Evaluation of Metformin and Temozolomide with Radiotherapy in Newly Diagnosed IDH Wild-Type Glioblastoma Grade 4 Patients

The primary objective of this study is to assess the **progression-free survival** of patients with newly diagnosed glioblastoma (GBM) IDH wild-type OXPHOS positive, either with or without FGFR3-TACC3 gene fusion, treated with radiotherapy (RT) plus temozolomide (TMZ) combined with metformin. This is clinically relevant as it aims to determine the efficacy of this combination therapy in delaying disease progression in a highly aggressive form of brain cancer.

Secondary objectives include:

• Evaluating the overall survival (OS) of treated patients, which is crucial for understanding the long-term benefits of the treatment.
• Assessing the overall response rate, providing insights into the proportion of patients who experience a significant reduction in tumor size.
• Evaluating the safety and tolerability of metformin in association with concomitant RT-TMZ, ensuring that the treatment regimen is manageable for patients.
• Investigating metabolic changes in the tumor by MR spectroscopy, specifically the lactate peak variations under metformin treatment, to understand the biochemical impact of the therapy.
• Measuring the penetration of metformin in the tumor at recurrence when second surgery is warranted, which could inform future therapeutic strategies and dosing considerations.

The clinical trial involves participants diagnosed with **glioblastoma grade 4**, specifically newly-diagnosed histologically-confirmed supra-tentorial glioblastoma IDH wild-type. The study population includes both male and female subjects aged 18 years and older, with no vulnerable populations selected. Participants are required to have adequate bone marrow and normal hepatic function, and they must be able to start radiotherapy within 7 weeks after histological diagnosis. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have a life expectancy of at least 16 weeks and be affiliated with an appropriate health insurance system. Lifestyle considerations such as diet and physical activity are not detailed in the available data. Key inclusion criteria include substantial recovery from surgical resection and the ability to receive concomitant radio-chemotherapy according to the Stupp protocol. The trial population was selected based on these criteria, ensuring that participants are willing and able to comply with the study protocol, including treatment and scheduled visits.

The clinical trial is designed to evaluate the efficacy of combining **temozolomide** and **metformin hydrochloride** with radiotherapy in patients with newly diagnosed **glioblastoma grade 4**. This is a Phase 4, randomized, double-blind, controlled trial aimed at assessing progression-free survival as the primary endpoint, with secondary endpoints including overall survival, overall response rate, and safety profile. The trial is expected to commence recruitment on April 1, 2024, and conclude by April 1, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate bone marrow function, normal hepatic function, and a life expectancy of at least 16 weeks. Following the screening, participants will be randomized to receive either the investigational treatment or a control. The treatment phase will involve the administration of **temozolomide** and **metformin hydrochloride** in conjunction with radiotherapy, following the Stupp protocol. The maximum treatment period for **temozolomide** is 54 weeks, while **metformin hydrochloride** is administered for up to 24 weeks.

Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. These visits will include assessments of progression-free survival using the RANO criteria, as well as evaluations of overall survival and response rates. Safety assessments will focus on the type, frequency, and severity of adverse events, including hematological toxicity and hypersensitivity reactions.

The end-of-study visit will occur after the completion of the treatment phase and follow-up period, during which final assessments will be conducted to evaluate the long-term outcomes of the treatment. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial's design ensures rigorous monitoring and adherence to protocol to maintain the integrity and validity of the study results.

The clinical trial involves the administration of **Temozolomide**, marketed under the name Temodal 20 mg hard capsules. This medication is presented in the form of hard capsules and is administered orally. The active substance, temozolomide, is a chemical compound classified under the ATC code L01AX03. The maximum daily dose is 200 mg/m², with a total maximum dose of 200 mg/m² over a treatment period of up to 54 weeks. The medication is produced by Merck Sharp & Dohme B.V. and is authorized for use in the treatment of malignant glioma, specifically in combination with radiotherapy.

In addition to temozolomide, the trial includes the use of **Metformin Hydrochloride**, marketed as METFORMINE ARROW LAB 500 mg, comprimé pelliculé. This medication is provided in the form of film-coated tablets and is also administered orally. Metformin hydrochloride is a chemical compound with an ATC classification of A10BA02, commonly used as an antidiabetic agent. However, in this study, it is utilized as an auxiliary treatment to target oxidative phosphorylation in malignant glioma. The maximum daily dose of metformin is 3000 mg, with a total maximum dose of 2190000 mg over a treatment period of up to 24 weeks. The product is manufactured by Arrow Generiques.

Both medications are administered orally, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules. The trial aims to assess the progression-free survival of patients with newly diagnosed glioblastoma multiforme (GBM) IDH wild-type, treated with radiotherapy plus temozolomide combined with metformin. The study does not include a placebo or comparator treatment, as the focus is on the combination of these two active substances.

Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression Free Survival** (PFS) using the RANO criteria. This endpoint will evaluate the time during which patients with newly-diagnosed glioblastoma multiforme (GBM) IDH wild-type, treated with radiotherapy plus temozolomide combined with metformin, remain free from disease progression. Secondary endpoints include overall survival, overall response rate (ORR) as estimated by the RANO criteria, and various safety parameters such as the type, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs), as well as dose interruptions, reductions, and dose intensity.

Data collection will involve scheduled assessments at predetermined intervals throughout the study duration, with specific timepoints for efficacy evaluations not explicitly detailed. The trial will also monitor laboratory values and record several safety aspects, including hematological toxicity, hypersensitivity reactions, and digestive effects. The study aims to provide comprehensive data on the efficacy and safety of the treatment regimen in the specified patient population.