Phase I/II Evaluation of Gadolinium-Chelated Polysiloxane Nanoparticles with Radiotherapy and Temozolomide in Newly Diagnosed Glioblastoma

The primary objective of this Phase I/II study is to evaluate the **recommended dose** of AGuIX nanoparticles in combination with radiotherapy and Temozolomide (TMZ) during the concomitant radiochemotherapy period for patients with newly diagnosed glioblastoma. This is crucial for determining the optimal dosing strategy that maximizes therapeutic efficacy while minimizing adverse effects. Additionally, the study aims to estimate the efficacy of the combination therapy, measured by the 6-month progression-free survival rate, which is a significant indicator of treatment success in glioblastoma management.

Secondary objectives include:

• Evaluating the pharmacokinetics of nanoparticles to understand their absorption, distribution, metabolism, and excretion.
• Assessing the distribution of nanoparticles and their ability to spare healthy tissues, which is vital for reducing collateral damage during treatment.
• Evaluating the safety of the combination therapy by monitoring acute and late toxicity, as well as any necessary changes in the dose and schedule of radiotherapy.
• Assessing the impact of the combination on efficacy, measured by overall survival at 6 and 12 months, response to treatment, and progression-free survival at 12 months.
• Studying potential predictive biomarkers and exploring the tumor microenvironment to identify factors that may influence treatment response and outcomes.

The clinical trial involves participants diagnosed with **newly diagnosed glioblastoma**, a grade IV brain tumor. The study population includes both male and female subjects, aged between 18 and 74 years, who are in generally good health with a Karnofsky Performance Status (KPS) of 70% or higher. Participants must have a life expectancy of at least six months and meet specific hematological and biochemical criteria, such as platelet counts of 100,000/mm³ or higher and hemoglobin levels of at least 10 g/L. The trial does not include a vulnerable population. The selection process for participants is not detailed, as the sponsor has not provided information on the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the ability to swallow and retain oral medication, stable or decreasing corticosteroid use for at least 14 days prior to inclusion, and adherence to contraception requirements for participants of childbearing potential. Participants must also provide signed informed consent and be affiliated with a social security regimen.

The clinical trial is designed to evaluate the safety and efficacy of **gadolinium-chelated polysiloxane nanoparticles** in combination with radiotherapy and Temozolomide for the treatment of newly diagnosed glioblastoma. This is a Phase I/II, randomized, double-blind, controlled study. The trial aims to determine the recommended dose of the nanoparticles during the Phase I segment and to estimate the efficacy of the combination therapy in terms of 6-month progression-free survival rate during Phase II. The trial is expected to run from March 2022 to March 2027, with participant involvement lasting approximately 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological diagnosis of grade IV glioblastoma, stable corticosteroid use, and adequate organ function. Follow-up visits will occur at regular intervals to monitor safety, pharmacokinetics, and treatment efficacy. The end-of-study visit will assess overall survival and neurological status. Participants may be withdrawn from the study if they experience dose-limiting toxicities, defined as any grade 3-4 toxicity excluding alopecia, nausea, and vomiting, or if they fail to comply with study protocols.

Key elements of the research methodology include the use of **intravenous administration** of the nanoparticles, with pharmacokinetic parameters such as Cmax, Tmax, AUC, and T1/2 being evaluated. Secondary endpoints include overall survival, objective response rate, and safety profile according to NCI CTC version 5.0 criteria. The study will also assess the distribution of nanoparticles via MRI and evaluate predictive biomarkers and tumor microenvironment. Participants are required to provide informed consent and adhere to contraception guidelines if applicable.

The experimental medication used in this clinical trial is **AGuIX**, which consists of **gadolinium-chelated polysiloxane nanoparticles**. This investigational product is formulated as a **solution for infusion** and is administered via **intravenous administration**. The primary objective of the trial is to determine the recommended dose of AGuIX in combination with radiotherapy and Temozolomide (TMZ) during the concomitant radiochemotherapy period. The study aims to estimate the efficacy of the combination radiochemotherapy plus AGuIX, measured by the 6-month progression-free survival rate in patients with newly diagnosed glioblastoma. The administration schedule and dosage are determined based on the phase of the trial, with specific dosing regimens established to ensure optimal therapeutic outcomes and participant safety.

In addition to the experimental treatment, the trial includes the use of **Temozolomide (TMZ)**, a standard-of-care therapy for glioblastoma. TMZ is administered concomitantly with radiotherapy and AGuIX during the trial. The dosing schedule for TMZ follows established clinical guidelines for its use in glioblastoma treatment, ensuring that participants receive the standard therapeutic regimen alongside the investigational product. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to assess the safety and efficacy of the treatment combination.

Efficacy in this clinical trial will be assessed primarily through the **6-month progression-free survival rate** using the RANO criteria during Phase II. This endpoint will provide a measure of the treatment's ability to delay disease progression in patients with newly diagnosed glioblastoma. Secondary efficacy endpoints include overall survival, which will be evaluated by calculating the median survival and survival rates at 6 and 12 months post-treatment initiation. Additionally, the objective response rate will be determined according to RANO criteria, and the 12-month progression-free survival rate will be assessed. Pharmacokinetic parameters such as Cmax, Tmax, AUC, and T1/2 will also be measured to understand the distribution and elimination of the nanoparticles. The distribution of nanoparticles will be evaluated through MRIs conducted after the first and last injection of AGuIX, although these MRIs will be optional for Phase II depending on the participating centers. Neurological status will be assessed clinically and using the Mini-Mental State Examination (MMSE) questionnaire, while corticosteroid intake will also be evaluated. The safety profile of AGuIX nanoparticles in combination with radiotherapy and Temozolomide will be monitored according to NCI CTC version 5.0 criteria throughout the study. Furthermore, predictive biomarkers and the tumor microenvironment will be assessed on the tumoral block used for glioblastoma diagnosis.