Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (BIOGUIDE-X) (BIOGUIDE-X)

The purpose of this study is to assess the performance and safety of Biology-Guided Radiotherapy (BgRT) using the RefleXion Medical Radiotherapy System (RMRS) via optimizing F18-Fluorodeoxyglucose (FDG) dosing, assessing the performance of the Positron Emission Tomography (PET) imaging subsystem for BgRT treatment planning and delivery, including its role as an interlock, and validating the dose delivery performance of the end-to-end BgRT workflow.

Study Overview

• Status: Completed
• Conditions: Cancer; Tumor, Solid; Cancer, Lung; Metastasis to Bone; Metastasis to Lung; Cancer, Bone
• Intervention / Treatment: Device: RMRS IDE Device

Detailed Description

The performance and safety of BgRT using the RMRS will be studied by to sequential cohorts of patients with one targetable metastatic lesion in either the lungs or bone. Patients with multiple metastases can be accrued, but these investigations will focus on only one lesion per patient.

Cohort I 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 system. Keeping ALARA ("As Low As Reasonable Achievable") 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 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 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. Quantitative metrics will be collected for each lesion in order to assess the performance of the RMRS PET subsystem at that dose. Up to 12 participant will be enrolled in Cohort I. Actual delivery of radiotherapy to the patient is not part of this investigation.

The chief objective of Cohort II 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, up 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. A single comparison third-party diagnostic PET/CT image will also be obtained on the day of the final fraction.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 the investigator to be FDG-avid (i.e. SUVmax≥6 on third-party diagnostic PET/CT performed within 60 days with no 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: 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

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort I: RRFD Cohort; Cohort I seeks to identify the Recommended RefleXion FDG dose (RRFD), which is the dose of administered FDG that allows for functioning of the RefleXion system. 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. The dose levels of 15 mCi and 20 mCi (if required) will be assessed sequentially in an escalation protocol. 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. Up to 12 participants will be enrolled in Cohort I, and will undergo one RMRS imaging session and one third-party Positron Emission Tomography (PET) /CT imaging session.	Device: RMRS IDE Device; Participants will be injected with FDG at the studied dose and will undergo imaging sessions using the RMRS IDE device and a third-party Positron Emission Tomography (PET)/CT imaging device.; Other Names: RefleXion Medical; Biology-Guided Radiotherapy (BgRT)
Experimental: Cohort II: Emulated Delivery Cohort; After the RRFD is determined by Cohort I, Cohort II enrollment will start enrollment. Cohort II seeks to determine whether BgRT dose distributions generated from Limited Time Sample (LTS) RMRS 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. Up to 22 participants will be enrolled in Cohort II, and will undergo three RMRS imaging sessions and one third-party Positron Emission Tomography (PET) /CT imaging session.	Device: RMRS IDE Device; Participants will be injected with FDG at the studied dose and will undergo imaging sessions using the RMRS IDE device and a third-party Positron Emission Tomography (PET)/CT imaging device.; Other Names: RefleXion Medical; Biology-Guided Radiotherapy (BgRT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort I Recommended RefleXion FDG Dose (RRFD) to Enable the Use of BgRT Planning.	The primary endpoint determined the number of cases that received the lowest FDG dose of 15 mCi, completed the RMRS image session and established an adequate target activity concentration to enable Biology guided Radiotherapy planning. The starting dose was 15mCi which was determined based upon preliminary physics studies done prior to this study. A FDG dose escalation to 20 mCi was not required.	During the RMRS imaging session
Cohort II: Delivery Emulation	The number of scans/fractions where the emulated BgRT dose distribution in a phantom was consistent with the BgRT treatment plan (i.e., 95% of DVH Delivered points for the BTZ and OAR fall within bounded DVH of the approved BgRT plan). There were 9 first fractions and 8 last fractions that were analyzed.	After SBRT First Fraction (standard of care) and after SBRT Last Fraction (standard of care)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort I: Endpoint 1 Percent Agreement Between SI and AS for BgRT PET Imaging-only Session	This endpoint evaluated percent of cases where there was an agreement between the site investigator SI and an Agreement Standard (AS) for the PET modeling localization decision. Six image comparisons were performed.	Immediately after RMRS imaging session
Cohort I Endpoint 2: Percent of Cases X1 PET vs. Third-party Diagnostic PET/CT Image Comparison	This endpoint evaluated Percent of cases where there was concordance of the positive "plan proceed" decision between the BgRT PET Imaging-only session and a third-party diagnostic PET/CT.	Immediately after RMRS imaging session
Cohort I Endpoint 3: Biology Guided Radiotherapy (BgRT) Plan Generation	Secondary Endpoint 3 evaluated the percent of cases where X1 PET images generated an Acceptable BgRT plan.	Immediately after RMRS imaging session
Cohort I Endpoint 4: Percent of Cases Where the Intended Dose Distribution of BgRT Plan Was Achieved in the Physical Phantom.	Secondary Endpoint 4 determined the percent of cases where the generated BgRT plan achieved acceptable quality assurance metrics in a physical phantom.	Immediately after RMRS imaging session
Cohort II Endpoint 1 Percent of Fractions With Concordance Between Physical and Digital Phantoms	Number 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.	Assessed after SBRT First Fraction (standard of care) and after SBRT Last Fraction (standard of care), reported after SBRT Last Fraction.
Cohort II Endpoint 2 Localization Decision	Number of Pre-scan images 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.	Assessed After PET Pre-Scan 1 and after PET Pre-Scan 2, reported after PET Pre-Scan 2.
Cohort II Endpoint 3 Image Concordance (Cohort II)	Number of Scans 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.	Assessed after Last fraction Imaging-only PET scan and Third-party PET/CT scan and reported after Third-party PET/CT scan.
Cohort II Endpoint 4 Toxicity Related to FDG Administrations	Number of Participants who experienced AEs related to 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.	Assessed at 72±24 hours after final FDG injection
Cohort II Endpoint 5 Workflow Characterization	Workflow characterization by; Number of participants with PET imaging-Only scans at RRFD that meet the Activity Concentration (AC) threshold for BgRT.; Number of participants with PET imaging-Only scans that generate an acceptable BgRT plans.; Number of participants with approved BgRT plans that Passed Physics Quality Assurance.	a. Immediately after RMRS imaging-Only sessions b. After acceptable BgRT plan generation c. During BgRT physics Quality Assurance
Cohort II Endpoint 5d Workflow Characterization: PET Evaluations That Elicited a "Pass" Signal	Number of PET Pre-Scans on the Day of Fraction Delivery that Elicited a "Pass" Signal Fraction Delivery.	Assessed after PET Pre-Scan 1 prior to First Fraction delivery and after PET Pre-Scan 2 prior to Last Fraction delivery, reported after PET Pre-Scan 2 prior to Last Fraction.

Collaborators and Investigators

• Sponsor: RefleXion Medical
• Investigators: Principal Investigator: Daniel Chang, MD, Stanford University; Principal Investigator: Aurelie Garant, MD, UT Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2021
• Primary Completion (Actual): December 20, 2021
• Study Completion (Actual): December 20, 2021

Study Registration Dates

• First Submitted: March 4, 2021
• First Submitted That Met QC Criteria: March 4, 2021
• First Posted (Actual): March 9, 2021

Study Record Updates

• Last Update Posted (Actual): October 31, 2023
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Radiotherapy; Radiation Therapy; Radiation Oncology; Biology-Guided Radiotherapy (BgRT); RefleXion Medical
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Lung Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: 985-00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes