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

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

Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (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.

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.

Radiation Oncology, Radiotherapy, Biology-Guided Radiotherapy (BgRT), RefleXion Medical, Radiation Therapy

This is an open-label, prospective study. The study is divided into two sequential cohorts of patients with one targetable primary or 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 seeks to identify the Recommended RefleXion FDG dose (RRFD), which is the dose of administered FDG that allows for functioning of the RefleXion system. To that end, dose levels of 15 mCi and 20 mCi (if required) are assessed sequentially in an escalation protocol. The RRFD identified in Cohort I is utilized in Cohort II, to emulate and assess the dose delivery performance of the end-to-end BgRT workflow.

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.

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.

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.

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.

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.

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.

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.

Secondary Endpoint 3 evaluated the percent of cases where X1 PET images generated an Acceptable BgRT plan.

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.

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.

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.

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.

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.

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

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.

Inclusion Criteria: Age greater than 21 years A new or prior diagnosis of biopsy-proven cancer with a solid tumor (non-hematologic, non-lymphoma) 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 Target tumor size ≥2cm and ≤5cm 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) ECOG Performance Status 0-3 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. Females of childbearing potential should have negative urine or serum pregnancy test within 14 days prior to initiation of study scans. Demonstrate adequate organ function: determined by ANC, platelets, hemoglobin, with no gross hematuria For Cohort II only: Patient is dispositioned to undergo SBRT to a bone or lung tumor Exclusion Criteria: Clinically significant blood glucose abnormalities that preclude a satisfactory FDG PET/CT scan. Previous history of external radiotherapy where prior radiotherapy fields are anticipated to overlap with the radiotherapy fields required for the present study Diffuse metastatic process (leptomeningeal disease, peritoneal carcinomatosis, diffuse bone marrow involvement, etc.) PET-avid structures not intended for radiation are within 2cm from target on third-party diagnostic PET/CT as assessed by investigator Known allergy to FDG Known psychiatric or substance abuse disorder that would interfere with conduct of the study Pregnant, breast-feeding or expecting to conceive during the study Patient weight exceeding the weight limit outlined per IFU. 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. 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. 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.