Evaluation of [18F]-Fludarabine and Gadoteric Acid PET/MR Imaging in Newly Diagnosed Primary CNS Lymphoma Patients Prior to Therapeutic Intervention

The primary objective of this study is to **characterize** the cerebral distribution and uptake of **[18F]-Fludarabine** in patients with newly diagnosed primary central nervous system lymphoma, prior to any surgical, chemotherapeutic, or radiotherapeutic interventions, utilizing PET-MR imaging. This is clinically relevant as it aims to enhance the understanding of the disease's metabolic activity and distribution, potentially informing treatment planning and prognostic assessments.

Secondary objectives include a descriptive comparison of the results of **[18F]-Fludarabine PET** with: - Morphological MRI with and without **Gadolinium** injection. - Multiparametric MRI (diffusion, perfusion, and spectroscopy) acquired with PET-MRI. - Histological or cytological diagnosis results. - **[18F]-FDG PET-CT** results, focusing on the anatomical location and intensity of pathological foci, as well as tumor/healthy tissue contrast.

The clinical trial involves **patients** with newly diagnosed primary central nervous system lymphoma who have not undergone surgery, radiotherapy, or chemotherapy. The study population includes both male and female participants aged 18 years and older. Participants are required to have a high-grade CNS lymphoma diagnosis confirmed histologically or cytologically, with a contrast-enhanced intracranial mass measuring at least 1 cm in the longest axis. The **Karnofsky index** must be 40 or higher, indicating a certain level of general health status. Additionally, participants must have a creatinine clearance of at least 30 mL/min and no evidence of systemic lymphoma on [18F]-FDG PET/CT. The trial does not include a vulnerable population, and all participants must have social security affiliation, excluding AME. The sponsor has not provided information regarding the total number of participants. Participants' lifestyle considerations, such as diet and physical activity, are not specified. Key inclusion criteria include the ability to provide informed consent, either personally or through a legal representative or close relative if the patient is unable to do so.

The clinical trial is designed as a **single-center, descriptive, non-randomized, open-label, cross-sectional pilot study** to evaluate the diagnostic potential of **[18F]-Fludarabine** in patients with newly diagnosed primary central nervous system lymphoma. The primary objective is to characterize the cerebral distribution and uptake of [18F]-Fludarabine using PET-MR imaging before any surgical, chemotherapy, or radiotherapy interventions. The trial is expected to commence recruitment on December 18, 2023, and conclude by June 18, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 18 years), histological or cytological confirmation of high-grade CNS lymphoma, and a Karnofsky index of ≥ 40. The screening will also ensure the absence of systemic lymphoma on [18F]-FDG PET/CT and adequate renal function with a creatinine clearance of ≥ 30 mL/min. Following the inclusion visit, participants will attend follow-up visits for imaging assessments, including PET-MR scans to measure the standardized uptake value (SUV) of [18F]-Fludarabine in tumor lesions compared to healthy tissue. Secondary endpoints will evaluate cerebral distribution, activity-time curves, and tumor-to-healthy tissue contrast, among other imaging parameters.

The expected duration of participant involvement is aligned with the trial's overall timeline, with specific visit schedules determined by the imaging protocol. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will utilize **gadoteric acid** as an auxiliary agent for MRI contrast enhancement. The study's findings aim to provide insights into the diagnostic utility of [18F]-Fludarabine in assessing primary CNS lymphoma, potentially informing future therapeutic strategies.

The clinical trial involves the use of **Gadoteric Acid**, a chemical compound utilized as an auxiliary agent. It is administered in the form of a **solution for injection**. The route of administration is **parenteral**, which involves delivering the medication directly into the body, bypassing the digestive system. The specific dosage and frequency of administration are not detailed in the provided data. Gadoteric Acid is not a pediatric formulation and is not classified as an orphan drug. The product is identified by the European Medicinal Product number SUB07865MIG and is currently authorized for use in the trial.

The primary experimental medication in this study is **[18F]fludarabine**, a chemical compound used as a test agent. It is provided as a **solution for infusion** and is administered via **parenteral use**. This involves the infusion of the solution directly into the bloodstream. The active substance, **18F-Fludarabine**, is classified under the ATC code V09AX, which pertains to other central nervous system diagnostic radiopharmaceuticals. The product is not a pediatric formulation and is not designated as an orphan drug. The European Medicinal Product number for [18F]fludarabine is PRD11636916, and it is authorized for use in this clinical trial. The trial aims to characterize the cerebral distribution and uptake of [18F]-Fludarabine in newly-diagnosed primary central nervous system lymphomas using PET-MR imaging.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint involves the standardized measurement of tumor uptake of **[18F]-Fludarabine**. This is quantified as the Standard Uptake Value (SUV) in tumor lesions, compared to the SUV of healthy tissue, using PET images superimposed on MRI. This measurement will provide a quantitative assessment of the radiopharmaceutical uptake in the target lesions.

Secondary endpoints include a comprehensive evaluation of cerebral distribution and activity-time curves for **[18F]-Fludarabine**, as well as the contrast between tumor and healthy tissue on PET images. Additional assessments will involve measuring the maximum SUV (SUVmax) of the tumor, the tumor-to-healthy tissue ratio in PET-**[18F]-FDG**, and lesion volumes in 3D T1 MRI with Gadolinium. Other secondary endpoints include the apparent diffusion coefficient (ADC) in diffusion MRI, tumor perfusion in perfusion MRI, metabolite ratios in spectroscopy, and histological or cytological diagnosis. These endpoints will collectively provide a detailed characterization of the radiopharmaceutical's distribution and its diagnostic potential in primary CNS lymphoma.