 
7 Gy 
Skin 
Outer 5 mm of the body surface 
extending ≥2 cm cranial and caudal 
to the PTV 
≤0.03 cc 
≤10 cc 
26 Gy 
23 Gy 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 22 of 43 
Confidential 
Chest wall 
2 cm radial expansion of the 
ipsilateral lung excluding 
mediastinal soft tissue, anterior 
vertebral body, and any extension 
outside of the external body 
contour; extended 2 cm cranial and 
caudal of the PTV. 
≤0.03 cc 
≤5 cc 
≤1 cc 
30 Gy 
27 Gy 
22 Gy 
Esophagus 
All muscular layers extending ≥2 
cm cranial and caudal to the PTV 
≤0.03 cc 
≤10 cc 
12.4 Gy 
11.2 Gy 
Stomach 
From the gastroesophageal 
junction to the pylorus 
≤0.03 cc 
≤5 cc 
≤10 cc 
12.4 Gy 
11.2 Gy 
9 Gy 
Duodenum 
From the pylorus to 4th part of 
duodenum 
≤0.03 cc 
≤5 cc 
≤10 cc 
12.4 Gy 
11.2 Gy 
9 Gy 
Small bowel 
Small bowel loops from the jejunum 
to 2 cm caudal to PTV 
≤0.03 cc 
≤5 cc 
≤10 cc 
12.4 Gy 
11.2 Gy 
9 Gy 
Large bowel 
Large bowel loops ≥2 cm cranial 
and caudal to the PTV 
≤0.03 cc 
≤5 cc 
≤10 cc 
18.4 Gy 
11.2 Gy 
9 Gy 
Kidney (right and left) 
Entire right and left kidneys 
Mean 
V10 
7 Gy 
33% 
Rectum 
From the rectosigmoid junction to 
anal canal 
≤0.03 cc 
≤5 cc 
≤10 cc 
18.4 Gy 
11.2 Gy 
9 Gy 
Bladder 
Entire bladder 
≤15 cc 
11.4 Gy 
 
6.7 
Treatment planning 
Step-and-shoot intensity modulated radiation therapy (IMRT) using 6 MV FFF photons 
will be used.  Ideally, ≥95% of the PTV and ≥99% of the GTV/CTV should receive 
≥100% of the prescribed dose.  However, depending on the proximity of the normal 
organs, especially gastrointestinal (GI) luminal structures, that may not be achievable 
without violating normal organ constraints. If the proximity of OARs results in a clinically 
significant reduction in dose to the GTV on the original plan, defined as ≤80% receiving 
≥100% of the prescribed dose and/or ≤90% receiving ≥90% of the prescribed dose, 
then multi-fraction SBRT off study should be considered although will not be required.  If 
patients remain on study in this scenario, then attempts should be made to optimize the 
internal anatomy on the day of treatment to improve target dose coverage as much as 
reasonably possible, for example ensuring appropriate bladder, rectal, or stomach 
filling.     
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 23 of 43 
Confidential 
Hotspots of at least 120-130% of the prescription dose are permitted, and in fact are 
encouraged, if they are located within the GTV and not in organs at risk (OARs).   
 
Meeting all OAR constraints should be prioritized, even at the expense of target volume 
coverage, while secondarily optimizing target volume coverage.   
For patients treated to multiple lesions, separate plans will be generated for each lesion.  
A planning CT dataset that includes all targets and relevant critical structures in the 
imaging study should be obtained when possible.  The cumulative dose to OARs from 
all treatment plans should be assessed.  If multiple lesions are treated, then OAR dose 
constraints as described in section 6.6 should be considered to be cumulative 
constraints that should be met in total across all treatment plans regardless of the 
number of lesions treated.   
 
For targets in the abdomen and pelvis, a PRVGI should be created that is defined as 
the union of the stomach + duodenum + small bowel + large bowel contours with a 5 
mm uniform expansion.  If there is any overlap of the PRVGI with the PTV then a 
PTVopt should be created, which is the PTV minus any overlap of the PRVGI.  The 
treatment plan should be prescribed to the PTVopt instead of the PTV, ensuring that all 
OAR constraints are met.  The dose to the overlapped region of the PTV and PRVGI 
should be as high as possible while meeting all OAR constraints, although no minimum 
coverage will be required.  If there is not overlap of the PRVGI with the PTV then the 
treatment plan should be prescribed to the PTV.   
 
6.8 
Treatment delivery and on-table adaptive replanning 
All patients will receive radiation therapy using photons on the MRIdian Linac system for 
alignment, dose prediction, tracking, gating, and on-table adaptive planning when 
clinically indicated.  
 
For each delivered fraction, a volumetric MRI data set will be obtained using system 
integrated sequences; the preferred sequence is a balanced gradient echo most similar 
to Siemens True FISP scan with T2*/T1 weighted image-characteristics with at least a 
1.5 x 1.5 x 3.0 mm image matrix resolution. The external contour of the patient should 
be inside the field of view where there are beam angles that will be used for treatment. 
 
The target volume will be rigidly aligned to a reference position by virtual couch 
movement in cranio-caudal, left-right and anterior-posterior direction to optimally align 
with the planned treatment isocenter.  Depending on operator assessment, these shifts 
are then executed, and treatment is initiated. 
 
If optimal target to isocenter alignment cannot be achieved, system integrated 
deformable image registration between the primary treatment image data (used for 
simulation and treatment planning) and the respective fraction MRI dataset will be 
performed. Original plan contours are propagated onto the respective fraction MRI 
dataset. If on-table adaptive planning is clinically indicated, then all tumor volumes and 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 24 of 43 
Confidential 
critical structures within 3 cm radially and 2 cm cranial-caudal from the surface of the 
PTV will be re-contoured as needed on the volumetric high-quality MRI data set. 
 
An estimated delivered dose will be calculated and saved using the software on the 
console (dose prediction). An adapted radiation therapy plan is created based on 
physician assessment of medical necessity. General guidelines to establish medical 
necessity include but are not limited to the following:  
 
• Any OAR constraint is violated.  The same constraints used to develop the 
original plan will be used to on the day of treatment to determine the need to 
create an adapted plan.  
• Reduction in GTV and/or PTV covered by the prescription isodose compared to 
the original plan. 
• Favorable shift in the relation between GTV and dose-limiting OARs, such that 
adaptive planning would likely improve the coverage of the GTV. 
 
For patients treated to multiple lesions, adaptive replanning may be required in order to 
ensure that cumulative dose to OARs meets constraints.  As the original treatment 
plans are required to cumulatively meet all OAR constraints, adaptive replanning must 
be performed on the day of treatment delivery in order to achieve at least the same 
dose avoidance as the original plans.  
 
Adaptive dose re-planning does not need to be performed if the dose prediction shows 
compliance with minimum dose coverage of the GTV and adherence to upper 
dose/volume limits of all OARs. 
 
If multiple lesions are to be treated on this study, it is recommended that each one 
should be treated separately as treatment of multiple lesions may significantly prolong 
total treatment time, which may be poorly tolerated by the patient. However, treatment 
of multiple lesions on this trial during the same session is permitted if the treating 
physician believes that treatment would be completed within a feasible amount of time.   
 
During radiation dose delivery, continuous cine MR image acquisition in at least one 
principal plane (suggested sagittal, but at the discretion of the treating physician) is 
mandatory for soft tissue tracking and radiation beam gating. To this end, a tracking 
slice of 7-10 mm thickness will be positioned to include a cross-sectional cut of the 
target for intra-fractional soft tissue tracking. The tracking/gating volume will be 
preferably delineated based on the GTV, or otherwise on a well visualized surrogate in 
proximity to the GTV.  
 
The software should be set so that if 5% or more of the tracked target extends outside 
of the boundary the beam will gate off.  For soft tissue tracking and gating, a minimum 
cine frame rate of 4 frames/second is mandatory throughout dose delivery although 
higher frame rates (e.g., 8 frames/second) may be used if available. 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 25 of 43 
Confidential 
During study treatment, a time log will be used to record  the following events, at a 
minimum: 
 
• Patient enters the treatment room 
• Volumetric scan initiated  
• Target volume/OAR contouring started 
• Target volume/OAR contouring ended 
• Predicted dose calculation completed 
• Treatment plan re-optimization finalized (if performed) 
• Treatment delivery started 
• Treatment delivery completed 
 
6.9 
Treatment plan storage 
All clinically approved plans, structures delineated for dose prediction, predicted doses, 
as well as all adapted radiation therapy plans will be saved and stored in the MRIdian 
associated software. All initial plans, structures delineated initially and on-table, 
predicted dose, and adapted plan data are to be backed up for permanent storage and 
potential later analysis.  
 
6.10 
Additional radiation therapy 
It is permissible for radiation therapy to be delivered to lesions other than those that are 
treated on this study.  This could be to other lesions that are present at the time that 
SABR is delivered as part of this study, or new lesions that may appear after the 
completion of SABR on this study.  However, additional radiation therapy should be 
avoided that would directly overlap or be in proximity to a lesion that previously received 
radiation therapy on this study that could significantly increase the risk of potentially 
severe toxicity.  It is strongly recommended that additional radiation therapy not be 
delivered off study to lesions within the same organ or otherwise within 3 cm of a lesion 
treated on this study so that any toxicity related to study therapy can be accurately 
assessed.  Otherwise, if it is medically necessary to deliver additional radiation therapy 
off study, especially if there are no reasonable treatment alternatives, and if the treating 
physician believes that the risk of severe toxicity is reasonably low and justified by the 
potential benefit of radiation therapy then it would be permissible to deliver additional 
radiation therapy regardless of location.   
 
6.11 
Systemic therapy 
There will not be any cytotoxic chemotherapy, targeted systemic agents, and/or 
investigational agent administered within 2 weeks prior to or following delivery of 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 26 of 43 
Confidential 
radiation therapy on this study, provided that the patient does not have any ongoing 
grade 2 or higher toxicity from any prior treatment.   
 
If a lesion is to be treated in the abdomen or pelvis, it is required that vascular 
endothelial growth factor (VEGF) inhibitors such as bevacizumab not be given at least 4 
weeks prior to or after study therapy because of a potentially increased risk of GI 
toxicity.   
 
Hormonal therapy or immunotherapy such as immune checkpoint inhibitors that had 
begun at least 4 weeks prior to SABR will be allowed, provided there are no grade 2 or 
higher toxicities ongoing as a result of such therapies.   
 
6.12 
Additional local therapy 
Surgery, percutaneous ablation, or other local therapy should not be planned to any 
lesion treated on this study at the time of patient enrolment.  However, in the event of 
local tumor progression then such therapies may be considered.   
 
7. 
STUDY PROCEDURES  
 
 
7.1 
Informed Consent 
Investigators or their authorized designees will be responsible for obtaining a signed 
informed consent form and authorization to use and disclose protected health 
information prior to conduct any study-specific procedures. 
  
7.2 
 Screening and Enrollment Procedures 
Subject eligibility for the study will be determined after the screening process. The site 
investigator or qualified designee will review all inclusion and exclusion criteria to 
ensure that the subject qualifies for the trial. 
 
The screening package will be uploaded in the Oncore Subject Console or sent by 
email to theMCI Multi-site Program. The following documents should be included: 
 
• Signed Informed Consent Form  
• Signed HIPAA form 
• Eligibility Form signed by the Investigator 
• Copy of redacted screening laboratory tests results 
• Copy of redacted pathology report confirming diagnosis 
• Copy of redacted imaging report. 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 27 of 43 
Confidential 
• RECIST 1.1 evaluation  
• Additional relevant documents or communications confirming subject eligibility. 
 
 
The MCI multi-site program designee will review the submitted documents in order to 
verify documentation of patient eligibility.  
 
Upon confirmation of eligibility, the Coordinating Center will provide authorization to the 
site study team to register the subject in OnCore.  
 
Subjects will be considered enrolled after they have given informed consent and passed 
eligibility criteria. The date of enrollment will be the date all eligibility criteria has been 
confirmed by the MCI Multi-site Program. 
 
8. 
PATIENT ASSESSMENTS 
 
All evaluations should be completed as detailed below and per the study calendar in 
Section 8.4 of this protocol. 
 
8.1 
Screening assessments 
All screeningprocedures must be done after the subject signs the informed consent. 
Assessments completed as part of the standard of care before patient signs the 
Informed Consent Form can be used for screening purposes as long as the 
test/procedure meets the protocol-required timelines. Note that source documents must  
identify the standard of care tests/procedures used for screening and must be reviewed 
by the investigator for clinical significance. Obtaining Informed Consent, FACT-G, 
RECIST 1.1 evaluation and confirming subject eligibility must be performed by a 
delegated study team member. 
 
Screening assessments include: 
 
• Signed informed consent  
• Medical History and cancer history and therapy 
• Physical Examination  
• Vital signs (blood pressure, heart rate, temperature, oxygen saturation via pulse 
oximetry, weight)  
• ECOG Performance Status  
• Concomitant Medication  
• Complete blood count (CBC) with differential and Comprehensive Metabolic 
Panel (CMP)  Note: Laboratory tests must be reviewed and documented by the 
investigator or sub-investigator for clinical significance to confirm eligibility of the 
potential research subject.   

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 28 of 43 
Confidential 
• Imaging: CT scan of the chest, abdomen, and pelvis (IV and/or oral contrast as 
per physician discretion) 
• RECIST measurements 
• FACT-G survey 
• Urine pregnancy test in women of childbearing potential (within 14 days of first 
day of study therapy) 
• SAE 
• Confirm Eligibility 
 
8.2 
During Study Therapy 
The following will be assessed on each day of radiation therapy after treatment delivery: 
• ECOG Performance Status 
• Vital Signs 
• Adverse Events / SAE  
• Concomitant Medications 
• Complete Study Time Log  
 
8.3 
After Study Therapy Completion 
After completion of SABR, an optional visit at 6 weeks (+/-14 days), can be performed 
as per treating physician criteria.  
 
The following will be assessed every  three (3) months until 12 month (+/- 28 days) after 
completion of SABR.  
  
• Physical Examination 
• ECOG Performance Status 
• CBC 
• CMP 
• Imaging: CT scan of the chest, abdomen, and pelvis (IV and/or oral contrast as 
per physician discretion) 
• RECIST 1.1 
• Adverse Events / SAE 
• Concomitant Medications 
• FACT-G Survey 
 
Assessments completed as part of the standard of care visits can be used for after 
treatment visits as long as the test/procedure meets the protocol-required timelines. 
Note that source documents must identify the standard of care tests/procedures used 
for this visit and must be reviewed by the investigator for clinical significance. FACT-G 
and RECIST 1.1, concomitant medications and adverse events evaluation must be 
performed by a delegated study team member. 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 29 of 43 
Confidential 
 
Remote visits:In the case when an in-person clinic visit is not possible, remote visits will 
be allowed only for “After Study Therapy” completion visits. When a remote visit occurs, 
all research specific assessments including the FACT-G questionnaire, concomitant 
medications, and adverse events will be collected by a delegated study team member. 
 
8.4 
Study Calendar 
 
 
 
1. 
Assessments will be collected each day after receiving study treatment as per the standard of care or per protocol.  
2. 
Vital signs include blood pressure, heart rate, temperature, oxygen saturation via pulse oximetry, weight. 
3.     Pregnancy test in women of childbearing potential is performed at baseline within 14 days of enrollment. 
4.     CT scan of the chest, abdomen, and pelvis (IV and/or oral contrast as per physician discretion). Please refer to section 9 of the     
        protocol. If a patient has a contraindication to contrast for a CT scan, then an alternate scan should be considered such as      
        PET/CT or MRI. 
5.     Only SAEs assessed by the investigator as related to any protocol-specific procedure or therapy will be collected and reported. 
6.     Study time log should be completed during study treatment visit a as per this protocol Appendix B. 
7.     Off Study Form to be completed during the 12 months After Therapy Completion Visit or earlier if applicable. 
 
 
Procedures 
Screening 
(within 28 days 
prior to Study 
Therapy) 
During Study 
Therapy1 
 
After Therapy 
Completion  
(Optional visit) 
6 weeks  
(+/-14 days) 
After Therapy 
Completion  
3m,6m,9m,12m  
(+/-28 days) 
Signed Informed 
Consent 
X 
 
 
 
Medical History/ 
Prior Cancer History 
and Therapy 
X 
 
 
 
Physical Exam 
X 
 
X 
X 
Vital Signs2 
X 
X 
 
 
ECOG Performance 
status 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
CBC W/ Differential 
X 
 
X 
X 
CMP 
X 
 
X 
X 
Urine pregnancy test3 
X 
 
 
 
Imaging 4 
X 
 
X 
X 
RECIST 1.1 
X 
 
X 
X 
FACT-G Survey 
X 
 
X 
X 
Adverse Events/SAE5 X 
X 
X 
X 
Confirm Eligibility 
X 
 
 
 
Study Time log 
completion6 
 
X 
 
 
Off Study7 
 
X 
X 
X 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 30 of 43 
Confidential 
9. 
TREATMENT RESPONSE EVALUATION 
 
9.1 
Imaging assessment 
Patients should have CT scans of the chest, abdomen, and pelvis at 6 weeks (±14 
days) if the six weeks visit is being performed, at 3 months (± 28 days), 6 months (± 28 
days), 9 months (± 28 days), and 12 months (± 28 days) after completion of SABR 
delivered on this study, or more often as clinically indicated.  IV and/or oral contrast 
should be used as per treating physician discretion and should be strongly considered if 
doing so would be critical for clearly visualizing the treated lesion to assess local 
response.   
 
If a patient has a contraindication to contrast for a CT scan, then an alternate scan 
should be considered such as PET/CT or MRI.  
 
Treatment response will be evaluated using the Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline, version 1.1.   
 
9.2 
Definitions for disease assessment 
• Measurable lesions:  Lesions that can be accurately measured in at least one 
dimension with longest diameter at least 10 mm.   
• Malignant lymph nodes:  A lymph node will be considered measurable if it 
measures at least 15 mm in short axis.   
• Non-measurable lesions:  All other lesions <10 mm or lymph nodes <15 mm in 
short axis. 
• Target lesions:  Target lesions should be identified and measured at baseline.  
Target lesions include measurable lesions up to a maximum of two lesions per 
organ and up to five lesions in total that are representative of all involved organs.  
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and are to undergo reproducible repeated measurements. If 
the largest lesion does not lend itself to reproducible measurement, it should not 
be considered a target lesion and instead the next largest lesion that can be 
measured reproducibly should be selected.  A sum of the longest diameters for 
all target lesions will be calculated and reported as the baseline sum diameters.  
The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.  
• Non-target lesions:  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.   
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 31 of 43 
Confidential 
9.3 
Definitions of Disease Response 
Definition of response in target lesions: 
 
• Complete Response (CR): Disappearance of all target lesions 
• Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters 
• Local Progressive Disease (LPD): At least a 20% increase in the sum of the 
diameters of target lesions compared to baseline sum of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  The sum must also demonstrate an absolute increase of at 
least 5 mm in addition to the relative increase of 20%. 
• Distant Progressive Disease (DPD): The appearance of at least 1 new lesion. 
• Stable Disease (SD): Neither sufficient decrease to qualify as a PR or sufficient 
increase to qualify as PD, taking as reference the smallest sum diameters while 
on study. 
 
Definition of response in non-target lesions: 
 
• Complete Response (CR): Disappearance of all target lesions 
• Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
• Incomplete Response/Stable Disease (SD): Persistence of one or more non-
target lesions 
 
9.4 
Evaluation of best overall response 
Best overall response is the best response recorded from the start of radiation therapy 
until disease progression or recurrence, taking as reference for progressive disease the 
smallest measurements recorded since SABR.   
 
Target Lesions Non-Target 
Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
PR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 32 of 43 
Confidential 
10. 
QUALITY OF LIFE ASSESSMENT 
 
The FACT-G patient-reported quality of life (QOL) assessment instrument will be 
completed by all patients at the following time points: 
• Screening6 weeks (±14 days) after completion of SABR if the six weeks visit is 
being performed. 
• 3 months (± 28 days) after completion of SABR  
• 6 months (±28 days) after completion of SABR 
• 9 months (±28 days) after completion of SABR 
• 12 months (±28 days) after completion of SABR 
11. 
SAFETY ASSESSMENT 
 
Safety parameters evaluated during this study will include AEs, vital signs, physical 
examination findings and clinical laboratory values.  All safety parameters will be 
performed in accordance with the study calendar (Section 8.4). 
 
11.1 
Adverse Event definition, Assessment and Reporting 
An Adverse Event (AE) is defined as any unfavorable medical occurrence in a human 
subject including any abnormal sign, symptom, or disease.    
The term AE is used to include both serious and non-serious AEs related to the 
radiation therapy specifically delivered on this study.  It should be noted that additional 
radiation therapy is permitted by this study protocol to other lesions than what is being 
treated on this study; the treating physician should use best clinical judgment about 
whether any AE may be related specifically to the treatment delivered on study. 
 
The Investigator or qualified designee will assess each subject to evaluate for potential 
or new worsening AEs as specified in the Schedule of Assessment and more frequently 
if clinically indicated.  
 
Adverse Events (AEs) will be graded and recorded throughout the trial using the 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria.  
 
A causal relationship between the radiation therapy delivered on this study and the AE 
should be determined with the treating physician using best clinical judgment to select 
one of the following for each AE: 
 
• Definitely related: There is a definite relationship between study treatment and 
the AE.  An alternative cause is highly unlikely.  There is a strong time-based 
relationship between study treatment and the AE.   
• Probably related:  There is a reasonable probability that the AE is likely to have 
been caused by study treatment.  The AE has a timely relationship to the study 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 33 of 43 
Confidential 
treatment and follows a known pattern of response, but a potential alternative 
cause is possible. 
• Possibly related:  There is a possible relationship between the AE and study 
treatment.  There may not be a known pattern of response and an alternative 
cause is more likely.  A possible relationship between the AE and study 
treatment cannot be reasonably ruled out. 
• Unrelated: There is not a reasonable causal relationship between study 
treatment and the AE.  For example, the unrelated AE may be due to disease 
progression and not study treatment. 
 
All AEs, regardless of the source of identification (e.g., physical examination, laboratory 
assessment, or reported by the patient), will be collected and recorded in the eCRF, 
upon initiation of treatment and for a minimum of 100 days after completion of radiation 
therapy or until resolution or stabilization or reported as SAEs if they become serious. 
 
11.2 
Serious adverse event definition and reporting 
A serious adverse event (SAE) is an AE occurring during any study phase that fulfills 
one or more of the following criteria: 
 
• Results in death; 
• Is immediately life-threatening; 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
 
It is important to note that hospital admission for a planned medical/surgical procedure 
or disease treatment is not considered a SAE. 
 
Only SAEs assessed by the investigator as related to any protocol-specific procedure or 
therapy will be collected and reported.  
 
The investigator at each site must review source documentation and describe pertinent 
information, provide a causality assessment of the event documented in OnCore. The 
SAE form generated in OnCore must be printed, signed and dated by the investigator.  
 
The study team will submit all SAEs to the MCI Multisite Research Program by email to: 
MCIMultisiteResearch@baptisthealth.net within 24 business hours of becoming aware 
of the initial event. 
 
After receipt of the initial report, the Sponsor-Investigator or designee will review the 
information and, if necessary, contact the site study team to obtain further information. 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 34 of 43 
Confidential 
Information to be reported in the description of each adverse event may include, but is 
not limited to: 
 
• Subject ID 
• Disease/histology  
• Protocol number and title 
• Date of the AE occurrence 
• Describe the nature of the AE (i.e., dermatitis) 
• The grade of the AE determined by CTCAE V5.0 
• Relationship of the AE to treatment  
• Whether the AE was expected or unexpected 
• The intervention to address the AE 
• A description of the subject’s condition 
• Outcome 
• Indication if the subject remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and date are required on this report. 
 
If an ongoing SAE change in its intensity or relationship to study treatment or if new 
information becomes available, a follow-up SAE report should be sent within 72 
business hours to MCI Multisite Research Program using the same procedure used for 
transmitting the initial SAE report. 
 
Any local incident, experience or outcome that is (a) unanticipated in terms of nature, 
severity, or frequency given the research procedures that are described in the protocol-
related documents, such as the IRB approve protocol and informed consent document; 
and the characteristics of the subject population being studied; and (b) Suggest that the 
research places subject(s) or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) related to the research, are considered 
Unanticipated Problems (UPs) involving risks to subjects or others.  
 
All Safety Reports that meet the following criteria are considered UPs involving risk to 
subjects: Unexpected, related or possibly related to participation in the research as 
determined by Sponsor Investigator and is Serious.  
 
UPs must be submitted to MCI Multisite Program following the SAEs reporting 
procedures. 
 
All SAEs and UPs will be reported to IRB of record in accordance with its policies and 
procedures.  
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 35 of 43 
Confidential 
11.3 
Management of adverse events   
Supportive care should be given according to routine clinical practice to manage AEs.    
 
11.4 
Data Safety Monitoring Committee 
The MCI Data Safety and Monitoring Committee (DSMC) will monitor this clinical trial 
according to the MCI Data and Safety Monitoring Plan (DSMP). In its oversight capacity, 
the MCI DSMC bears responsibility for suspending or recommending continuation of 
this study. 
 
DSMC oversight of study conduct includes ongoing review of adverse event data, and 
periodic review of feasibility and tolerability of study treatment.  The guidelines 
appearing in Section 11 of this protocol are offered for DSMC consideration in 
assessing adverse events and study objectives.  In addition, the DSMC will review 
reports from all audits, site visits, or study reviews pertaining to this clinical trial and take 
appropriate action. 
 
The DSMC will review toxicity outcomes after the first 4 patients are enrolled and have 
at least 90 days of follow-up after completion of study therapy.  
 
If any grade 3-5 toxicity is reported, the DSMC will determine if such toxicity is related to 
treatment. If the DSMC deems that toxicity rates are excessive then it can, at its 
discretion, recommend cessation of the trial, dose adjustment, or exclusion of certain 
treatment sites that are deemed as high-risk for complications. 
 
11.5 
Early study closure 
If >4 patients have grade 3+ toxicity within 90 days of treatment completion, or if any 
patient has grade 5 toxicity as a result of study therapy, then the study will close as 
tolerability will not have been demonstrated.   
 
11.6 
Pregnancy 
If it becomes known that a subject is pregnant or may have been pregnant at the time of 
study participation, the investigator must immediately notify MCI Multisite Research 
Office via email to MCIMultiSiteResearch@baptisthealth.net, the PI (Michael Chuong, 
MD at (786) 527-8140, and the Institutional Review Board of record (BHSF-IRB at (786) 
596-9280), and the patient will be discontinued from study participation.  
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 36 of 43 
Confidential 
11.7 
Overdose or misadministration of radiation 
Overdose or misadministration of radiation is defined as the accidental or intentional 
administration of any dose of radiation considered excessive and medically important.  
All occurrences of overdose or misadministration must be reported as an SAE. 
 
12. 
PATIENT DISCONTINUATION AND REPLACEMENT 
 
12.1 
Patient discontinuation 
Permanent withdrawal of a patient from the study will occur when any of the following 
occur pertaining to the subject in question: 
 
• Patient withdraws consent or is lost to follow-up. 
• Patient becomes pregnant or has the intent to become pregnant. 
• Patient is non-compliant with requirements of this study (i.e., refusal to adhere to 
scheduled visits) that in the opinion of the investigator warrants study withdrawal. 
• AE occurs that in the opinion of the investigator is a contraindication to further 
treatment on study. 
• Study closure. 
• Death 
 
If a patient is thought to be lost to follow-up, at least 3 documented attempts must be 
made to contact the patient before deemed lost to follow up. Any subject that is 
permanently discontinued from study participation will still be followed for safety and will 
also continue to have protocol-specified follow up evaluation, unless the subject 
withdraws consent, is lost to follow-up or enrolled in another clinical study.   
 
Subjects who do not return to the treating institution for evaluations required by the 
study protocol will be offered telephone follow up every 3 months.   
 
 
12.2 
Patient replacement 
Any patient that discontinues participation in this study for any reason other than 
unacceptable toxicity or progressive disease before the initial efficacy evaluation (CT 
scan 6 weeks after SABR lesion) may be replaced.  These cases will be recorded and 
accounted for in the report of the trial. 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 37 of 43 
Confidential 
13. 
STATISTICAL METHODS 
 
13.1 
Evaluation of study objectives 
13.2 
Primary objectives 
The point estimate for feasibility will be reported as a binary variable with its 95% 
confidence interval.  Feasibility will be achieved if all are true: 
• Successful completion of treatment to each lesion within 3 working days of 
intended treatment completion 
• Successful completion of treatment to each lesion within 90 minutes from the 
patient entering the treatment room until treatment completion. Any machine 
downtime during treatment delivery should be recorded and will not be included 
when assessing the time for completion of treatment. 
• Image guidance verification of treatment delivery within 5 mm of the planned 
delivery 
 
The point estimate for tolerability will be reported as a binary variable with its 95% 
confidence interval.  Tolerability will be achieved if all are true: 
 
• No greater than 4 of 30 patients experience grade 3 or higher acute toxicity 
within 90 days of completing SABR 
• No grade 5 toxicity is attributed to SABR 
 
13.3 
Secondary objectives 
1-year local control (LC) will be assessed according to RECIST 1.1 criteria and will be 
estimated using the Kaplan-Meier method along with the corresponding 95% confidence 
interval from the time of study treatment 
 
1-year overall survival (OS) will be estimated using the Kaplan-Meier method along with 
the corresponding 95% confidence interval from the time of study treatment 
 
The proportion of patients who experience acute grade 3 or higher toxicity attributable to 
SABR will be determined along with the corresponding 95% confidence interval.  For 
patients receiving SABR to multiple lesions, acute toxicity will be determined from the 
date of the initiation of SABR.   
 
Patient-reported quality of life will be determined using the FACT-G survey instrument 
prior to and after SABR.  
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 38 of 43 
Confidential 
13.4 
Sample size determination 
For this study, a sample size 30 is assessed pragmatically and not based on hypothesis 
testing. Table 1 shows 90% and 95% confidence intervals for different feasibility rates. 
 
Sample size 
Feasible 
cases 
Feasibility 
rate 
90% CI 
95% CI 
30 
27 
90% 
76% ‐ 97% 73% ‐ 98% 
30 
24 
80% 
64% ‐ 91% 61% ‐ 91% 
30 
21 
70% 
53% ‐ 83% 51% ‐ 85% 
 
Following criteria will be implemented for this feasibility study to advance to a phase II/III 
trial: 
 
1. Grade ≥3 toxicity in no greater than 4 out of 30 patients 
2. No grade 5 toxicity 
3. Treatment feasibility rate of at least 80% 
 
With a sample size of 30, if the true underlying grade 3 toxicity rate is 10.5%, the 
probability of no greater than 15% of patients in the sample (maximum 4 out of 30) 
suffering a grade 3 or higher acute toxicity is 80%. In other words, if the true underlying 
grade 3 toxicity rate is 10.5%, the probability of satisfying the specified tolerability 
threshold for escalation to a phase II/III trial is 80%. If the true underlying grade 3 
toxicity rate is 21.4%, the probability of no greater than 15% of patients (maximum 4 out 
of 30) should suffer a grade 3 or higher acute toxicity is 20%. In other words, if the true 
underlying grade 3 toxicity rate is 21.4%, the probability of satisfying the specified 
tolerability threshold for escalation to a phase II/III trial is 20%. 
 
With a sample size of 30, if the true underlying feasibility rate is 83.9%, the probability of 
at least 24 out of 30 patients satisfying the feasibility criteria is 80%. In other words, if 
the true underlying feasibility rate is 83.9%, the probability of satisfying the specified 
feasibility threshold for escalation to a phase II/III trial is 80%. If the true underlying 
feasibility rate is 71.3%, the probability of at least 24 out of 30 patients satisfying the 
feasibility criteria is 20%. In other words, if the true underlying feasibility rate is 71.3%, 
the probability of satisfying the feasibility tolerability threshold for escalation to a phase 
II/III trial is 20%. 
  
13.5 Accrual and study duration 
It is anticipated that approximately 30 patients will be enrolled and treated in this study. 
The expected accrual is an average of 1 patient at each participating site per month and 
a total of 2 patients per month across all participating sites.  We expect study accrual to 
be completed in 15 months.   
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 39 of 43 
Confidential 
14. 
 ETHICAL AND REGULATORY REQUIREMENTS 
 
14.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements. 
 
Study procedures may begin once IRB approval is secured and other details (e.g., study 
supplies, clinical trial agreements) are in place.  
 
14.2 
Informed consent 
All subjects must sign informed consent to participate in and register for this study. 
Investigators or their authorized designees will be responsible for obtaining informed 
consent and authorization to use and disclose protected health information prior to 
conduct any study-specific procedures. 
 
All subjects will be informed about the following: 
 
• Study aims 
• Possible adverse effects 
• Study procedures 
• Confidentiality of patient data 
• Medical records potentially being reviewed by authorized individuals other than 
the treating physician 
 
Patients should be given the opportunity to ask questions and be allowed time to review 
the information provided. It will be explained to each patient that participation is 
voluntary and that subjects have the right to refuse participation at any time during the 
study.  If any patient refuses to participate in this study, it will not affect the patient’s 
subsequent care quality.   
 
The written informed consent must be signed and personally dated by the subject or the 
subject’s legally acceptable representative and investigator. 
 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the 
signed document must be given to the patient. 
 
15. 
DATA MANAGEMENT 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 40 of 43 
Confidential 
The Miami Cancer Institute (MCI) Multisite Research Program will be responsible for all 
data management.  
 
The trial will use Advarra Electronic Data Capture (EDC)  system for all data collection. 
A web-based training for all eCRF users will be provided by MCI Multi-site research 
office. 
 
All data entered must be verifiable by source documentation or any discrepancy should 
be explained, and corrections should be dated, initialed and explained (if necessary) 
and should not obscure the original entry. 
   
Principal investigators are responsible for the accuracy, completeness, legibility and 
timelines of data reported to coordinating center in the eCRF/EDC and all required 
reports. 
 
15.1 
MONITORING, AUDITING AND QUALITY ASSURANCE 
Routine monitoring or audit activities for this study will be conducted by the MCI OCR 
Office of Research Integrity authorized personnel in accordance with current FDA 
Regulations, ICH GCP guidelines, site’s Standard Operating Procedures (SOPs), IRB 
and the respective local and national government regulations. The general scope of 
such visits would be to inspect study data including but not limited to, regulatory 
requirements, source documentation, original medical records/files and eCRF 
completion, as applicable, following a risk-based monitoring approach. 
 
The study will be monitored based on procedures established in the Risk-Based 
Monitoring Plan at the time of protocol activation. A series of monitoring forms, tools and 
templates including: 
 
MCI Clinical Research Monitoring/Audit Deficiencies Guidance and Summary  
 
Monitoring Letters are utilized to ensure standard and consistent monitoring practices. 
The monitoring frequency may also be adjusted as per the monitor’s discretion based 
on accrual rate, trial complexity, major deficiency findings, visit rating and safety 
reporting.  
 
To ensure compliance with current federal regulations and the ICH GCP guidelines, 
data generated by this study must be available for inspection upon request by 
representatives of the FDA, national and local health authorities, and duly authorized 
representatives of any entity providing support for this trial. 
 
 
 
 
 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 41 of 43 
Confidential 
16. 
REFERENCES 
 
1. 
Bolus NE. Basic Review of Radiation Biology and Terminology. J Nucl Med 
Technol. 2017;45(4):259-64. 
2. 
Gupta T, Agarwal J, Jain S, Phurailatpam R, Kannan S, Ghosh-Laskar S, et al. 
Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated 
radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized 
controlled trial. Radiother Oncol. 2012;104(3):343-8. 
3. 
Xu D, Li G, Li H, Jia F. Comparison of IMRT versus 3D-CRT in the treatment of 
esophagus cancer: A systematic review and meta-analysis. Medicine (Baltimore). 
2017;96(31):e7685. 
4. 
Zaorsky NG, Keith SW, Shaikh T, Nguyen PL, Horwitz EM, Dicker AP, et al. Impact 
of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities. Am 
J Clin Oncol. 2018;41(4):409-15. 
5. 
Molitoris JK, Diwanji T, Snider JW, 3rd, Mossahebi S, Samanta S, Badiyan SN, et 
al. Advances in the use of motion management and image guidance in radiation therapy 
treatment for lung cancer. J Thorac Dis. 2018;10(Suppl 21):S2437-S50. 
6. 
Das IJ, McGee KP, Tyagi N, Wang H. Role and future of MRI in radiation oncology. 
Br J Radiol. 2019;92(1094):20180505. 
7. 
Ma L, Wang L, Tseng CL, Sahgal A. Emerging technologies in stereotactic body 
radiotherapy. Chin Clin Oncol. 2017;6(Suppl 2):S12. 
8. 
Brown JM, Carlson DJ, Brenner DJ. The tumor radiobiology of SRS and SBRT: 
are more than the 5 Rs involved? Int J Radiat Oncol Biol Phys. 2014;88(2):254-62. 
9. 
Folkert MR, Timmerman RD. Stereotactic ablative body radiosurgery (SABR) or 
Stereotactic body radiation therapy (SBRT). Adv Drug Deliv Rev. 2017;109:3-14. 
10. 
Ng SSW, Ning MS, Lee P, McMahon RA, Siva S, Chuong MD. Single-Fraction 
Stereotactic Body Radiation Therapy: A Paradigm During the Coronavirus Disease 2019 
(COVID-19) Pandemic and Beyond? Adv Radiat Oncol. 2020;5(4):761-73. 
11. 
Videtic GM, Paulus R, Singh AK, Chang JY, Parker W, Olivier KR, et al. Long-term 
Follow-up on NRG Oncology RTOG 0915 (NCCTG N0927): A Randomized Phase 2 
Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically 
Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer. Int J Radiat 
Oncol Biol Phys. 2019;103(5):1077-84. 
12. 
Singh AK, Gomez-Suescun JA, Stephans KL, Bogart JA, Hermann GM, Tian L, et 
al. One Versus Three Fractions of Stereotactic Body Radiation Therapy for Peripheral 
Stage I to II Non-Small Cell Lung Cancer: A Randomized, Multi-Institution, Phase 2 Trial. 
Int J Radiat Oncol Biol Phys. 2019;105(4):752-9. 
13. 
Meyer JJ, Foster RD, Lev-Cohain N, Yokoo T, Dong Y, Schwarz RE, et al. A Phase 
I Dose-Escalation Trial of Single-Fraction Stereotactic Radiation Therapy for Liver 
Metastases. Ann Surg Oncol. 2016;23(1):218-24. 
14. 
Siva S, Bressel M, Murphy DG, Shaw M, Chander S, Violet J, et al. Stereotactic 
Abative Body Radiotherapy (SABR) for Oligometastatic Prostate Cancer: A Prospective 
Clinical Trial. Eur Urol. 2018;74(4):455-62. 
15. 
Chen WC, Baal JD, Baal U, Pai J, Gottschalk A, Boreta L, et al. Stereotactic Body 
Radiation Therapy of Adrenal Metastases: A Pooled Meta-Analysis and Systematic 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 42 of 43 
Confidential 
Review of 39 Studies with 1006 Patients. Int J Radiat Oncol Biol Phys. 2020;107(1):48-
61. 
16. 
Siva S, Correa RJM, Warner A, Staehler M, Ellis RJ, Ponsky L, et al. Stereotactic 
Ablative Radiotherapy for >/=T1b Primary Renal Cell Carcinoma: A Report From the 
International Radiosurgery Oncology Consortium for Kidney (IROCK). Int J Radiat Oncol 
Biol Phys. 2020. 
17. 
Pollom EL, Alagappan M, von Eyben R, Kunz PL, Fisher GA, Ford JA, et al. Single- 
versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: 
outcomes and toxicity. Int J Radiat Oncol Biol Phys. 2014;90(4):918-25. 
18. 
Sher DJ, Wee JO, Punglia RS. Cost-effectiveness analysis of stereotactic body 
radiotherapy and radiofrequency ablation for medically inoperable, early-stage non-small 
cell lung cancer. Int J Radiat Oncol Biol Phys. 2011;81(5):e767-74. 
19. 
Zhang HG, Yang P, Jiang T, Zhang JY, Jin XJ, Hu Y, et al. Lymphopenia Is 
Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma 
Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall 
Survival. Can J Gastroenterol Hepatol. 2019;2019:9691067. 
20. 
Siva S, Ball DL. Single Fraction SBRT for Early Stage Lung Cancer-Less is More? 
Int J Radiat Oncol Biol Phys. 2019;103(5):1085-7. 
21. 
Wang WJ, Chiou JF, Huang Y. Treatment of Liver Metastases Using an Internal 
Target Volume Method for Stereotactic Body Radiotherapy. J Vis Exp. 2018(135). 
22. 
Hall WA, Paulson ES, van der Heide UA, Fuller CD, Raaymakers BW, Lagendijk 
JJW, et al. The transformation of radiation oncology using real-time magnetic resonance 
guidance: A review. Eur J Cancer. 2019;122:42-52. 
23. 
Mittauer K, Paliwal B, Hill P, Bayouth JE, Geurts MW, Baschnagel AM, et al. A 
New Era of Image Guidance with Magnetic Resonance-guided Radiation Therapy for 
Abdominal and Thoracic Malignancies. Cureus. 2018;10(4):e2422. 
24. 
Finazzi T, Palacios MA, Haasbeek CJA, Admiraal MA, Spoelstra FOB, Bruynzeel 
AME, et al. Stereotactic MR-guided adaptive radiation therapy for peripheral lung tumors. 
Radiother Oncol. 2020;144:46-52. 
25. 
Vasmel JE, Charaghvandi RK, Houweling AC, Philippens MEP, van Asselen B, 
Vreuls CPH, et al. Tumor Response After Neoadjuvant Magnetic Resonance Guided 
Single Ablative Dose Partial Breast Irradiation. Int J Radiat Oncol Biol Phys. 
2020;106(4):821-9. 
26. 
Witt JS, Rosenberg SA, Bassetti MF. MRI-guided adaptive radiotherapy for liver 
tumours: visualising the future. Lancet Oncol. 2020;21(2):e74-e82. 
27. 
Chuong MD, Bryant J, Mittauer KE, Hall M, Kotecha R, Alvarez D, et al. Ablative 
5-fraction stereotactic magnetic resonance-guided radiation therapy (MRgRT) with on-
table adaptive replanning and elective nodal irradiation for inoperable pancreas cancer. 
Pract Radiat Oncol. 2020. 
28. 
Palacios MA, Bohoudi O, Bruynzeel AME, van Sorsen de Koste JR, Cobussen P, 
Slotman BJ, et al. Role of Daily Plan Adaptation in MR-Guided Stereotactic Ablative 
Radiation Therapy for Adrenal Metastases. Int J Radiat Oncol Biol Phys. 
2018;102(2):426-33. 
29. 
Prins FM, Stemkens B, Kerkmeijer LGW, Barendrecht MM, de Boer HJ, Vonken 
EPA, et al. Intrafraction Motion Management of Renal Cell Carcinoma With Magnetic 

Protocol # 2020-CHU-002 
 
 
 
 Version 7.0, dated 30 AUG 2022 
 
 
Page 43 of 43 
Confidential 
Resonance Imaging-Guided Stereotactic Body Radiation Therapy. Pract Radiat Oncol. 
2019;9(1):e55-e61. 
30. 
Werensteijn-Honingh AM, Kroon PS, Winkel D, Aalbers EM, van Asselen B, Bol 
GH, et al. Feasibility of stereotactic radiotherapy using a 1.5T MR-linac: Multi-fraction 
treatment of pelvic lymph node oligometastases. Radiother Oncol. 2019;134:50-4. 
31. 
Bruynzeel AME, Tetar SU, Oei SS, Senan S, Haasbeek CJA, Spoelstra FOB, et 
al. A Prospective Single-Arm Phase 2 Study of Stereotactic Magnetic Resonance Guided 
Adaptive Radiation Therapy for Prostate Cancer: Early Toxicity Results. Int J Radiat 
Oncol Biol Phys. 2019;105(5):1086-94. 
32. 
Finazzi T, de Koste JRvS, Palacios MA, Spoelstra FO, Slotman BJ, Haasbeek CJ, 
et al. Delivery of magnetic resonance-guided single-fraction stereotactic lung 
radiotherapy. Physics and Imaging in Radiation Oncology. 2020. 
33. 
Kron T, Thorwarth D. Single-fraction magnetic resonance guided stereotactic 
radiotherapy - A game changer? Phys Imaging Radiat Oncol. 2020;14:95-6.