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.

Eligibility Criteria:
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.