Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (BIOGUIDE-X)
Phase: NA
Conditions: Cancer, Tumor, Solid, Cancer, Lung, Cancer, Bone, Metastasis to Lung, Metastasis to Bone
Sponsor: RefleXion Medical

Clinical Study Protocol 
 
RefleXion Medical 
  
 
 
Performance and Safety of Biology-Guided Radiotherapy using the RefleXion Medical 
Radiotherapy System (BIOGUIDE-X) 
  
 
 
Protocol ID: 985-00001 
 
Version: 5.0 
  
 
 
Date: 23-AUG-2021 
 
  
 
Sponsor: RefleXion Medical, Inc.  
25841 Industrial Blvd, Suite 275  
Hayward, CA 94545 
 
Sponsor Representative: Sean Shirvani, MD 
Senior VP, Clinical and Medical Affairs 
RefleXion Medical, Inc. 
25841 Industrial Blvd, Suite 275  
Hayward, CA 94545 
 
Principal Investigator (Radiation Oncology): Daniel Chang, MD 
Sue and Bob McCollum Professor  
Department of Radiation Oncology  
875 Blake Wilbur Drive  
Stanford, CA 94305  
 
Principal Investigator (Radiation Physics): Murat Surucu, PhD, DABR 
Chief of Clinical Physics, Clinical Associate Professor 
Department of Radiation Oncology  
875 Blake Wilbur Drive  
Stanford, CA 94305  
 
Study Site(s): Stanford University, Department of Radiation Oncology 
University of Texas Southwestern Medical Center, Department of Radiation Oncology 
 
 
 

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Protocol Synopsis 
 
 
Study Objective 
Primary 
Objectives 
To identify the Recommended RefleXion FDG Dose (RRFD) that enables the use of biology-
guided radiotherapy (BgRT) on the RefleXion system. (Cohort I: RRFD) 
 
To determine whether BgRT dose distributions generated from Limited Time Sample (LTS) 
Positron Emission Tomography (PET) images obtained at the time of treatment delivery 
are consistent with the approved BgRT plan. (Cohort II: Emulated Delivery) 
Study Device 
 RefleXion Medical Radiotherapy System IDE device 
Device 
Description 
The RefleXion Medical Radiotherapy System (RMRS) is a hybrid imaging-therapy system 
that is designed to facilitate delivery of biology-guided radiotherapy (BgRT). The system 
uses PET emissions to guide radiotherapy delivery in real-time and consists of 6 MV 
photon radiotherapy delivery, PET imaging, kilovoltage (kV) X-ray CT imaging, MV X-ray 
detection, and treatment planning subsystems. 
Study Design 
Study Design 
Open-label, prospective study. 
Planned 
Number of 
Subjects 
Cohort I - RRFD: 6 to 12 subjects (3 to 6 bone tumors, 3 to 6 lung tumors) 
Cohort II - Emulated Delivery: 8 to 22 subjects (4 or more bone tumors, 4 or more lung 
tumors) 
Planned 
Number of 
Sites   
1 to 3 US sites 
Study Duration 
Enrollment: approximately 6 months 
Subject participation:  
Cohort I – RRFD: approximately 2 weeks 
Cohort II - Emulated Delivery: approximately 4 weeks 
Total study duration: approximately 9 months  
Primary 
Endpoints 
Cohort I: 
1. Recommended RefleXion FDG Dose (RRFD): The FDG dose that results in Activity 
Concentration necessary for BgRT functioning: 5 kBq/ml or higher.  
Cohort II: 
2. The 
percent 
of radiotherapy fractions where 
the 
emulated BgRT dose 
distribution in silico is shown to be consistent with the approved BgRT treatment 
plan 
(i.e., 
95% 
of DVHDelivered points 
for 
the 
BTZ 
and 
OAR 
fall 
within bounded DVH of the approved BgRT plan).   
Secondary 
Endpoints 
Cohort I: 
1. Percent of cases where there is agreement between a site investigator and the 
agreement standard for the BgRT PET Imaging-only session localization decision 
(overall percent agreement). Positive percent agreement and negative percent 
agreement will also be reported. 
2. Percent of cases where there is concordance of a positive “plan proceed” decision 
between the BgRT Imaging-only session PET and a cleared, third-party diagnostic 
PET/CT (positive percent agreement). Overall percent agreement and negative 
percent agreement will also be reported. 

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3. Percent of cases where RefleXion PET data can be used to generate an acceptable 
BgRT plan such that dosimetric parameters for the target and the nearby normal 
anatomy are met based on investigator assessment. 
4. Percent of cases where the intended dose distribution of the BgRT plan is 
achieved in a physical phantom, defined as meeting a standard gamma index for 
external beam radiotherapy quality assurance, i.e. whether 90% of pixels meet 
the 3mm/3% deviation standard. 
Cohort II: 
1. Percent of fractions where there is concordance between the physical and digital 
phantoms of emulated BgRT delivery derived from human subject PET emissions. 
Concordance is defined as a standard gamma index with a goal that 90% of pixels 
meet the 3mm/3% deviation standard.  
2. Percent of cases where there is agreement between a site investigator and the 
agreement standard for the BgRT PET PreScan localization decision (overall 
percent agreement). Positive percent agreement and negative percent 
agreement will also be reported. 
3. Percent of cases where there is concordance of a positive localization decision 
between the short-duration PET PreScan and a third-party diagnostic PET/CT scan 
(positive percent agreement). Overall percent agreement and negative percent 
agreement will also be reported. 
4. Safety of multiple FDG administrations and toxicity rates of bladder and bone 
marrow assessed by complete blood count, urinalysis and AEs specific to bladder 
and bone marrow determined by Common Terminology Criteria for Adverse 
Events (CTCAE) v5 at 72±24 hours after final FDG injection. 
5. Workflow characterization: 
a. Percent of PET imaging sessions at RRFD that meet the Activity Concentration 
threshold for BgRT (5 kBq/mL)  
b. Percent of PET imaging sessions which lead to acceptable BgRT plans, with 
acceptability based upon meeting user-defined coverage goals for tumor 
targets and avoidance goals for OARs 
c. Percent of approved BgRT plans that go on to pass physics quality assurance, 
as defined by 90% of pixels meeting the 3mm/3% deviation standard  
d. Percent of PET Evaluations on the day of fraction delivery that elicit a “Pass” 
signal 
Key Inclusion 
Criteria 
1. Age greater than 21 years 
2. A new or prior diagnosis of biopsy-proven cancer with a solid tumor (non-
hematologic, non-lymphoma) 
3. At least one active tumor in the bone or lung which is either the primary tumor 
or metastatic lesion determined either by biopsy or imaging suspicious of active 
disease 
4. Target tumor size ≥2cm and ≤5cm 
5. Target lesion in the bone or lung that is discrete and assessed by investigator to 
be FDG-avid (i.e. SUVmax≥6 on third-party diagnostic PET/CT performed within 60 
days with no new intervening oncologic therapies) 
6. ECOG Performance Status 0-3  
7. Must have completed any other oncologic therapies at least 15 days prior to 
planned start of study procedures (preferably 30 days) and must have no plans to 
initiate systemic therapy until after study follow up is complete  -OR- must be 

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recorded by physician to have an active candidate lesion that is unresponsive to 
ongoing systemic therapy 
8. Females of childbearing potential should have negative urine or serum pregnancy 
test within 14 days prior to initiation of study scans. 
9. Demonstrate adequate organ function: determined by ANC, platelets, 
hemoglobin, with no gross hematuria 
10. For Cohort II only: Patient is dispositioned to undergo SBRT to a bone or lung 
tumor 
Key Exclusion 
Criteria 
1. Clinically significant blood glucose abnormalities that preclude a satisfactory FDG 
PET/CT scan. 
2. Previous history of external radiotherapy where prior radiotherapy fields are 
anticipated to overlap with the radiotherapy fields required for the present study 
3. Diffuse metastatic process (leptomeningeal disease, peritoneal carcinomatosis, 
diffuse bone marrow involvement, etc.) 
4. PET-avid structures not intended for radiation are within 2cm from target on 
third-party diagnostic PET/CT as assessed by investigator 
5. Known allergy to FDG 
6. Known psychiatric or substance abuse disorder that would interfere with conduct 
of the study 
7. Pregnant, breast-feeding or expecting to conceive during the study 
8. Patient weight exceeding the weight limit outlined per IFU. 
9. For Cohort II only: Patients with pacemakers and other implantable devices who 
are deemed to be at high risk by the treating physician for complications 
secondary to radiotherapy. 
10. For Cohort II only: Patients with bone lesions who are determined to be high risk 
by the treating physician for pathologic fracture prior to beginning radiotherapy. 
11. For Cohort II only: Active inflammatory bowel disease, scleroderma, or other 
disorder deemed to be a risk factor for excess toxicity in the area of treatment by 
the treating physician. 
 
Baseline 
Assessments 
and Follow-Up 
Schedule 
Baseline Assessments within fourteen days prior to the PET Imaging-only session: 
1. Demographics, medical history & physical exam 
2. Complete Blood Count (CBC) 
3. Comprehensive Metabolic Panel (CMP)  
4. ECOG performance status 
5. Blood glucose 
6. Urinalysis 
7. Pregnancy test (required for women of child-bearing potential only; within 14 
days prior to the initiation of the study scans.) 
Cohort I Follow-Up (at 72±24 hours after completion of PET Imaging-only session) 
1. AE assessment by using Common Terminology Criteria for Adverse Events 
(CTCAE) v5  
Cohort II Follow-Up (at 72±24 hours after completion of final FDG administration)  
1. Safety of multiple FDG administrations and toxicity rates of bladder and bone 
marrow assessed by complete blood count and urinalysis  
2. AE assessment by using Common Terminology Criteria for Adverse Events 
(CTCAE) v5  
 

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Table of Contents 
Protocol Synopsis ....................................................................................................................................... 2 
List of Abbreviations .................................................................................................................................. 8 
1. 
Background and Rationale .................................................................................................................. 9 
1.1 
Biology-Guided Radiotherapy: Core Principle and Clinical Benefit............................................... 9 
1.2 
The Biology-Guided Radiotherapy Algorithm ............................................................................... 9 
1.3 
BgRT Workflow ........................................................................................................................... 11 
1.4 
FDG Administration in the Context of BgRT ................................................................................ 16 
1.5 
BgRT Evidence Landscape: Technical and Clinical Evidence ....................................................... 17 
2. 
STUDY OBJECTIVES ........................................................................................................................... 18 
2.1 
Cohort I: RRFD Cohort ................................................................................................................. 18 
2.2 
Cohort II: Emulated Delivery Cohort ........................................................................................... 18 
3. 
STUDY ENDPOINTS ........................................................................................................................... 19 
3.1 
Cohort I: RRFD Cohort ................................................................................................................. 19 
3.2 
Cohort II: Emulated Delivery Cohort ........................................................................................... 19 
4. 
STUDY DESIGN .................................................................................................................................. 20 
4.1 
Overview and Justification for Study Design .............................................................................. 20 
4.2 
Cohort I: RRFD Cohort ................................................................................................................. 21 
4.3 
Cohort II: Emulated Delivery Cohort ........................................................................................... 24 
5. 
STUDY POPULATION ......................................................................................................................... 28 
5.1 
Selection Criteria ......................................................................................................................... 28 
5.2 
Withdrawal and Replacement of Subjects .................................................................................. 30 
5.3 
Enrollment Controls .................................................................................................................... 30 
6. 
STUDY PROCEDURES......................................................................................................................... 30 
6.1 
Written Informed Consent .......................................................................................................... 30 
6.2 
Cohort I: RRFD Cohort ................................................................................................................. 31 
6.3 
Cohort II: Emulated Delivery Cohort ........................................................................................... 38 
7. 
DATA MANAGEMENT ....................................................................................................................... 49 
7.1 
Data Collection and Processing ................................................................................................... 49 
8. 
MONITORING PROCEDURES ............................................................................................................. 50 
8.1 
Monitoring .................................................................................................................................. 50 
8.2 
Auditing ....................................................................................................................................... 50 
8.3 
Device Accountability .................................................................................................................. 50 
9. 
ADVERSE EVENTS .............................................................................................................................. 51 

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9.1 
Adverse Event Definitions and Classification .............................................................................. 51 
9.2 
Potential Adverse Events ............................................................................................................ 53 
9.3 
Reporting Requirements ............................................................................................................. 54 
9.4 
Device Failures and Malfunctions ............................................................................................... 54 
9.5 
Reporting to Regulatory Authorities, Institutional Review Boards and Investigators ................ 55 
10. RISK BENEFIT ANALYSIS .................................................................................................................... 55 
10.1 
Study Risk Management Procedures .......................................................................................... 55 
10.2 
Known and Anticipated Risks ...................................................................................................... 55 
11. STUDY COMMITTEES ........................................................................................................................ 57 
11.1 
Safety Monitoring Committee .................................................................................................... 57 
11.2 
Independent Image Reviewers ................................................................................................... 58 
12. ETHICAL CONSIDERATIONS ............................................................................................................... 58 
12.1 
Compliance with Good Clinical Practices (GCP) .......................................................................... 58 
12.2 
Institutional Review Board .......................................................................................................... 58 
12.3 
Written Informed Consent Form ................................................................................................ 58 
12.4 
Amending the Protocol ............................................................................................................... 59 
12.5 
Emergency Actions ...................................................................................................................... 59 
12.6 
Protocol Adherence .................................................................................................................... 59 
13. STATISTICAL CONSIDERATIONS ........................................................................................................ 60 
13.1 
Sample Size Calculation .............................................................................................................. 60 
13.2 
General Consideration ................................................................................................................ 61 
13.3 
Statistical Analysis Plan ............................................................................................................... 63 
14. STUDY ADMINISTRATION ................................................................................................................. 63 
14.1 
Pre-Study Documentation .......................................................................................................... 63 
14.2 
Record Retention ........................................................................................................................ 63 
14.3 
Criteria for Suspension/Termination of a Study Site .................................................................. 64 
14.4 
Criteria for Suspension/Termination of Study ............................................................................ 64 
15. REFERENCES ...................................................................................................................................... 64 
Attachment 1: IDE Study Event Schedule ................................................................................................ 67 
 
 
 
 

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List of Figures 
Figure 1. BgRT principle of linear superposition. Just as the limited-time sample (LTS) images, Xt, 
sum to the full PET image X, the derived partial fluences sum to the complete 
intended fluence. BTZ: Biology-tracking zone ........................................................... 10 
Figure 2. BgRT delivery workflow. .................................................................................................. 16 
Figure 3: Study Flowchart .............................................................................................................. 21 
Figure 4. Cohort I schematic .......................................................................................................... 22 
Figure 5. Modified 3+3 Design ....................................................................................................... 22 
Figure 6. Cohort II Patient Encounters ........................................................................................... 25 
Figure 7. Physical and Dosimetric Validation of BgRT Plan Delivery Based upon Human-Subject 
Derived PET Data on the RefleXion System............................................................... 26 
Figure 8. Cohort II Patient Encounters (Duplicated from above). .................................................. 38 
 
 
 
 
List of Tables 
Table 1: Cohort I- Study Event Schedule ........................................................................................ 34 
Table 2: Cohort II - Study Event Schedule ...................................................................................... 45 
Table 3: Comparison of effective dose from multiple FDG administrations and other incidental 
radiation exposures from currently used procedures in conventional radiotherapy 56 
 
 
List of Attachments 
 
Attachment 1:  IDE Study Event Schedule 
 
 
 
 

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List of Abbreviations 
 
AE 
ALARA 
BgRT 
BTZ 
Adverse Event 
As Low As Reasonably Achievable 
Biology-Guided Radiotherapy 
Biology-Tracking Zone 
CT 
CTV 
CTCAE 
Computed Tomography 
Clinical Target Volume 
Common Terminology Criteria for Adverse Events 
FDG 
F18-Fluorodeoxyglucose 
GTV 
IB 
IGTV 
IPTV 
ITV 
kVCT 
LTS 
MLC 
NTS 
OAR 
PET 
PTV 
Gross Tumor Volume 
Investigator’s Brochure 
Internal Gross Tumor Volume 
Internal Planning Treatment Volume 
Internal Tumor Volume 
Kilovoltage Computed Tomography 
Limited Time Sample 
Multi-leaf Collimator 
Normalized Target Signal 
Organ-at-risk 
Positron Emission Tomography 
Planning Treatment Volume 
SAE 
SBRT 
SMC 
RMRS 
RRFD 
UADE 
Serious Adverse Event 
Stereotactic Body Radiotherapy 
Safety Monitoring Committee 
RefleXion Medical Radiotherapy System 
Recommended RefleXion FDG Dose 
Unanticipated Adverse Device Effect 

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1. 
Background and Rationale 
1.1 
Biology-Guided Radiotherapy: Core Principle and Clinical Benefit 
The RefleXion Medical Radiotherapy System (RMRS) is a hybrid imaging-therapy system that is designed 
to enable delivery of biology-guided radiotherapy (BgRT), a novel radiotherapy technique that aims to 
improve the conformality and precision with which external beam radiotherapy is delivered to malignant 
lesions, including those that are in motion. This system functions by utilizing outgoing Positron Emission 
Tomography (PET) emissions emanating from a tumor to direct beamlets of external radiotherapy back to 
the lesion with sub-second latency. This core process can be repeated until a desired total dose of external 
radiation is delivered to a CT-defined target volume anchored in space to the PET profile of the tumor. In 
this way, the PET profile of the tumor acts as an endogenous biological fiducial.  
 
BgRT is expected to improve radiation delivery for two reasons. Firstly, the use of the lesion’s own PET 
profile as a fiducial enables increased confidence in lesion localization during therapy, which in turn allows 
the radiation oncologist to reduce positional margins at treatment planning that account for set-up error 
and patient shifts; said differently, BgRT improves the conformality of radiotherapy dose to the lesion by 
creating conditions of plan delivery that compensates for a static shift at the time of treatment. The 
benefit of reduced margins around gross disease extent is that the surrounding normal tissue is exposed 
to less radiation, including at the high ablative dose range, which may result in a lower burden of acute 
toxicity and long-term morbidity.  
 
Secondly, BgRT addresses the challenge of motion management for mobile tumors by enabling the 
therapeutic beam to direct beamlets of radiation with sub-second (350-400 ms) latency. The aggregate 
effect of delivering a series of radiation beamlets this way is to effectively deliver a tracked dose 
distribution. This is a beneficial departure from current internal target volume (ITV) techniques that 
require ablation of the entire envelope of a tumor’s motion path plus margin in order to ensure tumor 
coverage at all times1–3. The fact that ITV approaches require more ablation of normal tissues to ensure 
coverage during tumor motion comes at the cost of clinically-evident patient toxicities arising from those 
injured tissues4–7.  
 
In summary, by using a tumor’s own biology as a fiducial signal, BgRT has the potential to improve the 
therapeutic index of radiotherapy through improved conformality and by enabling better motion 
management via tracked dose distributions that compensate for natural processes like respiration.   
 
1.2 
The Biology-Guided Radiotherapy Algorithm 
In traditional treatment planning, the desired dose to the target and constraints to normal tissue are met 
by optimizing for a set of machine-deliverable radiotherapy fluences that are delivered from many pre-
determined angles around the patient. The downside of this rigid approach is that the ablative 
radiotherapy must be directed to significant margins around the target or even the target’s entire path of 
motion in case there is variation in the target’s position or motion at the time of treatment.  BgRT 
improves upon this technique by enabling radiotherapy dose to be tailored to the target’s position and 
motion at the time of treatment delivery, which in turn may reduce the amount of normal anatomy that 
must be incidentally subjected to ablative radiotherapy. For achieving this outcome, the BgRT algorithm 
enables a linear accelerator system to capture sub-second PET acquisitions from a target, which are 

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termed limited-time sample (LTS) PET images, and to respond with beamlets of radiotherapy (partial 
fluences). This cycle is then repeated until the full intended dose of external beam radiotherapy is 
delivered to the target. Importantly, the portion of the LTS PET images used to guide beamlets is confined 
to a physician-defined anatomic region, termed the Biology-tracking zone (see section 1.3.2), that 
corresponds to the motion envelope of the target tumor. This feature prevents radiotherapy beamlets 
from being directed at PET emissions originating away from the tumor. 
Given the reactive nature of the beam delivery, the BgRT algorithm cannot optimize for machine-
deliverable fluence directly because rigid predetermination of machine instructions would not be capable 
of adjusting to a fluctuating LTS PET profile. Instead, the BgRT algorithm optimizes for fluence indirectly 
by calculating a transfer function, termed the firing matrix, that can translate a target’s PET profile into 
the desired fluence. To achieve this, the BgRT algorithm relies on a full PET dataset captured ahead of 
BgRT delivery to calculate an operator, termed a “firing filter” - that can convert this full PET image into a 
complete radiotherapy fluence that meets the physician’s objectives for target coverage and organ-at-risk 
avoidance. This optimization is similar to intensity-modulated radiotherapy (IMRT) algorithms that rely on 
a standard cost function that can iterate among candidate firing filters until those physician-defined 
objectives are best optimized.  
After the firing matrix is calculated using a full PET image, it can then be applied to LTS PET images to 
generate partial fluences. Importantly, adding all the partial fluences generated from a series of 
sequentially obtained LTS images is mathematically expected to sum to the complete fluence goals of the 
physician. This follows from the fact that the firing matrix is confined by the algorithm to take the form of 
a linear, shift-invariant operator, which in turn means that the principle of linear superposition applies to 
the conversion of LTS PET images to partial fluences. This principle ensures that, just as the sequential LTS 
images sum to a full PET image, the partial fluences will sum to the complete intended fluence. Figure 1 
is a visual representation of this principle. 
 
 
Figure 1. BgRT principle of linear superposition. Just as the limited-time sample (LTS) images, Xt, sum to the 
full PET image X, the derived partial fluences sum to the complete intended fluence. BTZ: Biology-tracking zone 

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Finally, a tumor’s PET profile and, by extension, its constituent LTS images can vary from one radiotracer 
administration to the next due to a variety of biological, physiological, and logistical factors. Therefore, 
BgRT treatment planning algorithm generates a range of possible radiotherapy dose distributions to 
reflect these possible variations in tumor motion and tumor contrast. As described below, prior to every 
radiotherapy delivery, the system checks that the PET profile on that day (and the resulting fluence) fall 
within that spectrum, or otherwise the treatment must be aborted. Of note, preliminary evidence 
suggests that variations in PET profile over the course of standard ablative radiotherapy are expected to 
be modest, at least in the case of FDG8.  
 
1.3 
BgRT Workflow 
The basic workflow for conventional radiotherapy acts as a foundation for BgRT. In essence, the BgRT 
workflow includes the typical composition of processes observed in radiation oncology along with 
additional steps to accommodate the introduction of PET information. These processes include the core 
steps of prescription, simulation, treatment planning, and treatment delivery9–12. For context BgRT 
treatment delivery directed at a patient is described in section 1.3.3 below as part of the envisioned BgRT 
product,  but the study investigation replaces this step with emulated delivery, which establishes anatomic 
dose distribution using offline tools, as later described.   
Summary of core workflow steps used in conventional radiotherapy:  
1. Prescription: The radiation oncologist determines that a patient requires radiotherapy as part of their 
cancer care. The clinician then selects the target, radiation dose, fraction size, and schedule for the 
treatment. The prescription process also includes specifying the tolerance limits for normal tissues 
near the target, which are also known as organs-at-risk (OAR).  
2. Simulation: The patient is placed in a CT simulator in a desired position along with immobilization 
devices like customized cradles or head-masks to reduce shifts. CT images are obtained in that 
position and used to plan treatment. In modern radiotherapy, four-dimensional (4D) CT image sets 
are often acquired to capture the differing positions of tumor across natural processes such as the 
inhalation-exhalation respiratory cycle.  
3. Treatment Planning: The radiation oncologist outlines targets and OARs on the simulation CT image, 
a process also known as “contouring”.  Contouring is followed by radiation delivery planning which 
entails in silico modeling of external beam delivery. This modeling includes the selection of differing 
particle types, particle energies, beam angles and beam intensities to achieve desired goals for target 
coverage and OAR avoidance. The approved in silico plan is then verified independently in a process 
called “quality assurance” (QA). During QA, the linear accelerator actually delivers the approved 
treatment plan into a physical phantom that can measure the delivered dose and distribution of 
radiation. The measured dose and distribution is checked to ensure that it is concordant to an in silico 
model of plan delivery into a digital facsimile of the physical phantom.  

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4. Treatment Delivery: The patient is set-up and immobilized on the linear accelerator couch in the same 
position as the CT simulation.  Alignment is verified using external markers and on-board imaging, and 
then the approved radiation plan is delivered from the linear accelerator. Each such treatment is 
called a fraction. This step is repeated until all planned fractions of the radiotherapy course have been 
delivered. Every five fractions, the radiation oncologist typically conducts an interview with the 
patient to address patient concerns and manage toxicities. 
BgRT adds to this conventional workflow by introducing PET into two key steps of the workflow: The PET 
Imaging-Only Session during treatment planning and the PET PreScan and LTS image acquisition at 
treatment delivery. These BgRT modifications to the conventional radiotherapy workflow are detailed 
below.  
1.3.1 
Prescription 
At the time of the patient’s initial encounter with a radiation oncologist, the patient must be deemed a 
candidate for biology-guided radiotherapy. As with conventional radiotherapy, this requires that the 
radiation oncologist first make a determination that radiotherapy itself is indicated. The radiation 
oncologist also specifies the usual parameters of the prescription: Dose, target volumes, coverage goals, 
and avoidance parameters for OARs. The next decision point for biology-guided radiotherapy is for the 
clinician to determine whether BgRT might confer therapeutic advantages to the patient via improved 
conformality and motion management compared to conventional radiotherapy. If so, the radiation 
oncologist can review any previously obtained diagnostic PET/CT images to determine qualitatively 
whether the target lesion appears to have adequate FDG activity over background, such that a more 
rigorous, quantitative assessment of BgRT candidacy on the RefleXion system itself is warranted.  
General guidance for adequate FDG avidity for BgRT candidacy, as observed on a previously-obtained 
diagnostic PET/CT, is that the maximum tumor SUV is 6 or higher. The physician can also consider 
qualitative factors such as the relative positions of OARs with FDG uptake to the tumor and the contrast 
of tumor to the background tissue. Again, it is important to emphasize that this assessment is meant to 
act as a first screen of candidates, and that formal assessment of BgRT candidacy is made on the RefleXion 
device.     
1.3.2 
Simulation and Treatment Planning 
If BgRT candidacy is considered, the patient must then undergo a simulation process for radiotherapy 
treatment planning that collects necessary PET emission data on the RefleXion system. In the workflow, 
this requires that the patient first undergo a traditional CT simulation which is then followed by a new PET 
imaging step on the RefleXion system, labeled the PET Imaging-Only Session. In this step, RMRS PET 
emission data is collected in the same treatment position as was established during the anatomic CT 
simulation.  
The sequencing of CT simulation prior to RMRS PET Imaging-Only Session is necessary because the PET 
Imaging-Only Session requires an overlay of (4D)CT-defined contours, which act to narrow down the 
anatomic location for PET emission collection. Specifically, a Biology-tracking zone (BTZ) defined as the 
motion envelope of the tumor on the (4D)CT image set plus a margin must be delineated ahead of the 

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PET Imaging-Only Session in order to localize where in the body the target tumor is located. In addition to 
the BTZ, other CT-defined tumor targets (GTV, CTV, PTV) and nearby organs-at-risk (OARs) are also 
contoured based upon the CT simulation images.  
At the PET Imaging-Only Session itself, the patient is injected with FDG and, after an approximate 1-hour 
uptake period, is setup in the RefleXion system in the same treatment position as was used during CT 
simulation. The same immobilization devices used during the CT simulation are likewise deployed. Next, 
the patient’s alignment is fine-tuned with CT-guidance using RefleXion’s on-board fanbeam kVCT, and the 
patient is moved on the treatment couch such that the PET detector arcs on the RefleXion system are 
aligned with the region of interest containing the target tumor.  
Next, the PET detector arcs capture PET emission data and generate a PET image. Of note, the time 
window for imaging relative to the injection must be controlled so that the activity is not too high, which 
could saturate the detectors, or too low secondary to FDG decay, which would result in inadequate PET 
activity for BgRT. After the PET emission data is collected, several steps occur to formally assess for BgRT 
candidacy and, if appropriate, to generate a high quality BgRT treatment plan. 
At the RMRS Device: 
1. The patient’s (4D)CT-defined BTZ is overlaid on the RMRS PET image. This overlay is enabled by the 
prior CT alignment step, which indexes the CT anatomy obtained in the treatment position on the 
day of the PET Imaging-Only Session to the CT anatomy obtained previously at CT simulation. Once 
the PET image is formed, the radiation oncologist confirms that the tumor in the PET image can, in 
fact, be visualized and localized to within the BTZ as expected.  
Notably, the BTZ overlay is a volume based upon (4D)CT images generated on a commercial, third-
party Sim CT device. Therefore, in addition to capturing PET information for the BgRT algorithm, this 
step also acts to verify the location accuracy of the RMRS PET image as compared to an external 
reference standard.  
The patient may leave the department once the RMRS PET image is acquired and validated by the 
radiation oncologist. Provided that localization/visualization of the tumor PET image within the BTZ is 
confirmed by the radiation oncologist, the PET data is then transmitted to the treatment planning 
system (TPS) for the next steps. 
At the Treatment Planning System Console: 
2. Specific quantitative parameters of the tumor PET image are calculated by the treatment planning 
software to determine whether BgRT is a viable option for BgRT planning and treatment delivery.  
These quantitative criteria for BgRT candidacy include: 
a. Activity Concentration: Greater than 5 kBq/ml 

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b. Tumor signal-to-background ratio as measured by the Normalized Target Signal (NTS): Greater 
than 2.7 
Notably, these values are indexed to RefleXion’s software and hardware architecture as well as the 
patient’s radiotherapy treatment position. Therefore, they cannot be extrapolated from a third-party 
PET/CT.  
3. The physician also qualitatively assesses the following: 
a. FDG-avid OARs are outside the BTZ  
b. No FDG-avid structures aside from the tumor are in the BTZ. 
If all of the qualitative and quantitative criteria are met, the PET emission data from within the BTZ can be 
incorporated into the treatment planning software for the BgRT algorithm’s dose calculations. As 
described in detail in the Investigator Brochure (IB) and summarized in section 1.2, the algorithm acts to 
optimize a firing matrix that converts PET projections to a machine-deliverable fluence such that the 
fluence in turn meets traditional radiotherapy dose objectives, such as coverage goals for the target and 
avoidance metrics for OARs.  
An important feature of a BgRT treatment plan is that it presents the clinician with a bounded dose volume 
histogram (DVH), which is significantly more detailed than a traditional dose volume histogram used in 
conventional radiotherapy systems. In a bounded DVH (bDVH), the nominal plan based on the tumor’s 
PET appearance on the day of the imaging session is indicated graphically by solid lines as per the usual 
DVH format. However, the bDVH also includes bands around these lines, which are calculated in order to 
visualize how dose and coverage would change in response to variations in tumor PET signal or tumor 
motion encountered on the day of treatment.    
To complete treatment planning, the clinician is recommended to create a back-up conventional SBRT 
plan based only on the CT simulation images, which can be used in scenarios where BgRT is unable to be 
delivered on the day of treatment (as described in the IB).  
As with conventional workflows, both completed treatment plans – BgRT and back-up SBRT - are then 
finalized by a dosimetrist and reviewed by a radiation oncologist for final approval. The standard practice 
of reviewing anatomic isodose lines and dose volume histograms for target coverage and OAR avoidance 
is done with the additional nuance that BgRT requires review of a bounded DVH as described above and 
in the IB.  
Next, standard quality assurance (QA) is performed by a qualified medical physicist, which consists of the 
approved plans undergoing a dry run on the linear accelerator with a physical phantom placed on the 
couch to measure the dose and distribution of actually delivered therapeutic radiation13. The measured 
dose is compared to in silico modeled delivery of the BgRT plan into a digital scan of the test phantom. 
For BgRT, confirmation that the physical delivery and modeled delivery are concordant is assessed using 
standard gamma index methods. Of note, the phantom test utilizes the PET information used by the BgRT 
plan and assumes the target is static. Once quality assurance is complete, the BgRT plan receives a final 

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approval from the medical physicist and radiation oncologist. The patient is then scheduled to return to 
the radiation oncology department to initiate treatment.  
1.3.3 
Treatment Delivery 
At each treatment fraction, the patient is injected with FDG, and the proper uptake period must elapse. 
The patient is then set up in the correct treatment position with deployment of the same immobilization 
devices used during both the CT simulation and the PET Imaging-Only Session. The patient’s alignment is 
fine-tuned using CT guidance with RefleXion’s on-board fanbeam kVCT. As was the case during the imaging 
session, this alignment is made possible by indexing the on-board CT images to the images acquired at CT 
simulation. The (4D)CT-defined BTZ is also again overlaid on the indexed images.   
Next, a PET PreScan is obtained, which represents a second new step introduced by the BgRT workflow. 
The PET PreScan image analysis, termed the PET Evaluation, is a critical safety interlock wherein the 
RefleXion system checks whether the pattern and quantitative characteristics of PET emissions observed 
in the BTZ on the day of treatment are consistent, within a tolerance threshold, to the PET emission profile 
observed during the PET Imaging-Only Session (upon which the BgRT plan is based). As with the PET 
Imaging-Only Session criteria, the checked parameters are calibrated to the RefleXion system hardware 
and software and cannot be meaningfully extrapolated from a different vendor’s system.  
The specifics of the PET PreScan process are as follows. Firstly, the PreScan itself, which is a short-duration 
RMRS PET acquisition, is performed to generate a PET image of the anatomic region containing the target. 
The user reviews the image set to visually confirm that the tumor PET image is localized within the (4D)CT-
defined BTZ. The user can also assess whether FDG-activity from neighboring OARs remains outside of the 
BTZ. Both of these localization features need to be verified in order to continue with BgRT. In addition to 
the PET image review, CT images from the alignment process can provide further confirmation of the 
relative positions of targets and OARs as is done in conventional radiotherapy.   
Next, the RefleXion system quantifies characteristics of the PET emission data from the PET PreScan to 
assure consistency with the PET imaging session. This is a critical safety interlock that occurs prior to 
activating the linear accelerator for BgRT delivery. These quantitative criteria include: 
1. Confirmation of Activity Concentration greater than 5 kBq/ml 
2. Confirmation that the tumor NTS larger than a threshold of 2, which allows for a value that is 25% 
lower than the NTS observed at PET Imaging-Only Session 
3. Predicted DVH: The RefleXion system calculates a BgRT dose distribution that is anticipated to be 
delivered based upon the short-duration emission profile of the PET PreScan. This Predicted DVH of 
the BTZ and OAR distribution (DVHPredicted)is confirmed to be “within the bounds” of the bDVH in the 
approved BgRT plan. This calculation involves confirming that 95% of the points on the DVHPredicted 
for the BTZ and OARs fall within the approved bDVH.  
If, in conjunction with visual localization of the tumor within the BTZ, all of these quantitative 
requirements for PET emission quality are met, then the user is allowed to proceed with BgRT delivery. 

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This means that the PET detectors are instructed to collect LTS PET emission data, and the linear 
accelerator and multi-leaf collimator (MLC)’s are instructed to direct partial fluences to the target in 
response to those LTS images in a continuous closed-loop system directed by the BgRT algorithm.  
If any of the above quantitative parameters are not met, then the user is locked out of using BgRT during 
that session and has the choice of either rescheduling therapy or substituting another mode of 
radiotherapy (i.e. SBRT) for that fraction. The reasons for not meeting the parameters may be due to 
intrinsic changes in the PET profile of the tumor or surrounding OARs, but may also be due to process 
issues, examples of which include misadministration of FDG at the time of injection or administration of 
a batch of FDG with poor activity due to manufacturing errors upstream at the FDG vendor 14.    
 
 
Figure 2. BgRT delivery workflow.  
 
To complete the course of treatment, the patient undergoes as many fractions of biology-guided 
radiotherapy as prescribed by the radiation oncologist. The PET PreScan is required before each fraction 
of therapy. A weekly on-treatment visit is also recommended as per standard radiotherapy practice.  
As mentioned previously, this description refers to the envisioned BgRT product where treatment delivery 
is directed at the patient. This IDE study does not direct the external radiation at the patient because in 
vivo measurement of dose delivery accuracy is not feasible. Instead, as detailed in sections 4 and 6, the 
study utilizes PET datasets from enrolled patients to predict and measure anatomic dose distribution using 
offline software tools and phantoms, an investigational technique that is termed “emulated delivery”. 
1.4 
FDG Administration in the Context of BgRT 
The initial radiotracer for use in the RefleXion system is FDG, because this agent is a widely available and 
well-understood diagnostic tracer that accumulates in many cancer cell types due to their shared 
biological feature of abnormal glucose uptake. As described, the BgRT workflow utilizes FDG at multiple 
steps including at the PET Imaging-Only Session in the context of simulation and treatment planning as 
well as during each fraction of radiation delivery as characterized by the PET PreScan and the active 
functioning of BgRT external beam delivery. Because biology-guided radiotherapy will be used to deliver 
ablative doses of radiation, which typically require 1 to 5 fractions of therapy, one can expect that BgRT 
regimens will require 2 to 6 injections of FDG: 1 injection for the PET imaging session and 1 injection for 
each treatment fraction. 

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1.5 
BgRT Evidence Landscape: Technical and Clinical Evidence 
In general, radiotherapy device validation evidence can be either Technical or Clinical.  
The technical evidence includes experiments conducted outside a clinical context, such as dosimetric and 
physics investigations, that validate performance and functioning of the radiotherapy device. This body of 
evidence is essential because it entails measurement of critical quantities that cannot otherwise be 
measured. The most important example is the use of physical phantoms, which enable the measurement 
of the actual dose and distribution of therapeutic radiation delivered by a linear accelerator, metrics that 
cannot be measured directly in vivo. Comparison of the actually delivered dose distribution in a phantom 
to a corresponding modeled dose distribution in a digital facsimile of the same phantom constitutes the 
core methodology for assuring linear accelerator performance.  
For BgRT, technical validation follows this precedent: The measurement of actually delivered radiation 
dose and distribution can be evaluated directly in an FDG-avid physical phantom (“FDG-phantom”) that 
mimics the conditions of an FDG-avid tumor. Furthermore, the accuracy of this delivery can be confirmed 
via comparison to modeled delivery in a digital facsimile of the FDG-phantom.  Experiments such as these 
form the foundational base of evidence for assessing the performance of radiotherapy techniques in 
general, and such technical evidence remains necessary and indispensable for BgRT.  
At the same time, this technical evidence can be supplemented by well-conceived clinical evidence 
obtained in a real-world practice setting. To that end, the present investigational device exemption (IDE) 
study aims to clinically validate RefleXion BgRT performance by evaluating end-to-end system functioning 
using human subject data obtained in the context of radiation oncology practice. The study’s first primary 
objective is to test the PET subsystem and to identify the Recommended RefleXion FDG Dose(RRFD) that 
enables the use of BgRT. The second primary objective is to assess end-to-end BgRT performance by 
determining the final accuracy of BgRT external beam dose distributions that are based upon tumor PET 
emissions obtained from human subjects in the radiotherapy treatment position. Additional objectives 
are to comprehensively characterize all key features in the BgRT process including PET imaging 
performance; BgRT plan creation, approval, and quality assurance; physical deliverability of BgRT fluence; 
workflow performance; and safety associated with multiple FDG administrations.  
Importantly, clinical validation of BgRT across the entire scope of radiotherapy indications is not feasible. 
Therefore, in choosing a study population, advantageous features are that the population (1) entails a 
degree of homogeneity in clinical characteristics to inform useful conclusions while (2) still being 
reasonably generalizable to a broad range of malignant conditions, especially when this clinical evidence 
is combined with a strong foundation of technical validation. To that end, the proposed IDE investigation 
focuses on two anatomic locations – the lung and osseous compartments – which together are 
representative of a comprehensive spectrum of scenarios for which biology-guided radiotherapy can be 
utilized. 
Tumors in the lung are an important, representative use case for motion management in radiotherapy 
because they undergo excursion with respiration in all directions. Furthermore, conformality is necessary 
in these tumors because of their close proximity to multiple organs at risk in the thorax and upper 

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abdomen. Finally, lung anatomy in the context of PET imaging is generally characterized by relatively high 
contrast between FDG-avid tumors and the background tissue (lung parenchyma). Given these 
characteristics, lung tumors represent one end of the range for motion and PET contrast against which 
the viability of a radiotherapy modality like BgRT should be demonstrated. 
In contrast, tumors in the bone are not subject to internal anatomic motion, but instead are subject to 
motion derived from set-up error and patient shifts during treatment. Also, the background tissue of bony 
lesions, which consists of soft tissues and normal bone, has on average more inherent FDG activity than 
lung parenchyma, which reduces the contrast between osseous tumors and their surrounding tissue. 
Therefore, demonstrating utility of BgRT in bony lesions addresses the opposite end of the motion 
management and PET contrast spectrum as lesions in the lung. Conformality remains of great importance 
for bone tumors as radiosensitive normal structures throughout the patient’s anatomy are in proximity to 
the skeleton. Indeed, in modern radiotherapy, conformality is a desired feature across all anatomic 
geographies and clinical contexts.  
In light of these features, clinical evidence derived from patients with lung and bone tumors represents a 
versatile set of real-world conditions with respect to motion and PET environment. In combination with 
technical and benchtop experiments, this IDE seeks to provide robust evidence for BgRT functioning and 
accuracy that can be applied to the spectrum of malignant conditions for which radiotherapy is indicated.  
 
2. 
STUDY OBJECTIVES 
2.1 
Cohort I: RRFD Cohort 
2.1.1 
Primary Objective 
To identify the Recommended RefleXion FDG Dose (RRFD) that enables the use of BgRT on the RefleXion 
system. 
2.1.2 
Secondary Objective 
To assess the performance of the BgRT PET Imaging-only session, treatment planning and quality 
assurance at the studied dose level. 
2.2 
Cohort II: Emulated Delivery Cohort 
2.2.1 
Primary Objective 
To determine whether BgRT dose distributions generated from Limited Time Sample (LTS) PET images 
obtained at the time of treatment delivery are consistent with the approved BgRT plan. 
2.2.2 
Secondary Objective 
To emulate and confirm deliverability of the fluence associated with the BgRT dose distribution generated 
from LTS PET images obtained at the time of treatment delivery as well as to assess imaging, process and 
safety characteristics of the end-to-end workflow. 

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3. 
STUDY ENDPOINTS 
3.1 
Cohort I: RRFD Cohort 
3.1.1 
Primary Endpoint 
RefleXion Recommended FDG Dose (RRFD): The FDG dose that results in Activity Concentration necessary 
for BgRT functioning: 5 kBq/ml or higher. 
3.1.2 
Secondary Endpoints 
1. Percent of cases where there is agreement between a site investigator and the agreement standard 
for the BgRT PET Imaging-only session localization decision (overall percent agreement). Positive 
percent agreement and negative percent agreement will also be reported. 
2. Percent of cases where there is concordance of a positive “plan proceed” decision between the BgRT 
Imaging-only session PET and a cleared, third-party diagnostic PET/CT (positive percent agreement). 
Overall percent agreement and negative percent agreement will also be reported. 
 
3. Percent of cases where RefleXion PET data can be used to generate an acceptable BgRT plan such that 
dosimetric parameters for the target and the nearby normal anatomy are met based on investigator 
assessment. 
4. Percent of cases where the intended dose distribution of the BgRT plan is achieved in a physical 
phantom, defined as meeting a standard gamma index for external beam radiotherapy quality 
assurance, i.e. whether 90% of pixels meet the 3mm/3% deviation standard. 
 
3.2 
Cohort II: Emulated Delivery Cohort 
3.2.1 
Primary Endpoint 
The percent of radiotherapy fractions where the emulated BgRT dose distribution in silico is shown to be 
consistent with the approved BgRT treatment plan (i.e., 95% of DVHDelivered points for the BTZ and OAR 
fall within bounded DVH of the approved BgRT plan).   
3.2.2 
Secondary Endpoints 
1. Percent of fractions where there is concordance between the physical and digital phantoms 
of emulated BgRT delivery derived from human subject PET emissions. Concordance is defined as a 
standard gamma index with a goal that 90% of pixels meet the 3mm/3% deviation standard.  
2. Percent of cases where there is agreement between a site investigator and the agreement standard 
for the BgRT PET PreScan localization decision (overall percent agreement). Positive percent 
agreement and negative percent agreement will also be reported. 

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3. Percent of cases where there is concordance of a positive localization decision between the short-
duration PET PreScan and a third-party diagnostic PET/CT scan (positive percent agreement). Overall 
percent agreement and negative percent agreement will also be reported. 
4. Safety of multiple FDG administrations and toxicity rates of bladder and bone marrow assessed by 
complete blood count, urinalysis and AEs specific to bladder and bone marrow determined by 
Common Terminology Criteria for Adverse Events (CTCAE) v5 at 72±24 hours after final FDG injection. 
 
5. Workflow characterization: 
a. Percent of PET imaging sessions at RRFD that meet the Activity Concentration threshold for BgRT 
(5 kBq/mL)  
b. Percent of PET imaging sessions which lead to acceptable BgRT plans, with acceptability based 
upon meeting user-defined coverage goals for tumor targets and avoidance goals for OARs 
c. Percent of approved BgRT plans that go on to pass physics quality assurance, as defined by 90% 
of pixels meeting the 3mm/3% deviation standard  
d. Percent of PET Evaluations on the day of fraction delivery that elicit a “Pass” signal 
 
4. 
STUDY DESIGN 
4.1 
Overview and Justification for Study Design 
In light of this new technology (BgRT) and its potential to improve radiotherapy dose distribution, we 
propose a single arm prospective study to optimize FDG dosing, assess the performance of the PET 
imaging subsystem for BgRT treatment planning and delivery, including its role as an interlock, and to 
validate the dose delivery performance of the end-to-end BgRT workflow.  
As described in section 1.5, this clinical evidence is intended to supplement and enhance technical 
validation studies of BgRT delivery which include, but are not limited to, in silico simulations and physical 
phantom measurements. As such, the patient population selected for this investigation is meant to 
optimally represent the spectrum of cases, with respect to motion and radiographic environment, that a 
radiation oncologist may encounter in practice. As described previously, patients with lung and bone 
tumors are specifically selected so that diverse omnidirectional motion profiles and different tumor-to-
background PET contrasts can be evaluated in the investigation.  
This is a single-arm, open-label, prospective study. The study will be divided into sequential cohorts of 
patients with one targetable metastatic lesion in either the lungs or bone (Figure 3). Patients with multiple 
metastases can be accrued, but these investigations will focus on only one lesion per patient.  

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Figure 3: Study Flowchart  
1Baseline assessments and CT Simulation should be collected within two weeks prior to the RefleXion PET Imaging-only session (Visit 2). Baseline assessments and 
CT Simulation completed as SOC within this period do not need to be repeated for study purposes. 
2 within 72±24 hours after the PET Imaging-only session 
3 within 72±24 hours after final FDG administration 
 
4.2 
Cohort I: RRFD Cohort 
This cohort will seek to identify the Recommended RefleXion FDG dose (RRFD), which is the dose of 
administered FDG – within a range concordant with the American College of Radiology and Society of 
Pediatric Radiology Practice Parameter for Performing PET/CT in Oncology (ACR-SPR Practice Parameter) 
– that allows for functioning of the RefleXion system15. Keeping ALARA principles in mind, this phase of 
the investigation seeks to optimize the balance between minimizing patient exposure to the radiotracer 
and achieving satisfactory performance of the RMRS PET subsystem for BgRT. This cohort will also seek to 
assess RMRS PET imaging performance in comparison to a third-party diagnostic PET/CT. 
To that end, dose levels of 15 mCi and 20 mCi (if required) will be assessed sequentially in an escalation 
protocol. Patients with at least one known FDG avid tumor (i.e. SUVmax≥6 on diagnostic PET/CT) in the 
bone or lung will be enrolled into this cohort. These patients will undergo a CT simulation in an acceptable 
radiotherapy treatment position and with immobilization devices as needed. After acquisition of (4D)CT 
images, contours for targets, OARs, and BTZ will be generated by the investigator. Next, the patient will 
undergo back-to-back PET scans on the RefleXion device and a third-party diagnostic PET/CT device after 
a single injection of FDG at the studied FDG dose level (in the unlikely event that the third-party diagnostic 
PET/CT scan cannot be initiated within 180 minutes of the FDG injection, the scan can be completed with 
a separate FDG injection 24 to 96 hours after the initial FDG injection). Quantitative metrics will be 
collected (described below) for each lesion in order to assess the performance of the RMRS PET subsystem 

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at that dose. This sequence of events is reflected in Figure 4. Actual delivery of radiotherapy to the patient 
is not part of this investigation.  
  
 
Figure 4. Cohort I schematic 
Primary Objective:  
The objective of this cohort study is to determine the lowest dose among candidate doses of administered 
[18F]-FDG that results in the Activity Concentration necessary for BgRT functioning: 5 kBq/ml or higher. 
An adequate Activity Concentration is the key parameter necessary for BgRT performance and is also the 
most sensitive quantity to FDG injection. It is calculated from the BTZ volume and includes activity from 
both the target and the enclosed background. To determine the RRFD, a modified 3+3 design will be 
utilized wherein meeting the Activity Concentration threshold – not dose-limiting toxicity as is typically 
used – will be the relevant criteria for escalating from one dose to the next (Figure 5). 
The first subjects will receive 15 mCi [18F]-FDG.  If the Activity Concentration in 2 of the first 3 patients is 
<5kBq/ml, accrual to this cohort will stop and the next cohort will receive 20 mCi [18F]-FDG.  If the Activity 
Concentration in 2 or more of the first 3 patients is >5kBq/ml, accrual in the 15 mCi cohort can continue. 
If the Activity Concentration in at least 5 of 6 patients at this cohort is >5kBq/ml, 15 mCi will be considered 
the RRFD.  If the Activity Concentration in two or more subjects at this cohort is <5kBq/ml, the subsequent 
group will receive 20 mCi [18F]-FDG, and an identical accrual schema will be followed for this group. Each 
dose-level will aim to have equal numbers of bone and lung tumors once all 6 subjects are accrued. 
 
 
Figure 5. Modified 3+3 Design 

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The initial FDG injection dose of 15 mCi was selected based on the internal analysis of prospective trial 
data sponsored by RefleXion Medical8, design specifications, and phantom testing results. This dose 
provides a good margin for handling different patient body sizes and for assessing the validity of PET 
evaluation criteria. In order to facilitate the enrollment of a representative and relevant patient 
population, the inclusion and exclusion criteria will not impose any limitations on BMI and participant 
weight will only be limited by device’s table weight limits. 
Secondary Objectives: Additional analyses of the RefleXion PET images will be performed to further assess 
the performance of the BgRT PET Imaging-only session, treatment planning and quality assurance at the 
studied dose level. Implied in these secondary objectives is that all other quantitative criteria for BgRT 
candidacy (i.e. NTS level) are met, and that the BgRT algorithm is then able to use the aggregate PET data 
to generate an acceptable BgRT plan that subsequently passes physics quality assurance. In other words, 
these endpoints comprehensively characterize the workflow through the steps that precede BgRT 
treatment delivery.     
These secondary endpoints will include the following:  
1. Percent of cases where there is agreement between a site investigator and the agreement standard 
for the BgRT PET Imaging-only session localization decision (overall percent agreement). Positive 
percent agreement and negative percent agreement will also be reported. 
2. Percent of cases where there is concordance of a positive “plan proceed” decision between the BgRT 
Imaging-only session PET and a cleared, third-party diagnostic PET/CT (positive percent agreement). 
Overall percent agreement and negative percent agreement will also be reported. 
3. Percent of cases where RefleXion PET data can be used to generate an acceptable BgRT plan such that 
relevant dosimetric parameters for the target and the nearby normal anatomy are met based on 
investigator assessment. 
4. Percent of cases where the intended dose distribution of the BgRT plan is achieved in a physical 
phantom, defined as meeting a standard gamma index for external beam radiotherapy quality 
assurance, i.e. whether 90% of pixels meet the 3mm/3% deviation standard. 
The first secondary endpoint measures inter-observer agreement for the localization decision made after 
the RMRS PET imaging session. As such, the decision made by the site investigator will be assessed against 
an agreement standard made by a panel of independent reviewers using the same RMRS PET image with 
overlaid BTZ. The two criteria required for a positive localization decision (tumor signal within BTZ, OAR 
signal outside BTZ) will be captured and reported for all observers for each case. Overall percent 
agreement will constitute the main analysis, but positive percent agreement and negative percent 
agreement will also be reported. Details of this analysis are described in section 6.2.3. 
The next secondary endpoint seeks to assess the RMRS PET image in relation to a third-party diagnostic 
PET/CT device. Importantly, the hardware architecture of the RMRS PET is not designed to have the same 
level of diagnostic performance as a dedicated, diagnostic PET/CT 16. This is an expected outcome as the 

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RMRS PET design utilizes two 90° arcs of detectors as opposed to a full 360° ring; additionally, the RMRS 
PET has a significantly shorter field of view in the patient superior-inferior direction compared to a 
diagnostic PET/CT device. These hardware limitations in the RMRS PET subsystem may result in a scenario 
where some tumors may not be visible in the RMRS PET image. However, this scenario does not pose a 
radiotherapy health risk to the patient as it would simply result in deciding that the patient is not a 
candidate for BgRT.  
Given these observations, the relevant question is whether a RMRS PET image that results in a positive 
plan proceed decision – which would result in proceeding on with the BgRT workflow – is concordant with 
a third-party diagnostic PET/CT obtained on the same encounter (positive percent agreement). Although, 
only cases with positive plan proceed decisions are clinically relevant from a BgRT workflow perspective, 
overall percent agreement and negative percent agreement will be reported to allow a more 
comprehensive view of plan proceed decision between the BgRT Imaging-only session PET and a cleared, 
third-party diagnostic PET/CT. Details of this analysis are provided in section 6.2.4.  
Dose Selection: As shown in Figure 5, the RRFD will be primarily based upon the lower FDG dose level 
where 0 to 1 failure events in the primary endpoint occur in 6 patients. If 2 or more failure events occur 
at the 15 mCi dose level, then accrual to that dose level will be stopped and subsequent patients will be 
enrolled at the next dose level (20 mCi). In the event that 2 failure events occur at the 20 mCi dose level, 
then accrual to the trial will be held and discussions with the sponsor will take place to determine if there 
is a feasible protocol amendment that would allow trial continuation. The 15mCi and 20mCi data will be 
used to extrapolate the next dose, if necessary.  
Adjudication will be done by the Safety Monitoring Committee (SMC) after every 3 patients or fewer are 
enrolled. The SMC will include individuals with pertinent expertise, including but not limited to a non-site 
radiation oncologist, site radiation oncologist and/or physicist, a RefleXion medical physician, and 
RefleXion technical staff. Finally, even if the 15 mCi dose level meets the primary endpoint for 
performance, the SMC can choose to close accrual to the 15 mCi dose level and enroll at the 20 mCi dose 
level if secondary objectives are found to be deficient at the 15 mCi dose level. Similarly, the SMC can 
choose to close accrual to the 20 mCi dose level if secondary objectives are found to be deficient. These 
analyses will be considered concurrently with the assessment of the primary endpoint.  
If an RRFD is established by meeting the statistical parameters outlined above, and there are no objections 
arising from the other analyses, then the SMC will have the discretion to open Cohort II to accrual.  
4.3 
Cohort II: Emulated Delivery Cohort 
The BgRT product design is such that when used to guide treatment delivery, the hardware instructions 
for the linear accelerator, gantry, and MLCs are determined during each fraction based upon the dynamic 
input of PET LTS images on that day. Therefore, each fraction of treatment delivery is expected to utilize 
different hardware instructions than the others. Nonetheless, each of these delivered variations and their 
individual dose volume histograms (DVHDelivered) should be reflected in the approved BgRT plan, which 
represents the spectrum of delivery possibilities (within an allowed threshold of variation) in the bounded 
dose volume histogram (bDVH).  

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The chief objective of this cohort is to confirm that the machine-deliverable fluence generated by applying 
the BgRT firing filter to PET LTS images obtained at the time of a radiotherapy delivery does in fact result 
in an anatomic dose distribution that is consistent with the approved BgRT plan. A secondary objective is 
to extend this analysis by also confirming that the linear accelerator subsystem hardware is able to deliver 
the received machine instructions. Importantly, this investigation comprehensively emulates and assesses 
(without actually delivering the radiation therapy to the patient) the entire end-to-end BgRT workflow 
from simulation to treatment planning to, finally, dose delivery. This design also provides an opportunity 
to assess imaging, workflow, and the toxicity, if any, associated with multiple administrations of FDG.  
To do this, 8 to 22 subjects dispositioned to undergo conventional SBRT for a single bone tumor or a single 
lung tumor will be enrolled. As noted previously, patients with multiple metastases can be accrued but 
the investigation will focus only one targeted lesion per patient. For each patient, RMRS PET collections 
will be added to the SBRT workflow at 3 timepoints representing the steps when the RMRS PET subsystem 
would be utilized during the BgRT workflow. Specifically, these timepoints will include a RMRS PET 
imaging-only session prior to the start of SBRT delivery that will be used to create a BgRT plan as well as 
RMRS PET collections before the first and final fractions of their planned course of SBRT (Figure 6). A single 
comparison third-party diagnostic PET/CT image will also be obtained (utilizing the same FDG injection) 
on the day of the final fraction.   
The two fractional timepoints are selected because they will capture any day to day PET variations as well 
as potential interference on the tumor PET signal arising from the radiotherapy itself. A PET collection 
prior to the start of the treatment course will not be influenced by the SBRT treatment itself, whereas the 
PET collection preceding the final fraction will be subject to the full impact of SBRT on the tumor PET 
profile.  
In order to emulate BgRT delivery, each of these fractional PET collections will consist of two phases: 
• 
Short-duration PET collection that corresponds to the duration of a PET PreScan Evaluation 
• 
Long-duration PET collection that corresponds to the duration of an active BgRT delivery fraction 
The long-duration PET collection data mimics RefleXion LTS PET image acquisition during live BgRT and 
will be used to determine the hardware instructions that would be transmitted to the RefleXion delivery 
hardware (linear accelerator, gantry, MLC, etc.) based upon the algorithmic interaction between the 
incoming LTS images and the approved BgRT treatment plan.  
 
 
Figure 6. Cohort II Patient Encounters 

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Primary Objective: The quality of each specific instance of emulated BgRT dose delivery will be validated 
in two ways. Firstly, the dose distribution resulting from the hardware instructions triggered by fraction 
timepoint LTS images will be modeled in silico on the patient’s CT anatomy. This radiotherapy dose 
distribution will be checked against the expectations of the approved BgRT plan. As such, the primary 
endpoint is the percent of radiotherapy fractions where the emulated BgRT dose distribution in silico is 
shown to be consistent with the approved BgRT treatment plan (i.e., 95% of DVHDelivered points for the BTZ 
and OARs fall within the bounded DVH of the approved BgRT plan).   
Secondary Objectives: The second test of dose distribution quality is to confirm that the machine 
instruction-set generated by the BgRT algorithm can be effectively and accurately carried out by the linear 
accelerator hardware to deliver the intended dose and distribution.  
To that end, the fluence resulting from the hardware instruction set will be delivered into a physical 
phantom in order to emulate delivery during BgRT. The dose and distribution measured in the phantom 
will be judged against in silico delivery of the same instruction set to a digital facsimile of the phantom, as 
per standard physics quality assurance methodology. 
As such, the first secondary endpoint will be the following: 
1. Percent of fractions where there is concordance between the physical and digital phantoms 
of emulated BgRT delivery derived from human subject PET emissions. Concordance is defined as a 
standard gamma index with a goal that 90% of pixels meet the 3mm/3% deviation standard.  
Collectively, these primary and secondary analyses emulate end-to-end BgRT delivery insofar as they 
enable visualization of anatomic dose distributions resulting from varying PET LTS conditions and confirm 
quality assurance and delivery of those dose distributions by the linear accelerator hardware. In this way, 
these analyses address the known limitation of human subjects research in radiotherapy device validation 
(see section 1.5), which is that dose distributions are not directly measurable in vivo.  
These two analyses of emulated delivery are graphically characterized in Figure 7 below:  
 
Figure 7. Physical and Dosimetric Validation of BgRT Plan Delivery Based upon Human-Subject Derived 
PET Data on the RefleXion System 

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To reflect clinical conditions, these analyses of BgRT dose distribution are necessarily limited to those 
fractions where BgRT would have been delivered in practice. Therefore, a dose distribution is evaluable 
for the primary endpoint if, preceding the long-duration PET collection, (1) an acceptable BgRT plan was 
approved and (2) the PET PreScan evaluation delivered a “Pass” signal. In order to obtain a total of 16 
evaluable dose distributions for assessing delivery quality in Cohort II, a minimum of 8 subjects (4 bone 
tumors and 4 lung tumors) and up to 22 subjects can be accrued. For an enrolled subject, if a PET PreScan 
delivers a “Fail” signal prior to long-duration PET collection, then the investigator can choose to repeat 
FDG administration at a subsequent treatment fraction for that subject (which again reflects clinical 
practice). If a data point is ultimately non-evaluable, then an additional patient with the same anatomic 
type of tumor can be accrued. Once a total of 16 evaluable dose distributions are acquired, Cohort II 
accrual will stop. 
The next two secondary endpoints assess the imaging performance of the PET PreScan. The first of these 
endpoints seeks to assess the inter-observer agreement for the localization decision made after each 
RMRS PreScan. A positive or negative decision on the PET PreScan will be indexed against current standard 
of care for radiotherapy tumor localization: CT-based localization. As such, whether the tumor PET signal 
is within the BTZ – which is a rigid volume defined on and registered to the patient’s CT anatomy – will 
underpin this determination. The localization decision made by the site investigator will be assessed 
against an agreement standard made by a panel of independent reviewers using the same RMRS PreScan 
images with the overlaid BTZ: 
2. Percent of cases where there is an agreement between a site investigator and the agreement standard 
for the BgRT PET PreScan localization decision (overall percent agreement). Positive percent 
agreement and negative percent agreement will also be reported. 
The next imaging secondary endpoint seeks to validate the qualitative visualization of the tumor and OARs 
on the PreScan against an established reference standard. To establish this concordance, a third-party 
diagnostic PET/CT scan following the RMRS PET acquisitions obtained prior to the last fraction.  
3. Percent of cases where there is concordance of a positive localization decision between the short-
duration PET PreScan and a third-party diagnostic PET/CT scan (positive percent agreement). Overall 
percent agreement and negative percent agreement will also be reported. 
Details of these two imaging analyses are described in section 6.3.8 and 6.3.9. Of note, these endpoints 
will not be limited to only those cases that are evaluable for the primary endpoint. Nonetheless, 
interpretation of the results of this analysis should bear in mind that the clinically meaningful localization 
decisions are the positive ones because they would prompt BgRT external beam delivery; negative 
localization decisions at the RMRS PET PreScan would result in aborting BgRT delivery in clinical practice.  
A fourth secondary endpoint is to measure toxicity arising from multiple administrations of FDG. As 
described in detail in the IB, the theoretical risk is minimal given first principles of radiation exposure and 
reassuring animal and human studies of very high-dose FDG administrations. This secondary endpoint will 
seek to further confirm safety by assessing the organs most likely to be affected by repeat FDG 
administrations:  

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4. Safety of multiple FDG administrations and toxicity rates of bladder and bone marrow assessed by 
complete blood count, urinalysis and AEs specific to bladder and bone marrow determined by 
Common Terminology Criteria for Adverse Events (CTCAE) v5 at 72±24 hours after final FDG injection. 
 
Finally, characterization of the different steps in the workflow and the robustness of the PET Evaluation 
pre-delivery will be assessed to better characterize RefleXion system functioning. This data will be 
collected for all enrolled subjects regardless of the evaluability of their BgRT dose distributions: 
5. Workflow characterization: 
a. Percent of PET imaging sessions at RRFD that meet BTZ activation concentration threshold for 
BgRT (5 kBq/ml)  
b. Percent of PET imaging sessions that lead to acceptable BgRT plans, with acceptability based upon 
meeting user-defined coverage goals for tumor targets and avoidance goals for OARs 
c. Percent of approved BgRT plans that go on to pass physics quality assurance as defined by 90% of 
pixels meet the 3mm/3% deviation standard.  
d. Percent of PET PreScan Evaluations on the day of fraction delivery that elicit a “Pass” signal.  
For each of these conversion assessments, the constituent metrics underling the outcomes will be 
recorded. For example, the underlying measurements for the PET PreScan Evaluation (i.e., Activity 
Concentration, NTS level, predicted DVH, predicted 3D dose distribution, and calculated agreement 
between the predicted DVH and bounded DVH) will be recorded for each assessment.  
Additional exploratory analysis for Cohort II may include pairwise dosimetric comparison of the BgRT and 
SBRT plans for each lesion. When additional time-paired third-party images are available, they may be 
compared to RMRS PET images and a qualitative assessment may be performed. 
 
5. 
STUDY POPULATION 
5.1 
Selection Criteria 
5.1.1 
Inclusion Criteria 
1. Age greater than 21 years 
 
2. A new or prior diagnosis of biopsy-proven cancer with a solid tumor (non-hematologic, non-
lymphoma) 
 
3. At least one active tumor in the bone or lung which is either the primary tumor or metastatic lesion 
determined either by biopsy or imaging suspicious of active disease 
 
4. Target tumor size  ≥2cm and ≤5cm 

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5. Target lesion in the bone or lung that is discrete and assessed by investigator to be FDG-avid (i.e. 
SUVmax≥6 on third-party diagnostic PET/CT performed within 60 days with no new intervening 
oncologic therapies)  
6. ECOG Performance Status 0-3  
7. Must have completed any other oncologic therapies at least 15 days prior to planned start of study 
procedures (preferably 30 days) and must have no plans to initiate systemic therapy until after study 
follow up is complete -OR- must be recorded by physician to have an active candidate lesion that is 
unresponsive to ongoing systemic therapy 
8. Females of childbearing potential should have negative urine or serum pregnancy test within 14 
days prior to initiation of study scans. 
9. Demonstrate adequate organ function: 
a. Absolute neutrophil count (ANC) > 1,500 /mcL 
b. Platelets > 50,000 / mcL 
c. Hemoglobin > 8 g/dL 
d. No gross hematuria 
10. For Cohort II only: Patient is dispositioned to undergo SBRT to a bone or lung tumor 
 
5.1.2 
Exclusion Criteria 
1. Clinically significant blood glucose abnormalities that preclude a satisfactory FDG PET/CT scan. 
2. Previous history of external radiotherapy where prior radiotherapy fields are anticipated to 
overlap with the radiotherapy fields required for the present study. 
3. Diffuse metastatic process (leptomeningeal disease, peritoneal carcinomatosis, diffuse bone marrow 
involvement, etc.) 
4. PET-avid structures not intended for radiation are within 2cm from target on third-party diagnostic 
PET/CT as assessed by investigator 
5. Known allergy to FDG 
6. Known psychiatric or substance abuse disorder that would interfere with conduct of the study 
7. Pregnant, breast-feeding or expecting to conceive during the study 
8. Patient weight exceeding the weight limit outlined per IFU 

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9. For Cohort II only: Patients with pacemakers and other implantable devices who are deemed to be at 
high risk by the treating physician for complications secondary to radiotherapy  
10. For Cohort II only: Patients with bone lesions who are determined to be high risk by the treating 
physician for pathologic fracture prior to beginning radiotherapy   
11. For Cohort II only: Active inflammatory bowel disease, scleroderma, or other disorder deemed to be 
a risk factor for excess toxicity in the area of treatment by the treating physician. 
5.2 
Withdrawal and Replacement of Subjects 
While study withdrawal is discouraged, subjects may withdraw their consent at any time, with or without 
reason and without prejudice to further treatment. Subject’s withdrawal of consent must be documented. 
Withdrawn subjects will not undergo any additional follow-up, nor will they be replaced. 
Subjects whose imaging sessions do not adhere to the sequence and timing defined in the protocol (see 
section 6. Study Procedures) may be replaced at the discretion of the investigator in consultation with 
the SMC. The reasons for not adhering could be due to patient choice or due to scheduling issues 
or device operation delays with the RefleXion or third party PET/CT equipment. All subjects will be 
accounted for in the study tables and all subject data will be reviewed by the SMC.  
 
5.3 
Enrollment Controls 
Enrollment will be monitored to ensure that no more than the maximum planned number of subjects is 
enrolled. An electronic data capture system will be used, and the system will be set to automatically notify 
the Project Manager and/or CRA of all subject enrollments being entered within the system. Study sites 
will be notified as enrollment nears maximum allowed. 
 
6. 
STUDY PROCEDURES 
6.1 
Written Informed Consent 
Written Informed Consent must be obtained for all subjects who are screened and meet the general 
inclusion/exclusion criteria prior to enrollment.  
The subject or the subject’s Legally Authorized Representative (LAR) will be asked to sign the Informed 
Consent form before any study-specific tests or procedures are performed. The Informed Consent Form 
(ICF) must be approved by the study Institutional Review Board (IRB). Electronic informed consent 
procedures may be utilized if approved by the IRB and consistent with FDA guidance on use of electronic 
informed consent in clinical investigations. Study personnel should explain that even if a subject agrees to 
participate in the study and signs an Informed Consent Form, imaging or other tests may demonstrate 
that the subject is not a suitable candidate for study participation/treatment. All subjects that have signed 

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the ICF, met all study eligibility criteria (and none of the exclusion criteria), and present for the RefleXion 
Imaging-only session will be considered enrolled at the time of FDG administration. 
A Screening and Enrollment Log will be maintained by the site to document basic information such as date 
screened and reason for screen failures for subjects who fail to meet the study eligibility criteria. Screen-
failed subjects and their reason(s) for screen failure will be documented and may be entered into the 
electronic database, but they will not be followed beyond the screening visit, and no further data will be 
collected/recorded. 
Investigator and/or study personnel at the site will review the study requirements with the subject to 
maximize compliance with the follow-up schedule. Study personnel will instruct subjects to return for 
study assessments per Study Event Schedule for the applicable cohort the patient is enrolled in. 
6.2 
Cohort I: RRFD Cohort 
6.2.1 
Baseline Visit 
The following baseline data should be collected within two weeks prior to the Imaging-only PET session 
for all subjects enrolled in Cohort I and documented in the case report form (CRF): 
• 
Confirmation that all inclusion criteria and none of the exclusion criteria are met. 
• 
Demographics, medical history and physical exam 
• 
Complete Blood Count (CBC) 
• 
Comprehensive Metabolic Panel (CMP)  
• 
ECOG performance status 
• 
Blood glucose 
• 
Urinalysis 
• 
Pregnancy test (required for women of child-bearing potential only; within 14 days prior to the 
initiation of study scans.)   
For patients undergoing systemic therapy at the time of enrollment, decisions regarding whether to 
continue the systemic therapy or undergo a wash-out will be made by the treating physician in 
accordance with standard of care for combining radiation and drug therapy. 
Additionally, a Sim CT should be obtained within two weeks prior to the PET Imaging-only session if not 
already planned to be obtained as standard of care. Any additional institutional guidelines must be 
followed regarding negative pregnancy testing in patients about to undergo radiation therapy. 
 
 
 

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6.2.2 
PET Imaging-Only Session, BgRT Treatment Planning, and Quality Assurance  
All subjects enrolled in Cohort I will undergo a PET Imaging-only session including a single injection of the 
applicable FDG dose. Standard-of-care Sim CT images of subjects who are dispositioned to have SBRT will 
be collected and utilized for the PET Imaging-only session. For subjects who do not have a Sim (4D)CT 
within two weeks prior to the PET Imaging-only session and are not planned to undergo a Sim-CT for SBRT 
(e.g. follow-up patients), a Sim (4D)CT obtained as a part of the study protocol within two weeks prior to 
the PET Imaging-only session will be utilized. The images from the Sim-CT will be used to outline structures 
necessary for treatment planning including target volumes, organs-at-risk, and the biology-tracking zone.  
Once the structures have been delineated and imported into the RefleXion treatment planning system, a 
BgRT plan is initiated, and the patient can return to the site to undergo passive PET collection on the RMRS 
system (the PET Imaging-only session). The patient will undergo FDG injection in accordance with standard 
diagnostic PET/CT protocols. Prior to FDG injection, patients should be fasting for 4-6 hours. A blood 
glucose measurement will be obtained prior to FDG injection to confirm a level less than or equal to 200 
mg/dL. Patients will be rescheduled should the blood glucose value exceed this threshold. After injection 
the patients should be resting in the uptake area for 60 minutes (±15min).   
After the uptake period, patient set-up will include positioning patients on the RefleXion system couch in 
the treatment position, followed by immobilization (if necessary) and rough alignment using lasers and 
tattoos. A localization kVCT scan will be performed for refining anatomical alignment in the region of 
interest and to localize the treatment target area. Sim CT images will be registered with the kVCT to 
propagate contoured volumes. Specifically, the BTZ will be overlaid digitally on the kVCT images once 
positioning is completed. A RMRS PET Imaging-only session will then be performed over the 12-20 minutes 
depending on the size of region of interest. The resulting PET dataset will be transmitted to the RefleXion 
treatment planning workstation.  
Immediately following the RMRS PET imaging session, subjects will be imaged again with a third-party 
PET/CT in the same treatment position. A second dose of FDG will not be administered for the scan 
immediately following the RMRS PET Imaging-only session. Sites will make every effort to minimize the 
time between two scans. To ensure adequate FDG activity, third-party PET scan will be initiated within 
180 minutes after the FDG injection. In the unlikely event that third-party PET scan cannot be initiated 
within 180 minutes, third-party scan can be completed with a separate FDG injection 24 to 96 hours after 
the initial FDG injection in the same treatment position as per the RMRS PET scan. 
Data collected during the RMRS PET Imaging-only and third-party PET/CT scans will be documented on 
the appropriate CRF and will include the time of FDG injection, start and end times for RMRS PET and 
third-party diagnostic PET/CT scans. Sites will be provided with instructions for how images should be 
collected and submitted to RefleXion Medical within five days of the PET Imaging-only session. AEs will be 
assessed by using Common Terminology Criteria for Adverse Events (CTCAE) v5 at 72±24 hours after the 
end of PET Imaging-only session. 
After the Imaging-only PET dataset is transmitted to the RefleXion treatment planning workstation, BgRT 
treatment planning can be completed with dose calculation and optimization employing the BgRT 

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algorithm as described in the BgRT User Manual. Scoring of a successful BgRT plan requires positive 
localization at the RMRS device during the PET Imaging-only session; reaching the necessary quantitative 
thresholds (i.e. Activity Concentration and NTS); and meeting coverage goals for target and avoidance 
goals for OARs. In Cohort I, physician intent, which includes radiotherapy dose and coverage goals, should 
match institutional practice for ablative radiation for the tumor type and anatomic region being targeted. 
Dose constraints are recommended to follow NRG Oncology guidelines. As in conventional radiotherapy 
planning, dose, fractionation, and volume modifications are allowed if such changes are in accordance 
with institutional practice for the clinical scenario. Similarly, changes to the BTZ volume are allowed at the 
time of planning. However, the original BTZ must be utilized for the primary endpoint and secondary 
imaging endpoints described in section 6.2.3 and 6.2.4 since those endpoints precede treatment planning. 
The BgRT plan is considered to be successfully completed when approved by physics and the treating 
physician.  
The BgRT physics quality assurance process verifies that the treatment planning system calculated dose 
in a phantom is equal to the measured dose in the phantom.  Once the BgRT plan is ready (optimization 
and dose calculation are completed and the plan quality meets desired treatment objectives) a 
Verification Plan is generated in the treatment planning system as described in the BgRT User Manual.  As 
is common practice, this QA plan is generated by taking the calculated treatment plan fluence and 
projecting the fluence in a forward dose calculation onto the CT image of an ArcCHECK phantom. The QA 
plan is then delivered to the ArcCHECK phantom.  Upon completion of the dose delivery, the accuracy of 
the plan delivery can be assessed by comparing the dose in the phantom calculated by the treatment 
planning system with the actual measured dose in the phantom using gamma analysis software provided 
with the ArcCHECK phantom. 
  
 

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Table 1: Cohort I- Study Event Schedule 
 
Screening 
&Baseline1 
 
PET Imaging-Only 
Session 
Follow-Up 
(72±24 hours after the 
PET Imaging-only 
session) 
Informed Consent2 
x 
 
 
Demographics, 
Medical History & 
Physical Exam 
x 
 
 
CBC 
x 
 
 
CMP 
x 
 
 
Blood glucose 
x 
x 
 
Urinalysis 
x 
 
 
ECOG performance 
status 
x 
 
 
Pregnancy test3 
x 
 
 
Sim CT4 
(if not done as 
standard of care) 
x 
 
 
FDG injection5 
(15mCi or 20mCi ) 
 
x 
 
RMRS PET w/ kVCT 
localization4,5 
 
x 
 
Third-party 
diagnostic PET/CT4,5 
 
x 
 
AE Assessment6 
 
x 
x 
1 Baseline Assessments should be completed within 14 days prior to the PET Imaging-only session 
2 Informed consent is not considered a baseline assessment and has no requirement to be completed within a specific 
time window from study visits 
3Women of child-bearing potential only; within 14 days prior to the initiation of the study scans. 
4Images should be de-identified before submitting to RefleXion Medical.  
5 In the event that third-party PET scan cannot be initiated within 180 minutes of original FDG injection, then the 
third-party scan can be completed with a separate FDG injection 24 to 96 hours after the initial FDG injection. 
6AEs to be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5 
 
6.2.3 
Schema for Cohort I Secondary Endpoint #1: RMRS Image Inter-Observer Agreement 
6.2.3.1 The first read will occur at the clinical study site and will be the localization decision by a site 
Investigator as part of the planned clinical workflow. This comparison will check the decision 
that is made after investigator review of the RMRS PET image against an agreement standard. 

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6.2.3.1.1 
The site investigator (radiation oncologist) will be presented with the RMRS PET 
image obtained at the PET Imaging-only session. The contours of the sim CT-
defined biology-tracking zone (BTZ) will be presented on the RMRS PET image, 
which was acquired after anatomic registration of the sim CT with the RMRS 
localization kVCT. The site investigator will make a localization decision in 
accordance with the BgRT workflow.  
6.2.3.1.2 
The localization decision will be “Yes” if (a) the PET tumor signal is fully within the 
BTZ and (b) OAR and non-target PET signal(s) are outside the BTZ. Each of these 
two criteria will be recorded for each case. If either criterion is not met, then the 
localization decision will be “No”. The site investigator localization decision will 
be logged for comparison to an agreement standard.  
6.2.3.2 The second read will be to create the determination of an Agreement Standard to match 
against the localization decision of a site Investigator. This will be conducted offline at an 
independent center and will be done by a panel of readers.   
6.2.3.2.1 
Three radiation oncologists will be selected. All the readers will be trained using 
identical training data set and image review software programs as detailed in the 
image review charter (IRC). Readers will be blinded to reader evaluations, patient 
diagnosis and other clinical data.  
6.2.3.2.2 
The RMRS PET will be transferred to a workstation for image viewing and image 
registration. Readers will be presented with the RMRS PET image obtained at the 
Imaging-only session. The contours of the biology-tracking zone (BTZ) 
radiotherapy structure will be presented throughout the reading process using 
the same registration process as 6.2.3.1.  
6.2.3.2.3 
Each reader makes a localization decision as “Yes” if (a) the PET tumor signal is 
fully within the Biology Tracking Zone (BTZ) and (b) Organ-at-risk (OAR) and non-
target PET signal(s) are outside the BTZ. Each of these two criteria will be 
recorded. If either criterion is not met, then the localization decision will be “No”. 
6.2.3.2.4 
If reader 1 and reader 2 both rate the localization decision the same, then no 
third reader is required. 
6.2.3.2.5 
If reader 1 and reader 2 are in a disagreement, then a third reader who is masked 
to the first two reads will perform an independent read as a tie breaker. Two 
agreeing out of the three read results will be selected as the Agreement Standard.   
6.2.3.3 Inter-observer agreement between the site investigator (SI) and the agreement standard 
(AS) will be calculated as follows: 

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1. If both SI and AS localization decisions are “yes” then the rating should be “A” 
2. If SI decides “yes” for localization but AS decides “no” then the rating should be “B”.  
3. If SI decides “no” for localization but AS decides “yes” then the rating should be “C”. 
4. If both SI and AS localizations decisions are “no” then the rating should be “D”.  
6.2.3.4 Based on the rating performed in above section for inter-observer agreement, an overall, 
positive and negative % agreement will be calculated.  
Percent overall agreement = (A+D)/(A+B+C+D) {main analysis} 
Percent positive agreement = A/(A+C) 
Percent negative agreement = D/(D+B) 
 
6.2.4 
Schema for Cohort I Secondary Endpoint #2 - RMRS PET vs Diagnostic PET/CT Comparison:  
6.2.4.1 The comparison of the PET image from the RMRS imaging-only session and the third-party 
diagnostic PET/CT will be conducted and descriptive statistics including positive and negative 
percent agreement will be provided as outlined below.  
The positive percent agreement analysis seeks confirmation of RMRS findings in clinically 
relevant cases based on an affirmative scoring of two questions which correspond to the plan 
proceed decision. For the two questions, FDG-avid targets or organs are defined qualitatively as 
discrete structures with visually discernable FDG-PET signal above immediate background. The 
two questions are: 
• 
Q1 (target avidity): Is there an FDG-avid target that correlates to the tumor location on 
the registered CT image? 
• 
Q2 (confounding non-target signal): Are FDG-avid organs an adequate distance away (≥1 
cm) from the FDG-avid tumor for biology-guided radiotherapy?  
It should be noted that cases that do not meet these criteria on the RMRS PET imaging-only 
session do not create a radiotherapy health risk, since the result is that the physician will not 
choose to use BgRT as the treatment modality. Nonetheless, the overall percent agreement and 
negative percent agreement will also be reported to allow for comprehensive imaging 
comparison with the third-party, diagnostic PET/CT.  
Although calculation of the agreement endpoint will be based on the qualitative questions 
above (Q1 and Q2), data on target avidity and non-confounding target signal in relationship to 
the CT-defined, overlaid biological tracking zone (BTZ) will also be collected: 

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• 
Q3: Does the FDG-avid target fall within the BTZ? 
• 
Q4: Do all FDG-avid OARs fall outside the BTZ? 
6.2.4.2 As described previously, after each PET Imaging-only session on the RMRS PET, the patient 
undergoes sequential PET imaging on a cleared, 3rd party diagnostic PET/CT system.  
6.2.4.3 The RMRS PET, localization kVCT, Sim CT & third-party diagnostic PET/CT images will be 
transferred to a workstation after the completion of imaging sessions for offline image 
viewing. These images will be reviewed by two separate groups of image reviewers blinded 
to the other device. 
6.2.4.4 RMRS PET review: Three radiation oncologists will assess the RMRS PET images 
independently. All the readers will be trained using an identical training data set and image 
review software programs as detailed in the image review charter (IRC). Readers will be 
blinded to patient diagnosis, reader evaluations, images from the compared device (i.e. 
third-party diagnostic PET/CT), but not to the localization kVCT obtained on the RMRS device 
on the same day, Sim CT and other clinical data.  
6.2.4.4.1 
Each reader answers the same set of questions for rating whether the patient is 
suitable for BgRT planning. A positive plan proceed decision requires a “yes” to 
both Question 1 and Question 2 above. A negative decision is any other 
combination of answers to the two questions.  
6.2.4.4.2 
Individual read results will be compared to the agreement standard. A case rating 
will also be collected based upon agreement of two or of the three read results. 
6.2.4.5 Third-party Diagnostic PET/CT review: Three radiologists and/or nuclear medicine 
physicians with significant PET/CT experience will assess the third-party diagnostic PET/CT 
images independently. All the readers will be trained using an identical training data set and 
image review software programs as detailed in the image review charter (IRC). Readers will 
be blinded to patient diagnosis, reader evaluations, images from the compared device (i.e. 
RMRS PET and RMRS kVCT for localization) but not Sim CT and other clinical data.  
6.2.4.5.1 
Each reader answers the same set of questions for rating whether the patient is 
suitable for BgRT planning. A positive decision requires a “yes” to both Question 
1 and Question 2 above. A negative decision is any other combination of answers 
to the two questions.  
6.2.4.5.2 
Two or more agreeing out of the three read results will be selected as the case 
rating. Individual read results will also be provided. 
6.2.4.6 Based on the decisions performed in the above sections, the following table will be 
constructed for each RMRS PET reader individually and for the case rating collectively.  Tables 
will be used to provide descriptive statistics for agreement as described below 

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Plan Proceed Decision 
RMRS PET Positive 
RMRS PET Negative 
Diagnostic PET Positive 
A 
B 
Diagnostic PET Negative 
C 
D 
 
Percent positive agreement = A/(A+C) {Main analysis for clinically relevant cases} 
Percent negative agreement = D/(B+D) 
Percent overall agreement = (A+D)/(A+B+C+D) 
 
6.3 
Cohort II: Emulated Delivery Cohort 
The primary objective of this cohort is to determine whether BgRT dose distributions generated from 
Limited Time Sample (LTS) PET images obtained at the time of treatment delivery are consistent with the 
approved BgRT plan. To achieve this objective, RMRS PET scans will be added to the SBRT workflow at 
timepoints representing some of the instances when the RMRS PET subsystem would be utilized during a 
BgRT workflow. Specifically, subjects will undergo RMRS PET collections at the time of planning, and then 
before the first and final fractions of their planned course of SBRT treatment (Figure 8).  
 
 
 
Figure 8. Cohort II Patient Encounters (Duplicated from above). 
 
6.3.1 
Baseline Visit 
The following baseline data should be collected within two weeks prior to RMRS PET Imaging-only 
session for all subjects enrolled in Cohort II and documented in the case report form (CRF): 
• 
Confirmation that all inclusion criteria and none of the exclusion criteria are met. 
• 
Demographics, medical history and physical exam 
• 
Complete Blood Count (CBC) 
• 
Comprehensive Metabolic Panel (CMP)  
• 
Blood glucose 
• 
Urinalysis 

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• 
ECOG performance status 
• 
Baseline assessment of bladder and bone marrow with CTCAE grading 
• 
Pregnancy test (required for women of child-bearing potential only, if applicable within 14 days 
prior to the initiation of the study scans.) 
For patients undergoing systemic therapy at the time of enrollment, decisions regarding whether to 
continue the systemic therapy or undergo a wash-out will be made by the treating physician in 
accordance with standard of care for combining radiation and drug therapy. 
Additionally, a Sim CT should be obtained within two weeks prior to the PET Imaging-only session if not 
already planned to be obtained as standard of care. Any additional institutional guidelines must be 
followed regarding negative pregnancy testing in patients about to undergo radiation therapy. 
6.3.2 
Radiation Therapy Intent and Planning 
Each patient enrolled in Cohort II will have been deemed an SBRT candidate by the investigating physician. 
Physician intent including selection of radiation prescription and treatment planning for SBRT will be done 
as per institutional practice. To create a parallel BgRT plan, patients will also undergo an RMRS PET 
Imaging-only session as described in Section 6.3.4; this entails a visit that includes a single FDG injection 
of RRFD; setting up the patient on the RMRS couch; undergoing one kVCT scan to ensure alignment with 
the patient’s Sim CT; and then a passive collection of the PET emissions by the RMRS. The final step of the 
planning process is physics quality assurance of the SBRT and BgRT plans, respectively. This sequence is 
detailed below.  
6.3.2.1 Radiation Therapy Guidelines  
Radiotherapy will be performed according to best practices. Machine-level quality assurance should 
be performed per its guidelines for any linear accelerator system used in the conduct of this clinical 
trial. Stereotactic body radiotherapy (SBRT), when utilized, must be performed on a cleared, 
commercial linear accelerator system.  
6.3.2.2  Radiation Prescription: Dose and Fractionation 
Radiotherapy dose planned in Cohort II will be in the range delineated below. A minimum of 24 hours is 
required between fractions and 40 hours is recommended. 
Fractions 
Recommended Dose 
3 Fractions 
15-45 Gy 
5 Fractions 
25-50 Gy 
 
6.3.2.3 CT Simulation  

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Patients will undergo CT simulation, immobilization, and image set acquisition using standard procedures 
and with the assistance of patient-customized devices for the anatomy being treated. The devices used 
for patient immobilization and setup must be compatible with the RMRS couch, as the scans on the RMRS 
device must occur with the patient in the same position as the CT simulation.  
For lung tumors, this includes a thoracic cradle, and if tolerable, a T-bar for arm positioning above the 
head. Image acquisition during CT simulation must include capture of a four-dimensional (4D) image set 
across a full respiratory cycle as well as average and maximum intensity projections (MIP) image sets. The 
use of IV contrast is encouraged when medically feasible and applicable per the investigating physician.   
For bony sites, immobilization should use a cradle at the site of the lesion. The use of (4D)CT and contrast 
(IV or oral) contrast are encouraged when medically feasible and deemed applicable by the investigating 
physician. For example, (4D)CT may be desired in the setting of a rib lesion; oral contrast may be desirable 
for bowel delineation in the setting of treatment for a pelvic osseous lesion.   
The slice thickness for the simulation CT scan used for treatment planning should follow the site’s standard 
clinical practice for SBRT to the specific treatment location.  Uniform CT slice thickness must be used. 
6.3.2.4 Target Delineation and Treatment Planning 
The treatment volume will generally consist of the Gross Tumor Volume (GTV) expanded per the treating 
physician by 3-10 mm to generate a Planning Target Volume (PTV).  
For lung tumors in the context of BgRT planning, the GTV and PTV contouring should be performed on a 
single phase of respiration. The GTV is contoured on this single phase and then expanded by 5 mm to 
generate the PTV. For the BTZ, GTV contours from all phases of respiration are first summed to generate 
an Internal GTV (IGTV) and then expanded by 8 to 20 mm to generate a BTZ. In contrast, for SBRT planning, 
GTV contours from all phases of respiration will be summed to generate the IGTV and then expanded by 
3-10 mm to generate the final prescription volume, called the internal planning treatment volume (IPTV).  
For bone tumors in the context of BgRT planning, the GTV and PTV contouring should be performed on a 
static image set or a single phase of respiration if a (4D)CT set is obtained. Again, a 5 mm expansion of the 
GTV will be used for the PTV. The BTZ will be a 8 to 20 mm expansion of the static GTV or IGTV if (4D)CT 
is used. For SBRT planning, either a static GTV contour or an IGTV, if applicable, will be expanded by 3-10 
mm to generate the final prescription volume, called the internal planning treatment volume (IPTV). 
SBRT dose calculation and optimization will be done as per institutional practice using validated treatment 
planning software. The SBRT plan must also be evaluated with a robust quality assurance protocol as per 
institutional practice with necessary procedures performed and verified by physics and the treating 
physician. Likewise, BgRT dose calculation and quality assurance are performed as described in section 
6.2.2 with one clarification: In order to be consistent with normal BgRT workflow, if the BTZ is modified 
during treatment planning then the modified BTZ should be used for timepoints that occur after treatment 
planning (i.e., time points described in 6.3.5, 6.3.6, and 6.3.7) . 

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The coverage goal for both BgRT and SBRT plans is for 95% of the prescription volume (PTV or IPTV) to 
receive 95% of the prescription dose. Dose modifications can be employed in either the SBRT or BgRT plan 
if necessary to meet OAR constraints provided that the resulting dose remains in accordance with 
institutional practice. Quality assessment of the treatment plan, both with anatomically correlated 
isodose lines and with DVH (SBRT) or bDVH (BgRT), is mandatory.  
6.3.2.5 OAR Dose Constraints 
Dose constraints should adhere to NRG guidelines for 3 and 5 fraction SBRT as described in NRG BR002.  
Planning should avoid hot spots (defined as 105% of the prescription dose) in adjacent OARs. These are 
hard constraints, and dose de-escalation is required whenever necessary to meet these constraints. For 
non-adjacent OARs, prudent planning based on the principle of ALARA should be observed. 
6.3.3 
Image Guidance Requirement 
At each imaging session or prior to any PET collection on the RMRS PET, the patient’s initial positioning 
based upon external markers must be confirmed and adjusted with the use of the on-board fan-beam 
kVCT capability of the RMRS PET. 
6.3.4 
PET Imaging-Only Session including FDG Administration 
Prior to the imaging-only session, the simulation CT and contoured structures will be imported into the 
RefleXion treatment planning system. The physician intent and plan setup for the BgRT plan will then be 
created in the treatment planning systems. Once this has been done, the BgRT plan can be initiated, and 
the patient can return for the PET Imaging-only session.   
On the day of the imaging-only session, the patient will undergo FDG injection at the RRFD dose in 
accordance with standard diagnostic PET/CT protocols. Prior to FDG injection, patients should be fasting 
for 4-6 hours. A blood glucose measurement will be obtained prior to FDG injection to confirm a level less 
than or equal to 200 mg/dL. Patients will be rescheduled should the blood glucose value exceed this 
threshold. After injection the patients should be resting in the uptake area for 60 minutes (±15min).   
After the uptake period, patient set-up will include positioning patients on the RefleXion system couch in 
the treatment position, followed by immobilization (if necessary) and rough alignment using lasers and 
tattoos. A localization kVCT scan will be performed for refining anatomical alignment in the region of 
interest and to localize the treatment target. Sim CT images will be registered with the kVCT to propagate 
contoured volumes. Specifically, the BTZ will be overlaid digitally on the kVCT images once positioning is 
completed. A RMRS PET imaging session will then be performed over the 12-20 minutes depending on the 
size of region of interest. The resulting PET dataset will be transmitted to the BgRT treatment planning 
workstation. BgRT dose calculation performed on the RMRS treatment planning system and physics 
quality assurance are then performed as described in section 6.2.2 to generate a final BgRT plan that must 
then be approved by physics and the treating physician.  
Data collected during the RMRS PET imaging-only session will be documented on the appropriate CRF and 
will include the time of FDG injection and start and end times for RMRS PET scans. Sites will be provided 
with instructions for how images and image data (e.g. contours) should be collected and submitted to 

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RefleXion Medical within five days of the PET Imaging-only session. 
6.3.5 
First Fraction of SBRT: Short-Duration PET PreScan and Long-Duration PET Collection 
Subjects enrolled in Cohort II will undergo conventional SBRT treatment on a commercial linear 
accelerator system. The investigation seeks to emulate BgRT patient set-up and treatment delivery as this 
course of SBRT is ongoing. The study procedure requires that an approved BgRT plan was generated 
previously for the relevant lesion.  
Passive collection of PET emission data will be performed prior the first SBRT fraction. On the day of PET 
data collection, the patient will undergo FDG injection at the RRFD dose in accordance with standard 
diagnostic PET/CT protocols. Prior to FDG injection, patients should be fasting for 4-6 hours. A blood 
glucose measurement will be obtained prior to FDG injection to confirm a level less than or equal to 200 
mg/dL (note: patients can be rescheduled to undergo their PET data collection at the next fraction should 
the blood glucose value exceed this threshold). After FDG is injected, the patients should be resting in the 
uptake area for 60 minutes (±15min).   
After the uptake period, patient set-up will include positioning patients on the RefleXion system couch in 
the treatment position, followed by immobilization (if necessary) and rough alignment using lasers and 
tattoos. A localization kVCT scan will be performed for refining anatomical alignment in the region of 
interest and to localize the treatment target. Sim CT images will be registered with the kVCT to propagate 
contoured volumes. Specifically, the BTZ will be overlaid digitally on the kVCT images once positioning is 
completed. 
In the BgRT delivery workflow, a short-duration PET PreScan is first conducted prior to BgRT delivery to 
confirm consistency (within tolerance thresholds) of the PET emission profile when compared to the 
original PET imaging-session used for planning. For study purposes in Cohort II, a short-duration PET 
PreScan will be obtained to emulate this workflow step. The scan will be acquired over the axial extent of 
the planned treatment region over approximately 3-5 minutes depending on BTZ size. The quantitative 
measures that would guide the PET PreScan Evaluation to be considered a “pass” or “fail” signal as 
described in section 1.3 will be collected. Next, a long-duration PET acquisition will be obtained consisting 
of four passes of the planned treatment region through the gantry over approximately 12-20 minutes, 
which emulates LTS PET data collection during live BgRT. An additional kVCT for localization may be 
performed immediately prior to the long-duration PET acquisition.  
The time window to collect this data is within 96 hours prior to the start of the first SBRT fraction; ideally 
this would be done on the same day as the SBRT fraction. Data collected before the first fraction of SBRT 
will be documented on the appropriate CRF and will include the time of FDG injection as well as start and 
end times for RMRS PET scans, and the results of the quantitative calculations based on the short duration 
PET scan.  
6.3.6 
Final Fraction of SBRT: Short-Duration PET PreScan, Long-Duration PET Collection and third-
party Diagnostic PET 

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Before the last fraction of conventional SBRT, subjects enrolled in Cohort II will undergo RMRS PET scans 
in similar fashion as prior to the first SBRT fraction (section 6.3.5), with the addition of an scan on a third 
party Diagnostic PET/CT system. As such, steps will include setting up the patient on the RMRS couch; 
undergoing kVCT scan(s) to ensure alignment with the patient’s Sim CT; and then a passive collection of 
the PET emissions by the RMRS.  
Following the short-duration PET PreScan and long-duration PET collection, subjects will be imaged again 
with a third-party PET/CT in the same treatment position. A second dose of FDG will not be administered 
for the scan following the RMRS PET session. Sites will make every effort to minimize the time between 
two scans. To ensure adequate FDG activity, third-party diagnostic PET/CT scan should be initiated within 
180 minutes after the FDG injection. In the unlikely event that third-party PET scan cannot be initiated 
within 180 minutes, third-party scan can be completed with a separate FDG injection 24 to 96 hours after 
the initial FDG injection in the same treatment position as the RMRS PET scan. 
 The time window to collect this data is within 96 hours prior to the start of the final SBRT fraction, and 
ideally would be done on the same day. Data collected at the last fraction of SBRT will be documented on 
the appropriate CRF and will include the time of FDG injection, start and end times for RMRS PET and 
third-party diagnostic PET/CT scans, and the results of the quantitative calculations based on the short 
duration PET scan. Sites will be provided with instructions for how images should be collected and 
submitted to RefleXion Medical within five days of the RMRS PET and third-party diagnostic PET/CT scans.   
Additionally, the safety of multiple FDG administrations and toxicity rates of bladder and bone marrow 
will be assessed. Complete blood count, urinalysis and AEs specific to bladder and bone marrow 
determined by Common Terminology Criteria for Adverse Events (CTCAE) v5 will be collected at 72±24 
hours after the final FDG injection. 
6.3.7 
Emulated Delivery and Analysis of collected PET Data 
Several of the endpoints require in silico and phantom analysis of the collected RMRS PET information and 
resulting BgRT external beam dose distribution that is generated by this PET information. The sponsor will 
set up a workstation at the clinical site and provide validated tools, training and procedures that will allow 
the site staff (most likely the site medical physicist) to perform the required analyses. Depending on the 
complexity, the sponsor may contract with an independent expert to conduct the analyses at a central 
location. In addition, the collected images and detailed machine log files will be provided to the sponsor 
for off-line analysis after de-identification.  Sites will be provided with instructions for how images should 
be collected and submitted to RefleXion Medical within five days of the last fraction of SBRT. 
For the in-silico dose distribution analysis, a long-duration PET scan is obtained on the day of a 
radiotherapy treatment. This PET scan is subdivided by the BgRT software into sequential LTS PET images. 
The beam station location and number of rotations required for sampling these LTS images are 
determined by the approved BgRT plan. Next, the LTS image set is inputted into the delivery algorithm to 
calculate the machine instructions for external beam delivery. The machine instructions are used to model 
delivery of their associated fluences in silico to emulate dose distribution in the patient’s CT anatomy in 
the treatment position. This emulated dose distribution is then checked to ensure that it is concordant 

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with the originally approved BgRT plan, which is established by demonstrating that 95% of the DVHDelivered 
points for the BTZ and surrounding OARs fall within the BgRT plan’s bounded DVH (see cohort II primary 
endpoint). A 3D visualization of the emulated dose distribution on the patient’s CT anatomy will also be 
generated.  
For physical validation, the emulated fluence (dose) from the primary endpoint analysis is utilized. 
RefleXion offline tools will convert the machine instructions into a deterministic radiotherapy (RT) plan. 
Deliverability of the plan is confirmed by comparing its resultant dose distribution, measured in a physical 
phantom, to a model of plan delivery in a digital representation (CT image) of the same phantom. A 
standard gamma index will be utilized for this confirmation with a goal that 90% of the pixels meet the 
3mm/3% deviation standard (see cohort II secondary endpoint 1). The ArcCHECK platform will be utilized 
to perform this assessment.  
 
 
 
 
 
 

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Table 2: Cohort II - Study Event Schedule 
 
Screening & 
Baseline1 
 
Planning / PET 
Imaging-only 
session 
(within 7 days 
prior to the 
first fraction of 
SBRT) 
First 
Fraction of 
SBRT 
Last 
Fraction 
of SBRT 
Follow-Up 
(72±24 
hours after 
final FDG 
administrati
on) 
Informed Consent2 
x 
 
 
 
 
Demographics, Medical 
History & Physical Exam 
x 
 
 
 
 
CBC 
x 
 
 
 
x 
CMP 
x 
 
 
 
x 
Blood glucose 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
 
 
x 
ECOG performance status 
x 
 
 
 
x 
Pregnancy test3 
x 
 
 
 
 
FDG injection4 
(RRFD based on Cohort I) 
 
x 
x 
x 
 
RMRS PET w/ kVCT 
localization 4,5 
 
x 
x 
x 
 
Third-party diagnostic 
PET/CT4,5 
 
 
 
x 
 
AE assessment6 
x 
x 
x 
x 
x 
1Baseline Assessments should be completed within 14 days prior to the PET Imaging-only session 
2Informed consent is not considered a baseline assessment and has no requirement to be completed within a specific 
time window from study visits 
3Women of child-bearing potential only, if applicable within 14 days prior to the initiation of the study scans. 
4At the last SBRT fraction timepoint, if the third-party PET scan cannot be initiated within 180 minutes of original FDG 
injection, then the third-party scan can be completed with a separate FDG injection 24 to 96 hours after the initial 
FDG injection. 
5Images should be de-identified before submitting to RefleXion Medical. Type of RMRS PET acquisition (short-
duration, long-duration, etc.) as per written protocol.  
6AEs to be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5. In Cohort II, directed grading 
for bladder and bone marrow toxicity will be completed at baseline and 72±24 hours after final FDG administration. 
 

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6.3.8 
Schema for Cohort II Secondary Endpoint #2: RMRS PreScan Image Inter-Observer 
Localization Agreement 
6.3.8.1 The first read will occur at the clinical study site and will be the localization decision by a site 
Investigator. This comparison will check the decision that is being made by the investigator 
after review of the RMRS PET PreScan image against an agreement standard. 
6.3.8.1.1 
The site investigator (radiation oncologist) will be presented with the RMRS PET 
PreScan images. The contours of the sim CT-defined biology-tracking zone (BTZ) 
will be presented on the RMRS PET image, which was acquired after anatomic 
registration of the sim CT with the RMRS localization kVCT. The site investigator 
will make a localization decision in accordance with the BgRT workflow.  
6.3.8.1.2 
The localization decision will be “Yes” if (a) the PET tumor signal is fully within the 
BTZ, and (b) OAR and non-target PET signal(s) are outside the BTZ. Each of these 
two criteria will be recorded for each case. If either criterion is not met, then the 
localization decision will be “No”. The site investigator localization decision will 
be logged for comparison to an agreement standard. 
6.3.8.2 The second read will be to create the determination of an Agreement Standard to match 
against the localization decision of a site Investigator. This will be conducted at an 
independent center and will be done by a panel of readers.  
6.3.8.2.1 
Three radiation oncologists will be selected. All the readers will be trained using 
identical training data set and image reviewed software programs as detailed in 
the image review charter (IRC). Readers will be blinded to reader evaluations, 
patient diagnosis and other clinical data.  
6.3.8.2.2 
The RMRS PET will be transferred to a workstation for image viewing and image 
registration. Readers will be presented with the RMRS PET PreScan images. The 
contours of the biology-tracking zone (BTZ) radiotherapy structure will be 
presented throughout the reading process using the same registration process as 
6.3.8.1.1.  
6.3.8.2.3 
Each reader makes a localization decision as “Yes” if (a) the PET tumor signal is 
fully within the BTZ, and (b) OAR and non-target PET signal(s) are outside the BTZ. 
Each of these two criteria will be recorded for each case. If either criterion is not 
met, then the localization decision will be “No”. The site investigator localization 
decision will be logged for comparison to an agreement standard. 
6.3.8.2.4 
If reader 1 and reader 2 both rate the localization decision the same, then no 
third reader is required. 

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6.3.8.2.5 
If reader 1 and reader 2 are in a disagreement, then a third reader who is masked 
to the first two reads will perform an independent read as a tie breaker. Two 
agreeing out of the three read results will be selected as the Agreement Standard.   
6.3.8.3 Inter-observer agreement between the site investigator (SI) and the agreement standard 
(AS) will be calculated as follows: 
6.3.8.3.1 
If both SI and AS localization decisions are “yes” then the rating should be “A” 
6.3.8.3.2 
If SI decides “yes” for localization but AS decides “no” then the rating should be 
“B”.  
6.3.8.3.3 
If SI decides “no” for localization but AS decides “yes” then the rating should be 
“C”. 
6.3.8.3.4 
If both SI and AS localizations decisions are “no” then the rating should be “D”.  
6.3.8.4 Based on the rating performed in above section for inter-observer agreement, an overall, 
positive and negative % agreement will be calculated.  
Percent overall agreement = (A+D)/(A+B+C+D) {main analysis} 
Percent positive agreement = A/(A+C) 
Percent negative agreement = D/(D+B) 
 
6.3.9 
Schema for Cohort II Secondary Endpoint #3: RMRS Short-Duration PreScan PET vs. 
Diagnostic PET Concordance Agreement 
6.3.9.1 The comparison of the PET PreScan image after short-duration acquisition and the third-
party diagnostic PET/CT image will be conducted and descriptive statistics including positive 
and negative percent agreement will be provided as outlined below.  
The positive percent agreement analysis seeks confirmation of RMRS findings in clinically 
relevant cases based on an affirmative scoring of two questions which qualitatively correspond 
to a positive localization decision, which is necessary in conjunction with passing quantitative 
criteria for a PreScan “Pass” signal. For the two questions, FDG-avid targets or organs are 
defined qualitatively as discrete structures with visually discernable FDG-PET signal above 
immediate background. The two questions are: 
• 
Q1 (target avidity): Is there an FDG-avid target that correlates to the tumor location on 
the registered CT image? 
• 
Q2 (confounding non-target signal): Are FDG-avid organs an adequate distance away (≥1 
cm) from the FDG-avid tumor for biology-guided radiotherapy?  

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It should be noted that cases that do not meet these criteria on the PreScan do not create a 
radiotherapy health risk, since the result is that BgRT delivery would be aborted. Nonetheless, 
overall percent agreement and negative percent agreement will be reported for a 
comprehensive imaging comparison with third-party, diagnostic PET/CT. 
Although calculation of the agreement endpoint will be based on the qualitative questions 
above (Q1 and Q2), data on target avidity and non-confounding target signal in relationship to 
the CT-defined, overlaid biological tracking zone (BTZ) will also be collected: 
• 
Q3: Does the FDG-avid target fall within the BTZ? 
• 
Q4: Do all FDG-avid OARs fall outside the BTZ? 
6.3.9.2 As described previously, after the last-fraction RMRS scans which include the PET PreScan, 
the patient undergoes third-party diagnostic PET/CT imaging.  
6.3.9.3 The RMRS short-duration PET image, localization kVCT, Sim CT, and third-party diagnostic 
PET/CT images will be transferred to a workstation for image viewing. These images will be 
reviewed by two separate groups of image reviewers blinded to the other device. 
6.3.9.4 RMRS Short-Duration PET review: Three radiation oncologists will assess the RMRS PET 
images independently. All the readers will be trained using an identical training data set and 
image review software programs as detailed in the image review charter (IRC). Readers will 
be blinded to patient diagnosis, reader evaluations, images from the compared device (i.e. 
third-party diagnostic PET/CT), but not to the localization kVCT obtained on the RMRS device 
on the same day, Sim CT, and other clinical data. 
6.3.9.4.1 
Each reader answers the same set of questions for rating whether the patient is 
suitable for BgRT planning. A positive localization decision requires a “yes” to 
both Question 1 and Question 2 above. A negative decision is any other 
combination of answers to the two questions.  
6.3.9.4.2 
Individual read results will be compared to the agreement standard. A case rating 
will also be collected based upon agreement of two or of the three read results. 
6.3.9.5 Third-party Diagnostic PET/CT review: Three radiologists and/or nuclear medicine 
physicians with significant PET/CT experience will assess the third-party diagnostic PET/CT 
images independently. All the readers will be trained using an identical training data set and 
image review software programs as detailed in the image review charter (IRC). Readers will 
be blinded to patient diagnosis, reader evaluations, images from the compared device (i.e. 
RMRS short-duration PET and localization kVCT) but not Sim CT, and other clinical data.  
6.3.9.5.1 
Each reader answers the same set of questions for rating whether the patient is 
suitable for BgRT planning. A positive localization decision requires a “yes” to 

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both Question 1 and Question 2 above. A negative decision is any other 
combination of answers to the two questions.  
6.3.9.5.2 
Two or more agreeing out of the three read results will be selected as the case 
rating. Individual read results will also be provided. 
6.3.9.6 Based on the decisions performed in the above sections, the following table will be 
constructed for each RMRS PET reader individually and for the case rating collectively.  Tables 
will be used to provide descriptive statistics for agreement as described below: 
 
Localization Decision 
Short-duration PET 
Positive 
Short-duration PET 
Negative 
Diagnostic PET Positive 
A 
B 
Diagnostic PET Negative 
C 
D 
 
Percent positive agreement = A/(A+C) {Main analysis for clinically relevant cases} 
Percent negative agreement = D/(B+D) 
Percent overall agreement = (A+D)/(A+B+C+D) 
 
7. 
DATA MANAGEMENT 
7.1 
Data Collection and Processing 
Subject data will be collected in a secure electronic data capture (EDC) system via the Internet. All 
pertinent data will be entered by the study site personnel into the electronic Case Report Forms (eCRFs).  
A unique subject ID number will be assigned to each subject.  Every reasonable effort should be made to 
complete data entry within five days of data collection. Any data discrepancies may be queried during 
ongoing review of data by RefleXion Medical personnel or its designees, or may be identified and queried 
during routine monitoring visits.  Data monitoring will be performed to verify data accuracy and ensure 
queries are resolved. The Principal Investigator or Sub-investigator must ensure the accuracy and 
completeness of the recorded data and then provide his/her electronic signature on the appropriate CRFs. 
Changes to data previously submitted to the sponsor will require a new electronic signature by the 
investigator to acknowledge/approve the changes. 
Results from independent reviewers will also be entered into the EDC system and will be electronically 
signed by the reviewer responsible for entering this data. Ongoing data review will be performed to 

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identify possible data discrepancies. Manual and/or automatic queries will be created in the EDC system 
and will be issued to responsible parties for appropriate resolution. 
 
8. 
MONITORING PROCEDURES 
8.1 
Monitoring 
Monitoring visits to the clinical sites will be made periodically during the study, to ensure that all aspects 
of the current, approved protocol/amendment(s) are followed. Original source documents will be 
reviewed for verification of data in the electronic database. The Investigator/institution guarantees direct 
access to original source documents by RefleXion Medical personnel, its designees, and appropriate 
regulatory authorities. In the event that the original medical records cannot be obtained for a subject that 
is seen by a non-study physician at a non-study institution, photocopies of the original source documents 
must be made available for review. 
It is important that the Investigator and/or relevant study site personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. In order to perform her or his role 
well, the monitor must be given access to primary subject medical records, which support the data that 
has been entered into the study CRFs. Access to Protected Health Information (PHI) by the study monitor 
will be disclosed to the subject within the Informed Consent Form. 
8.2 
Auditing 
The study may be subject to a quality assurance audit by RefleXion Medical or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Investigator and relevant study 
personnel are available during any audits and that sufficient time is devoted to the process. 
8.3 
Device Accountability 
Device accountability records must be maintained at the study site. Investigational features of the RMRS 
system (BgRT mode) will be available after all essential documents are collected, the Site Initiation Visit 
and training of all required study personnel is completed, and the site is approved to enroll. In some 
circumstances, at the discretion of the Clinical Project Manager, the investigational device availability may 
precede the Site Initiation Visit, if a site is anticipated to complete all requirements to be eligible to begin 
enrollment during the visit.  
 
Study personnel authorized to operate BgRT mode will be identified on the Delegation of Authority Log. 
The operator will be instructed and trained to utilize BgRT mode only for study subjects. Operator training 
and understanding of study requirements will be documented in the electronic Trial Master File (eTMF) 
per Study Master File Index (SMFI). The system software will ensure via login credentials that BgRT mode 
is only accessible to delegated study personnel. Additionally, the BgRT mode will display an investigational 

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device notification indicating that the use is limited by Federal law to investigational use. The operator 
will need to acknowledge the notification to be able to move forward with the BgRT mode. 
 
9. 
ADVERSE EVENTS 
9.1 
Adverse Event Definitions and Classification 
 
Term 
Definition 
Reference 
Adverse 
Event (AE) 
Any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory 
findings) in subjects, users or other persons, whether or not 
related to the investigational medical device. 
NOTE 1 This definition includes events related to the 
investigational medical device or the comparator. 
NOTE 2 This definition includes events related to the 
procedures involved. 
NOTE 3 For users or other persons, this definition is restricted 
to events related to investigational medical devices. 
ISO 14155 
Adverse 
Device Effect 
(ADE) 
Adverse event related to the use of an investigational medical 
device. 
NOTE 1 This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of 
the investigational medical device. 
NOTE 2 This definition includes any event resulting from use 
error or from intentional misuse of the investigational device. 
ISO 14155 
Serious 
Adverse Event 
(SAE) 
Adverse event that 
1. 
led to death, 
2. 
led to serious deterioration in the health of the subject, 
that either resulted in 
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or 
a body function, or 
ISO 14155 

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Term 
Definition 
Reference 
c. in-patient or prolonged hospitalization, or 
d. medical or surgical intervention to prevent life- 
threatening illness or injury or permanent 
impairment to a body structure or a body 
function, 
3. 
led to fetal distress, fetal death or a congenital 
abnormality or birth defect. 
4. 
NOTE Planned hospitalization for a pre-existing 
condition, or a procedure required by the clinical 
investigational plan, without serious deterioration in 
health, is not considered a serious adverse event. 
Serious 
Adverse 
Device Effect 
(SADE) 
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
ISO 14155 
Unanticipated 
Adverse 
Device Effect 
(UADE) 
Any serious adverse effect on health or safety or any life- 
threatening problem or death caused by, or associated with a 
device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary 
plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or 
welfare of subjects. 
21 CFR Part 
812 
 
Underlying diseases are not reported as Adverse Events (AEs) unless there is an increase in severity or 
frequency during the course of the study. Death is not an adverse event but should be reflected as an 
outcome to another specific AE. Any AE experienced by the study subject after enrollment whether during 
or subsequent to the study procedures must be collected and recorded in the (e)CRF. 
9.1.1 
Relationship of Adverse Event to the Study Device and/or Procedures 
The investigator must assess the relationship of the adverse event to the study device using the following 
criteria: 
Unrelated: the adverse event is determined to be due to a concurrent illness or effect of another 
device/drug and is not related to the investigational device. 
Possible: the adverse event is determined to be potentially related to the investigational product, and an 
alternative etiology is equally or less likely compared to the potential relationship to investigational 
product. 

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Probable: there is a strong relationship to investigational product, or recurs on re-challenge, and another 
etiology is unlikely 
Highly probable: there is no other reasonable medical explanation for the event. 
The investigator must assess the relationship of the adverse event to the study procedures using the 
following criteria: 
Unrelated: the adverse event is determined to be due to a concurrent illness or effect of another 
device/drug and is not related to the study procedure. 
Possible: the adverse event is determined to be potentially related to the investigational product, and an 
alternative etiology is equally or less likely compared to the potential relationship to the study procedure. 
 Probable: there is a strong relationship to study procedure, or recurs on re-challenge, and another 
etiology is unlikely 
Highly probable: there is no other reasonable medical explanation for the event. 
9.2 
Potential Adverse Events 
Study subjects will continue to receive standard of care treatments throughout the study, which are not 
part of study procedures. The treating physician will counsel the subjects on the risk of the treatments 
including the risk of surgery, radiation therapy and any other treatment appropriate for their type and 
stage of cancer. Toxicities commonly associated with such treatments include but are not limited to 
fatigue, nausea, vomiting, anorexia, and weight loss. Some of these symptoms can also be due to tumor 
progression.  
Adverse events related to SBRT radiotherapy for the treatment of metastases are dependent on the 
location of the metastases treated, as well as from exposure of surrounding normal tissues. Fatigue and 
skin problems such as dryness, itching, blistering or peeling is likely to occur for all treated metastases and 
should be transient, lasting < 8 weeks. Patients who are receiving standard of care radiotherapy for lung 
tumors may experience difficulty swallowing, shortness of breath, breast or nipple soreness, shoulder 
stiffness and/or radiation pneumonitis characterized by cough, fever, and fullness of the chest associated 
with radiographic infiltrate. Anticipated adverse events for bone tumor patients who are undergoing 
standard of care radiotherapy may include erythema, desquamation, alopecia, fracture, and inflammation 
in nearby organs-at-risk (i.e. esophagitis, enteritis, pneumonitis, etc.).  
Study procedure and/or FDG exposure related AE may include: 
1. 
Allergic reaction, including itching, edema and rash, as well as brief or transient hypotension 
2. 
Hypoglycemia and hyperglycemia, especially in patients with Diabetes Mellitus 
3. 
Laboratory abnormalities, including increase in alkaline phosphatase, urinanalysis abnormalities, 
and cytopenias  

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Appropriate clinical assessments will be performed as indicated to identify all AEs. AEs will be graded 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5. Signs and 
symptoms of existing disease progression will not be considered AEs. Development of new cancer after 
the inclusion of subject in the study will be considered an AE. 
9.3 
Reporting Requirements 
Event 
Classification 
Communication Method to RefleXion 
Medical 
Communication Timeline to 
RefleXion Medical 
UADE* 
Complete AE (e)CRF page including 
UADE question with all available new 
and updated information. 
Within 24 hours of first becoming 
aware of the event. 
SAE* 
Complete AE (e)CRF page including 
UADE question with all available new 
and updated information. 
Within 24 hours of first becoming 
aware of the event. 
AE 
Complete AE (e)CRF page 
As soon as possible. 
Device Failure and 
Malfunction 
Complete applicable CRF fields/pages 
with all available new and updated 
information 
Within 24 hours of first becoming 
aware of the event. 
*Note: SAEs/UADEs are reported electronically via EDC. If the EDC system is not available, the paper SAE 
Back-up form should be used for reporting and EDC should be updated once available. The SAE Back-up 
form should be sent to Medpace Clinical Safety as follows:  
Email: Medpace-safetynotification@medpace.com OR Fax: +1-513-570-5196 or +1-866-336-5320.  
9.4 
Device Failures and Malfunctions 
All RMRS device failures and malfunctions related to the investigational aspects of the device (e.g. BgRT 
functionality) shall be reported within 24 hours after becoming aware to RefleXion Medical personnel via 
data entry to appropriate eCRFs. If EDC system is not available to report device malfunction, the 
appropriate paper CRF needs to be completed with the information and faxed to the RefleXion Medical 
personnel listed in the current Study contact list provided in the Study binder. Device failures and 
malfunctions should also be documented in subject’s medical record. 
Study-applicable device failures and malfunctions should be reported on the appropriate eCRF within 24 
hours after becoming aware of event, however failures and malfunctions should not be reported as 
adverse events in and of themselves. In the event that device failure or malfunction cause an AE, the AE 
and specific event causing the AE should be reported on the appropriate eCRFs. 
All RefleXion Medical non-study device failures or malfunctions should be reported to the RefleXion 
customer service organization. 

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9.5 
Reporting to Regulatory Authorities, Institutional Review Boards and Investigators 
RefleXion Medical will code and report all verbatim adverse events to study investigators and regulatory 
authorities, as applicable. RefleXion Medical or its designees will utilize Medical Dictionary for Regulatory 
Affairs (MedDRA) to code all AEs reported in the trial. RefleXion Medical will report any UADEs to FDA as 
per Medical Device Reporting guidelines (21 CFR 803). 
The site Principal Investigator is responsible for informing the IRB of UADE, SAE and/or AEs per local 
requirements. A copy of this report should be provided to RefleXion Medical study personnel. 
Adverse events and protocol deviations along with the sites they occurred will be identified by RefleXion 
Medical in applicable reports and correspondence with FDA. 
 
10. 
RISK BENEFIT ANALYSIS  
Engineering evaluation of the RMRS has demonstrated that the safety features of the RMRS have been 
shown to be effective through testing and that the overall residual risk is considered to be within the 
clinically acceptable level. 
10.1 
Study Risk Management Procedures 
Eligibility criteria have been selected that exclude patients who are at a higher risk for experiencing an 
anticipated adverse event in order to reduce the risks to patients who participate in this study.   
Study subjects will continue to receive standard of care treatments throughout the study, which are not 
part of study procedures. The treating physician will counsel the subjects on the risk of the treatments 
including the risk of surgery, radiation therapy and any other treatment appropriate for their type and 
stage of cancer.  
Monitoring will take place throughout the study and adverse events will be recorded in the Patient’s 
charts and on Case Report Forms developed for the study.  Investigational device training will be 
conducted at each initiated study center and appropriate training records will be maintained.  
10.2 
Known and Anticipated Risks  
The study procedures may include multiple administrations of FDG. Reviews of the oncology and 
cardiology literature have not revealed known adverse reactions attributable to FDG administration aside 
from sporadic hypersensitivity reactions17. Even at multiple administrations, FDG is not expected to result 
in meaningful toxicity due to radioactivity exposure as each injection results in a total whole body dose of 
20 mSV (2000 mrem) or less18,19. Therefore, exposure from multiple administrations in the BgRT workflow 
is comparable to the annual federal limit for radiation workers (50 mSv; 5000 mrem) and is significantly 
below that experienced by patients undergoing radio-iodine therapy for thyroid disease (200 mSv; 20,000 

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mrem). In fact, the radiation exposure of the multiple FDG injections is considerably less than the 
incidental exposures experienced by patients during other routine aspects of current radiotherapy 
practice; for instance, cumulative radiation exposure originating from both daily image-guidance using 
cone beam computed tomography and from scatter dose during high-energy beam delivery meaningfully 
exceed the radiation exposure that can result from multiple FDG administrations. These observations are 
summarized in the following table:  
Table 3: Comparison of effective dose from multiple FDG administrations and other incidental radiation 
exposures from currently used procedures in conventional radiotherapy 
 
 
Approximate Effective Dose (mSv) 
2-6 FDG injections (10-20 mCi each) 
10-120 
Conventional Radiotherapy: 
30 CBCT Image-Guidance Procedures 
Up to 1000 
Conventional Radiotherapy: 
Scatter Dose from 60 Gy Prescription 
120-200 
 
This comparison of FDG dose versus incidental dose from routine aspects of current radiotherapy also 
holds true for individual organs. For example, the organ most at risk from FDG exposure, the bladder, 
receives approximately 6-12 cGy from each FDG injection (36-72 cGy in the case of 6 injections). This 
exposure is an order of magnitude below the incidental radiation that the bladder receives from a course 
of conventional prostate radiation, which can range from approximately 500 cGy to 8100 cGy, depending 
on the proximity of the portion of bladder being assessed to the prostate gland.  
This argument for tolerability, which is based upon first principles of radiation safety, is further supported 
by empiric evidence from human and animal studies. Cox et al. conducted a phase I trial of very high doses 
of FDG to determine whether the radiation emitted by FDG could be utilized for therapeutic effect20. In 
their study, three patients were given progressively higher doses of FDG (100 mCi/m2, 150 mCi/m2, and 
200 mCi/m2) with a single injection. With a median follow-up of 6 months, no dose limiting toxicities were 
observed. Notably, the third patient in the study received 400 mCi of FDG. Multiple investigations have 
utilized serial weekly FDG PET scans over a 6 week course of fractionated radiotherapy to assess early 
tumor response during treatment; although toxicity was not a formal endpoint in these imaging studies, 
nonetheless no unexpected adverse events attributable to multiple administrations of the tracer were 
reported21,22. Moadel et al. determined that the dose-limiting organ in human patients treated with high-
dose FDG would be the red marrow using the Medical Internal Radionuclide Dosimetry Formalism, and 
further determined that the tolerance dose that would result in 5% risk of red marrow suppression at 5 
years (TD 5/5) was 4760 mCi23,24. In addition to these human investigations, a number of animal studies 
of very high FDG doses (up to 6 mCi per 20 g mouse) have, to date, not resulted in any observable 
toxicity22.  

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Although this evidence and first principles of radiotherapy safety provide reassurance that multiple FDG 
administrations at a diagnostic dose are unlikely to cause measurable toxicity, nonetheless this 
investigation seeks to provide additional evidence for the safety of multiple FDG administrations. Cohort 
II will seek to capture evidence regarding the tolerability of multiple FDG administrations through 
standard grading of toxicities during therapy. Study subjects will be observed for potential FDG 
administration related toxicity and AEs related to the organs at theoretical risk, which include the bladder 
and bone marrow. These adverse events may include anemia, thrombocytopenia, bleeding, lymphopenia, 
neutropenia, hematuria, bladder spasms, transient hypotension, hypo- or hyperglycemia and/or had 
transient increases in alkaline phosphatase. 
Other potential FDG exposure related risks and mitigations include:  
• 
Overexposure of bladder to FDG, mitigated by proper hydration prior to FDG (besides fasting) and 
frequent voiding for at least one hour after completion of the procedure  
• 
Radiation exposure to nearby individuals, mitigated by limitation of exposure to others until the FDG 
decay is complete 
• 
Risk of FDG overdose, mitigated by proper documentation of FDG administration and corresponding 
radiation exposure 
In addition to FDG exposure risk, subjects will receive localization (positioning) scans with the RefleXion 
system integrated fan-beam kVCT imaging prior to each PET image collection session. The risks to the 
patient from this imaging procedure are expected to be in accordance with the general risks of low-dose 
radiation exposure, including the long-term risk of secondary malignancy. 
 
11. 
STUDY COMMITTEES  
11.1 
Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) consisting of individuals with pertinent expertise (including but not 
limited to a non-site radiation oncologist, site radiation oncologist and/or physicist, RefleXion Medical 
physician and RefleXion Medical technical staff) will be formed. Responsibilities of the committee are 
outlined in the SMC charter and will include oversight of the overall conduct of the study with regard to 
study progress, ensuring subject safety and overall data quality and integrity. The SMC will be responsible 
for assessing Cohort I data to identify and confirm the RRFD in the context of the primary endpoint 
(achieving the minimum activity level in the treatment target area [BTZ]) according to the modified 3+3 
design outlined in Figure 5. Additionally, the SMC will review Cohort I secondary analyses and has the 
discretion to consider the performance of the studied FDG dose in the context of secondary endpoints. If 
at the RRFD, the performance of emulated BgRT delivery meets statistical parameters for success in the 
primary endpoint and there are no objections arising from the other secondary analyses, then the SMC 
will open Cohort II to accrual. Additionally, the SMC will monitor patient safety by reviewing AEs and SAEs 

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including AE onset, intensity, action taken, and outcome on a regular basis for the duration of the study 
for both cohorts.  
11.2 
 Independent Image Reviewers 
Independent image reviewers with pertinent expertise in radiation oncology and/or radiology will assess 
RMRS PET and third-party diagnostic PET/CT images in order to determine the agreement standard and 
external image concordance secondary endpoints for Cohort I and Cohort II. All the readers will be trained 
using identical training data set and image review software programs as detailed in the image review 
charter (IRC).  RMRS PET images will be read by three radiation oncologists and third-party diagnostic 
PET/CT images will be read by three radiologists. Readers will be blinded to patient diagnosis, reader 
evaluations, images from the compared device (i.e. the radiologist reviewers for the diagnostic PET/CT 
would be blinded to the patient’s RMRS PET and RMRS kVCT for localization) but not the patient’s Sim CT 
and other clinical data.  Each reader will use the applicable schema and answer the same set of questions 
to generate a positive or negative decision as outlined in Section 6. Image assessments will be directly 
entered by the central reviewers in the dedicated imaging eCRF and signed electronically. 
12. 
ETHICAL CONSIDERATIONS 
12.1 
Compliance with Good Clinical Practices (GCP) 
The investigator is responsible for ensuring the study is conducted in accordance with clinical principles 
and practices originating from the Declaration of Helsinki. The study should be conducted in accordance 
to the Good Clinical Practices (GCP) and applicable local requirements, whichever provides subjects 
greater protection. 
12.2 
Institutional Review Board 
A copy of the protocol, proposed ICF, other written subject information, including any proposed 
advertising material must be submitted to the IRB for written approval. A copy of the written IRB approval 
of the protocol and ICF must be received by RefleXion Medical before recruitment of subjects into the 
study. 
The principal investigator is responsible for submitting and, where necessary, obtaining approval for all 
subsequent amendments to the protocol, and any changes to ICF, as well as obtaining annual IRB approval 
and renewal throughout the study. The principal investigator must also notify the IRB regarding protocol 
deviations, UADEs, SAEs occurring at the site and other UADE/SAE reports received form RefleXion 
Medical in accordance to the local requirements and procedures. 
Copies of the investigator reports and all IRB approvals, including continuance of IRB approval, must be 
sent to RefleXion Medical. 
12.3 
Written Informed Consent Form 

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RefleXion Medical will provide the Study Informed Consent Form Template to the investigator to prepare 
for use at his/her site. The written Informed Consent documents should be prepared in the language(s) of 
the potential subject population. 
RefleXion and the reviewing IRB must first approve the study ICF before use. The ICF must be in alignment 
with current guidelines as outlined by the GCP guidelines, Declaration of Helsinki and International 
Conference on Harmonization (ICH). 
Prior to participating in the study, each subject must give written Informed Consent after the context has 
been fully explained to the subject in a language that is easily understood by the subject. The subject must 
be given enough time and opportunity to ask questions and have those questions answered to his/her 
satisfaction. Written Informed Consent process must be recorded appropriately by means of the subject’s, 
or his/her legal representative’s, dated signature. The consent process must be documented in the 
subject’s medical chart. 
12.4 
Amending the Protocol 
This protocol must be followed exactly and can be altered only by written amendments. Following 
appropriate approval, the revised protocol will be distributed to all participating sites. Each site must 
obtain IRB/EC approval before implementing the revised protocol. 
12.5 
Emergency Actions 
RefleXion Medical accepts the rights of the Investigator to deviate from the protocol in an emergency 
when necessary to safeguard the life or the physical well-being of a study subject. The Investigator must 
give notice of any emergency deviations and justification for the deviation to RefleXion Medical and IRB 
as soon as possible after the deviation, in any event no later than 24 hours after the emergency. 
12.6 
Protocol Adherence 
Prior to beginning of the study, the Investigator must sign the Investigator Agreement documenting 
his/her agreement to conduct the study in accordance with the protocol. The Investigator must not make 
any changes or deviate from this protocol, except to protect the life and physical well-being of a subject in 
an emergency. Each deviation from the protocol must be documented with the date and reason for the 
deviation and reported to RefleXion Medical as soon as possible, and to the IRB per local guidelines and 
regulations. 
 
 
 

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13. 
STATISTICAL CONSIDERATIONS  
13.1 
Sample Size Calculation  
13.1.1 Cohort I: RRFD Cohort 
This objective of Cohort I is to identify the Recommended RefleXion FDG Dose (RRFD). Dose levels of 15 
and 20 mCi (if necessary) will be assessed sequentially in an escalation protocol. To that end, a modified 
3+3 design will be utilized wherein meeting the activity level threshold, not dose-limiting toxicity, will be 
the relevant endpoint. The RRFD will be primarily based upon the lower FDG dose level where 5 to 6 out 
of 6 subjects have an Activity Concentration greater than 5 kBq/ml. As mentioned in section 4.2, dose 
escalation to the second dose level can also be triggered by secondary analysis of technical factors related 
to radiotherapy plan quality derived from the RMRS PET imaging data.  
The modified 3+3 design with 6 patients at the ‘Recommended RefleXion FDG Dose level’ aims to ensure 
that the observed proportion of patients below activity threshold to be less than 33%. The following table 
shows the probability of observing at most 1 of 6 below activity threshold with various true below activity 
rates: 
Probability of Observations at Most 1 of 6 below Activity Threshold 
True below activity rate 
40% 
30% 
20% 
10% 
Probability at most 1 of 
6 patients below activity 
threshold 
0.233 
0.420 
0.655 
0.886 
 
As such, either 6 patients will be accrued if 15 mCi FDG meets criteria or 9 or 12 total patients will be 
accrued if escalation to 20 mCi is required.  
Descriptive statistics will be utilized for all secondary endpoints.  
13.1.2 Cohort II: Emulated Delivery Cohort  
The purpose of Cohort II is to emulate delivery of BgRT plans based upon clinical PET data obtained on the 
RefleXion system from human subjects using the RRFD established in Cohort I.  
The primary endpoint is the percent of radiotherapy fractions where the emulated BgRT dose 
distribution in silico is shown to be consistent with the approved BgRT treatment plan (i.e., 95% 
of DVHDelivered points for the BTZ and OARs fall within the bounded DVH of the approved BgRT plan).    
As previously described in Section 4.3, a BgRT dose distribution is considered evaluable if: 
• 
The subject has successfully undergone BgRT plan creation, physics quality assurance, and plan 
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• 
A “pass” signal is achieved at the PET PreScan evaluation preceding the long-duration PET emission 
collection 
The sample size was determined a priori to represent a sufficient number of dose distributions for a robust 
sampling of BgRT deliveries under clinical conditions, including both before and after start of external 
beam radiotherapy. A sample size of 16 evaluable dose distributions from 8 to 22 subjects will be obtained 
to inform the concurrence between BgRT dose distributions and approved BgRT plan.  Assuming the 
concurrence rate by the outcomes of primary endpoint follows a binomial distribution, the sample size 
achieves cumulative probability of approximately 0.81 that at most 1 inconsistency out of 16 evaluable 
dose distributions when true inconsistency rate is 5%, as shown in below table: 
Cumulative Probability at most 1 inconsistency out of 16 evaluable distributions: 
True inconsistency rate 
40% 
30% 
20% 
10% 
5% 
Probability at most 1 non-
concurrence out of 16 assessments 
0.003 
0.026 
0.141 
0.515 
0.811 
 
Given that no prior data exists for biology-guided radiotherapy, we will report descriptive statistics for 
secondary endpoints, as defined in section 4. The summary statistics for BgRT workflow steps will be 
described for all enrolled patients including those with non-evaluable dose distributions.  
13.2 
General Consideration 
Data collected will be presented using summary tables, patient data listings, and figures (TLFs). Continuous 
variables will be summarized using descriptive statistics with the mean (standard deviation), median, 
minimum, and maximum. Categorical variables will be summarized by frequencies and percentages. TLFs 
will be presented separately for each Cohort. Cohort I will be summarized by dose level, if more than 1, 
and total. Cohorts I and II will be summarized by site of disease (bone, lung) and total. 
13.2.1 Patient Disposition 
A summary of patient disposition including patients who enrolled in the study, patients who completed 
the study, terminated study early, and the reasons for early study termination 
13.2.2 Demographics and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, gender, baseline height, and baseline body 
weight) and baseline characteristics such as ECOG PS, disease status etc. will be summarized and listed. 
Categorical characteristics (e.g., gender, ethnicity and race, ECOG) will be summarized by frequency and 
percentage. 
13.2.3 Prior and Concomitant Medications 

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Each medication will be coded to a preferred term and an Anatomic Therapeutic Classification (ATC) code 
using WHO Drug dictionary. Prior concomitant medication is defined as any medication ended prior to the 
first day of the FDG administration. The number and percentage of patients taking each prior or 
concomitant medication will be displayed by medication class, preferred term and treatment group. 
13.2.4 Safety Analyses 
Extent of FDG exposure will be summarized by number of doses, cumulative dose, any dose interruption 
and dose reduction. Safety will be assessed through AEs, changes in laboratory parameters, and vital signs. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA); AE severities will be 
graded using the CTCAE criteria.  
All AE data will be listed. Notably, actual delivery of BgRT treatment to the patient is not part of this 
investigation. All treatment-emergent AEs (TEAEs), defined as adverse events not present prior to FDG 
exposure and study procedures,  will be summarized, as follows: 
• 
All TEAEs by worst Grade 
• 
All TEAEs related to the study device and/or FDG exposure by worst Grade 
• 
All Grade 3/4/5 TEAEs 
• 
All Treatment Emergent SAEs by worst Grade 
• 
All Related Treatment Emergent SAEs related to study device and/or FDG exposure by worst Grade 
Observed and changes from baseline in laboratory values will be summarized. Laboratory values outside 
the corresponding normal ranges will be flagged in listings. 
Observed and Changes from baseline vital signs and ECOG data will be summarized similarly as laboratory 
values. 
13.2.5 Primary and Secondary Endpoints 
Continuous primary and secondary endpoints will be summarized descriptively using the mean 
(standard deviation), median, minimum, and maximum. Categorical primary and secondary endpoints 
will be summarized descriptively by frequencies and percentages. 
For Cohort I secondary imaging endpoints, agreement comparison analysis between different readers 
will also be performed. The descriptive statistics including overall, positive and negative percent 
agreement will be calculated for each endpoint. 
For categorical endpoints of Cohort II, the primary analysis will use the number of evaluable radiation 
dose distributions (Dose Volume Histograms) instead of number of subjects as the denominator under 
the assumption that all assessments are independent to each other. To evaluate the robustness of the 
primary analysis results, a sensitivity analysis will be carried out taking the within-subject correlation 
into account. 

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13.3 
Statistical Analysis Plan 
The Statistical analysis plan (SAP) will be finalized prior to database lock. Any analysis that is different 
than what is in the protocol will be described in detail in the SAP. 
 
14. 
STUDY ADMINISTRATION 
Sites will make every effort to ensure the study is conducted in compliance with GCP and all applicable 
regulatory requirements. 
14.1 
Pre-Study Documentation 
The site must complete all essential pre-study documentation prior to enrolling a subject into the study. 
The following pre-study documentation should be on file with RefleXion Medical: 
• 
Site PI’s CV and current medical license 
• 
Fully executed Clinical Trial Agreement 
• 
IRB approval of the study protocol and ICF 
• 
Documentation of a completed Site Initiation Visit 
• 
Documentation of all required study training 
• 
W-9 from site to facilitate payment 
Sites need to have written authorization/approval from RefleXion Medical to start enrolling subjects into 
the study. 
14.2 
Record Retention 
The Investigator will maintain all essential study documentation and source documentation that support 
the data in collected on study subjects in their original format and in compliance with ICH/GCP guidelines. 
Study documentation must be retained for at least two years after the last approval of marketing 
application until at least two years have elapsed after the formal discontinuation of the clinical study. 
These documents may be retained for a longer period of time by agreement with RefleXion Medical or by 
other regulatory requirements. It is RefleXion Medical’s responsibility to inform the Investigator when 
these documents no longer needed to be maintained. Investigator will take appropriate measures to 
ensure study documents are not accidentally damaged or destroyed. If for any reason, Investigator 
withdraws responsibility for maintaining essential study documents, custody must be transferred to 
another individual who will assume the responsibility and RefleXion Medical must be provided a written 
notification of the custodial change. 
 
 

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14.3 
Criteria for Suspension/Termination of a Study Site 
RefleXion Medical holds the right to suspend or terminate the study at a study site at any time during the 
course of the study if enrollment rate is significantly lower than previously projected, or if the site has 
multiple or severe protocol violations without justification or fails to implement remedial actions. 
RefleXion Medical will notify appropriate regulatory agencies regarding termination of any study sites, as 
required. 
14.4 
Criteria for Suspension/Termination of Study 
RefleXion Medical reserves the right to suspend or terminate the study but intends to only exercise this 
right for valid scientific or administrative reasons, and reasons related to protection of subjects. In the 
event of suspension or early termination of the study, RefleXion Medical will notify investigators and IRBs 
in writing. 
 
15. 
REFERENCES 
1.  
ICRU. International Commission on Radiation Units and Measurements (ICRU) Report 50 
[Internet]. [cited 2020 Jan 21];Available from: https://icru.org/home/reports/prescribing-recording-and-
reporting-photon-beam-therapy-report-50 
2.  
ICRU. International Commission on Radiation Units and Measurements (ICRU) Report 62 
[Internet]. [cited 2020 Jan 21];Available from: https://icru.org/home/reports/prescribing-recording-and-
reporting-photon-beam-therapy-report-62 
3.  
ICRU. International Commission on Radiation Units and Measurements (ICRU) Report 83 
[Internet]. [cited 2020 Jan 21];Available from: https://icru.org/testing/reports/prescribing-recording-and-
reporting-intensity-modulated-photon-beam-therapy-imrt-icru-report-83 
4.  
Gargett M, Haddad C, Kneebone A, Booth JT, Hardcastle N. Clinical impact of removing respiratory 
motion during liver SABR. Radiat Oncol [Internet] 2019 [cited 2020 Jan 16];14. Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547575/ 
5.  
Al-Ward S, Wronski M, Ahmad SB, et al. The radiobiological impact of motion tracking of liver, 
pancreas and kidney SBRT tumors in a MR-linac. Phys Med Biol 2018;63(21):215022.  
6.  
Karava K, Ehrbar S, Riesterer O, et al. Potential dosimetric benefits of adaptive tumor tracking 
over the internal target volume concept for stereotactic body radiation therapy of pancreatic cancer. 
Radiat Oncol 2017;12(1):175.  
7.  
Caillet V, Keall PJ, Colvill E, et al. MLC tracking for lung SABR reduces planning target volumes and 
dose to organs at risk. Radiotherapy and Oncology 2017;124(1):18–24.  

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8.  
Tian S, Sethi I, Yang X, et al. Characterization of Inter-Fraction 18-FDG PET Variability During Lung 
SBRT: Results of a Prospective Pilot Study. International Journal of Radiation Oncology, Biology, Physics 
2019;105(1):E536.  
9.  
Potters L, Kavanagh B, Galvin JM, et al. American Society for Therapeutic Radiology and Oncology 
(ASTRO) and American College of Radiology (ACR) Practice Guideline for the Performance of Stereotactic 
Body Radiation Therapy. International Journal of Radiation Oncology • Biology • Physics 2010;76(2):326–
32.  
10.  
McShan DL. Workflow and Clinical Decision Support for Radiation Oncology. Efficient Decision 
Support Systems - Practice and Challenges in Biomedical Related Domain [Internet] 2011 [cited 2020 Jan 
17];Available from: https://www.intechopen.com/books/efficient-decision-support-systems-practice-
and-challenges-in-biomedical-related-domain/workflow-and-clinical-decision-support-for-radiation-
oncology 
11.  
Manyam B. A review of strategies for optimizing workflow, quality improvement, and patient 
safety within radiation oncology departments [Internet]. [cited 2020 Jan 17];Available from: 
https://appliedradiationoncology.com/articles/a-review-of-strategies-for-optimizing-workflow-quality-
improvement-and-patient-safety-within-radiation-oncology-departments 
12.  
Jaffray DA, Gospodarowicz MK. Radiation Therapy for Cancer [Internet]. In: Gelband H, Jha P, 
Sankaranarayanan R, Horton S, editors. Cancer: Disease Control Priorities, Third Edition (Volume 3). 
Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2015 
[cited 2020 Aug 19]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK343621/ 
13.  
Halvorsen PH, Cirino E, Das IJ, et al. AAPM-RSS Medical Physics Practice Guideline 9.a. for SRS-
SBRT. Journal of Applied Clinical Medical Physics 2017;18(5):10–21.  
14.  
Boellaard R. Standards for PET Image Acquisition and Quantitative Data Analysis. J Nucl Med 
2009;50(Suppl 1):11S-20S.  
15.  
ACR–SPR Practice Parameter for Performing FDG-PET/CT in Oncology. :17.  
16.  
PET-CT Scanner - an overview | ScienceDirect Topics [Internet]. [cited 2020 Mar 5];Available from: 
https://www.sciencedirect.com/topics/nursing-and-health-professions/pet-ct-scanner 
17.  
021870s004lbl.pdf 
[Internet]. 
[cited 
2020 
Mar 
5];Available 
from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021870s004lbl.pdf 
18.  
Hays MT, Watson EE, Thomas SR, Stabin M. MIRD dose estimate report no. 19: radiation absorbed 
dose estimates from (18)F-FDG. J Nucl Med 2002;43(2):210–4.  
19.  
Quinn B, Dauer Z, Pandit-Taskar N, Schoder H, Dauer LT. Radiation dosimetry of 18F-FDG PET/CT: 
incorporating exam-specific parameters in dose estimates. BMC Med Imaging 2016;16(1):41.  

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20.  
Cox BW, Vallabhajosula S, Rini J, et al. A Phase I Dose Escalation Study of Targeted Radionuclide 
Therapy of Malignant Tumors Using 18F Fluorodeoxyglucose (18F-FDG): Initial Experience and Early 
Results. International Journal of Radiation Oncology • Biology • Physics 2016;96(2):E510–1.  
21.  
Hentschel M, Appold S, Schreiber A, et al. Serial FDG-PET on patients with head and neck cancer: 
Implications for radiation therapy. International Journal of Radiation Biology 2009;85(9):796–804.  
22.  
Edet-Sanson A, Dubray B, Doyeux K, et al. Serial assessment of FDG-PET FDG uptake and functional 
volume during radiotherapy (RT) in patients with non-small cell lung cancer (NSCLC). Radiotherapy and 
Oncology 2012;102(2):251–7.  
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Moadel RM, Nguyen AV, Lin EY, et al. Positron emission tomography agent 2-deoxy-2-[18F]fluoro-
D-glucose has a therapeutic potential in breast cancer. Breast Cancer Res 2003;5(6):R199-205.  
24.  
Jaini S, Dadachova E. FDG for therapy of metabolically active tumors. Semin Nucl Med 
2012;42(3):185–9.  
 
 
 

Clinical Study Protocol 
Attachment 1: IDE Study Event Schedule 
Event 
Screening & 
Baseline1 
 
PET Imaging-only  
Cohort I  
Follow-Up  
(end of study - Cohort I) 
at 72±24 hours after PET 
Imaging-only session 
First Fraction of 
SBRT 
Last Fraction of 
SBRT 
Cohort II  
Follow-Up 
(end of study - Cohort II) 
at 72±24 hours after final 
FDG administration 
Informed Consent2 
X 
 
 
 
 
 
 
Demographics, 
Medical History & 
Physical Exam 
X 
 
 
 
 
 
CBC 
X 
 
 
 
 
X (Cohort II only) 
CMP 
X 
 
 
 
 
X (Cohort II only) 
ECOG performance 
status 
X 
 
 
 
 
X (Cohort II only) 
Blood glucose 
X 
X 
 
X (Cohort II only) 
X (Cohort II only) 
X (Cohort II only) 
Urinalysis 
X 
 
 
 
 
X (Cohort II only) 
Pregnancy test3 
X 
 
 
 
 
 
Sim CT 4, 5 
X 
 
 
 
 
 
RRFD FDG injection 
 
X† 
 
X (Cohort II only) 
X ‡(Cohort II only) 
 
RMRS PET w/ kVCT 
localization 4 
 
X 
 
X (Cohort II only) 
X (Cohort II only) 
 
Third-party 
diagnostic PET/CT4 
 
X (Cohort I only) 
 
 
X (Cohort II only) 
 
AE Assessment6  
X (Cohort II only) 
X 
X (Cohort I only) 
X (Cohort II only) 
X (Cohort II only) 
X (Cohort II only) 
1Baseline Assessments should be completed within 14 days of RMRS PET Imaging-only session 
2Informed consent is not considered a baseline assessment and has no requirement to be completed within a specific time window from study visits 
3Women of child-bearing potential only; urine or serum, within 14 days prior to the initiation of the study scans. 
4Images should be de-identified before submitting to RefleXion Medical. 
5If Sim CT is not done (or planned to be done) as a part of standard of care, a Sim CT will be obtained at baseline 
6AEs to be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5. In Cohort II, directed grading for bladder and bone marrow toxicity will be completed at 
baseline and 72±24 hours after final FDG administration. 
†At the PET Imaging-only session timepoint in Cohort I, if the third-party PET scan cannot be initiated within 180 minutes of original FDG injection, then the third-party diagnostic 
PET/CT scan can be completed with a separate FDG injection 24 to 96  hours after the initial FDG injection. 
 ‡At the last fraction of SBRT timepoint in Cohort II, if the third-party PET scan cannot be initiated within 180 minutes of original FDG injection, then the third-party diagnostic PET/CT 
scan can be completed with a separate FDG injection 24 to 96 hours after the initial FDG injection.