Evaluation of diagnostic performances of 18F-FDOPA PET KInetics as biomarkers for the improvement of care of MRI Non-contrast enhanced Gliomas : a phase IIIb exploratory trial

The primary objective of this study is to assess the **diagnostic performances** of **18F-FDOPA PET Time-To-Peak (TPP)** in suspected low-grade gliomas (LGGs) without MRI contrast enhancement. The aim is to characterize aggressive lesions, which are defined as having a high histopathological grade (3 or 4) or possessing dismal molecular characteristics, such as CDKN2A/B deletion in IDH-mutant astrocytomas or molecular features of glioblastoma in IDH-wildtype gliomas. This characterization is based on pathology analyses conducted within six months post-inclusion. The clinical relevance of this objective lies in its potential to improve the diagnostic accuracy and subsequent management of patients with suspected LGGs, thereby enhancing patient outcomes.

Secondary objectives include evaluating the diagnostic performances of the **18F-FDOPA "slope"** to characterize aggressive lesions, assessing the diagnostic performances of **18F-FDOPA SUV static conventional parameters** and/or radiomics analyses associated with the TTP kinetic parameter, estimating the prevalence of aggressive forms within suspected LGGs without any MRI contrast enhancement, and determining the clinical impact of the **18F-FDOPA PET kinetic TTP parameter**. These secondary objectives aim to provide a comprehensive understanding of the diagnostic capabilities and clinical implications of 18F-FDOPA PET in the context of non-contrast enhanced gliomas.

The clinical trial focuses on participants diagnosed with **Low Grade Glioma**. The study population includes both male and female subjects, aged between 18 and 75 years, who are in a general health condition classified as WHO grade ≤2. Participants were selected based on the identification of a unifocal brain tumor at initial diagnosis, with no contrast enhancement on MRI, and suspected to be a low-grade glioma. The trial does not involve a vulnerable population. Participants must have undergone an MRI within three weeks prior to inclusion, which includes conventional morphological sequences. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified as part of the selection criteria. Key inclusion criteria include the requirement for participants to be affiliated with or beneficiaries of a social security plan, and to have provided informed consent after receiving comprehensive information about the research. The trial aims to assess the diagnostic performance of 18F-FDOPA PET Time-To-Peak in characterizing aggressive lesions in suspected low-grade gliomas.

The clinical trial is designed to evaluate the diagnostic performance of **18F-FDOPA PET** kinetics as biomarkers for the improvement of care in patients with suspected low-grade gliomas (LGGs) that do not exhibit contrast enhancement on MRI. This is a phase IIIb exploratory trial, employing a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to span from April 2023 to August 2026, with participant involvement lasting up to six months from the time of inclusion.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age between 18 and 75 years, WHO general condition ≤2, and the presence of a unifocal brain tumor suspected to be a LGG. The initial MRI must be performed within three weeks prior to inclusion. Following the screening, participants will receive an intravenous injection of **Dopacis 90 MBq/mL**, a solution for injection containing the active substance **fluorodopa (18F)**, to assess the time-to-peak (TTP) parameter of the PET scan. Subsequent follow-up visits will monitor the sensitivity, specificity, and predictive values of the TTP and other kinetic parameters, with the primary endpoint being the characterization of aggressive lesions.

The end-of-study visit will occur within six months post-inclusion, during which pathology analyses will be conducted to confirm the histopathological grade or molecular characteristics of the lesions. Participants may be terminated early from the study if they experience adverse reactions, withdraw consent, or if the investigator deems it necessary for safety reasons. The trial aims to provide valuable insights into the use of **18F-FDOPA PET** in the management of LGGs, potentially leading to improved diagnostic and therapeutic strategies.

The clinical trial involves the use of **Dopacis 90 MBq/mL**, a **solution for injection** containing the active substance **fluorodopa (18F)**. This experimental medication is administered intravenously. The dosage is calculated based on the patient's weight, with a maximum daily dose of 2 MBq/kg and a maximum total dose of 2 MBq/kg. The treatment period is limited to a single administration. The use of Dopacis in this trial is specifically for patients with suspected low-grade glioma without contrast on MRI, who are scheduled for biopathology analysis within six months. This application is outside the current marketing authorization indications.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The trial focuses solely on the diagnostic performance of the 18F-FDOPA PET kinetics as biomarkers. Participant compliance with the dosing schedule is monitored through standard clinical trial procedures, ensuring adherence to the protocol and accurate data collection.

Efficacy in this clinical trial will be assessed by evaluating the diagnostic performance of **18F-FDOPA PET** kinetics as biomarkers for the characterization of aggressive lesions in suspected low-grade gliomas (LGGs) without MRI contrast enhancement. The primary endpoints include the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the **18F-FDOPA** kinetic Time-To-Peak (TTP) parameter. These metrics will be used to identify aggressive lesions defined by high histopathological grades or unfavorable molecular characteristics.

Secondary endpoints will further assess the sensitivity, specificity, PPV, and NPV of the **18F-FDOPA** kinetic "slope" parameter, as well as conventional parameters such as SUVmax, SUVmean, and SUVpeak. Additionally, radiomics analysis associated with the TTP kinetic parameter will be evaluated. The trial will also determine the proportion of aggressive lesions as an instantaneous prevalence and calculate the number of patients required to diagnose an aggressive lesion using the **18F-FDOPA** kinetic TTP parameter. These assessments will be conducted on patients referred for biopsy or surgery within six months of the initial diagnosis.