Evaluation of Troriluzole and Pegargiminase in Newly Diagnosed and Recurrent Glioblastoma: A Phase II/III Adaptive Randomization Trial

The primary objective of this study is to identify experimental therapies that improve **overall survival (OS)** for patients with **glioblastoma (GBM)** during the Screening stage (Stage 1). This involves determining if predefined patient subtypes or associated biomarkers uniquely benefit from the treatment. Additionally, the study aims to confirm the efficacy of identified experimental therapies and associated biomarker signatures in an expansion stage (Stage 2), which is designed to support a new drug application. This objective is clinically relevant as it seeks to enhance survival outcomes for GBM patients, a population with limited treatment options and poor prognosis.

Secondary objectives include:

• Evaluating **Progression Free Survival (PFS)**, duration of response, and tumor response by each biomarker/therapeutic combination.
• Assessing OS by each biomarker/therapeutic combination.
• Determining short- and long-term safety signals and quality of life (QOL) measures of an experimental arm in GBM patients versus standard of care.

The clinical trial involves a total of **1565 participants** diagnosed with **glioblastoma (GBM)**, an aggressive form of brain cancer. The study population includes both male and female subjects, aged 18 years and older, encompassing a vulnerable population. Participants were selected based on specific criteria, including a confirmed diagnosis of Grade IV GBM, either newly diagnosed or recurrent, with histological confirmation and specific imaging requirements. The trial considers lifestyle factors such as the use of dexamethasone, with a restriction of no more than 4mg per day within five days prior to randomization. Participants are required to have a Karnofsky performance status of at least 60% for newly diagnosed cases and 70% for recurrent cases, ensuring a baseline level of general health. The selection process also mandates the availability of tumor tissue from surgery or biopsy, which is crucial for the study's objectives. The trial aims to identify and confirm experimental therapies that improve overall survival for GBM patients, with a focus on predefined patient subtypes or associated biomarkers.

The clinical trial is designed to evaluate multiple regimens in patients with newly diagnosed and recurrent **glioblastoma** (GBM). This is a randomized, double-blind, controlled trial with a seamless Phase II/III response adaptive randomization platform. The trial aims to identify experimental therapies that improve overall survival for GBM patients and confirm the efficacy of these therapies in an expansion stage. The trial is expected to run from June 2021 to December 2026, with participant involvement potentially lasting up to 104 weeks, depending on the treatment regimen.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and availability of tumor tissue. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The primary endpoint is overall survival, while secondary endpoints include progression-free survival, tumor response, and duration of response. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Early termination from the study may occur if a participant experiences unacceptable toxicity, disease progression, or withdrawal of consent. The trial involves the administration of two investigational products: **Troriluzole**, administered orally in capsule form, and **ADI-PEG-20**, administered via intramuscular injection. The maximum treatment period for Troriluzole is 48 weeks, while ADI-PEG-20 may be administered for up to 104 weeks. The trial is not classified as low intervention and follows the guidelines for a Category 2 trial as per EMA disclosure rules.

The clinical trial involves the administration of **Troriluzole**, an experimental medication provided in the form of a **capsule**. The active substance, **troriluzole**, is of chemical origin and is manufactured by Biohaven Pharmaceuticals, Inc. The medication is administered orally with a maximum daily dose of 400 mg. The treatment period for Troriluzole is set to a maximum of 48 weeks. Participants' compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Another experimental treatment used in the trial is **ADI-PEG-20**, which is provided as a **powder and solvent for intramuscular injection**. The active substance, **pegargiminase**, is of biological/biotechnological origin and is produced by Polaris Group. The maximum daily dose for ADI-PEG-20 is 36 mg/m², and the treatment period extends up to 104 weeks. The administration route is intramuscular, and participant compliance will be closely monitored to ensure proper adherence to the dosing schedule.

Both experimental treatments are being evaluated for their efficacy in improving overall survival in patients with newly diagnosed and recurrent **glioblastoma**. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study aims to identify therapies that may benefit specific patient subtypes or those with particular biomarker profiles. Compliance monitoring will be an integral part of the trial to ensure accurate assessment of the treatments' effects.

Efficacy in the clinical trial will be assessed using several key endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the time from randomization to death from any cause. This will be measured to determine the effectiveness of the experimental therapies in improving survival rates for patients with Glioblastoma (GBM). Secondary endpoints include **Progression-Free Survival (PFS)**, which is the time from randomization to clinically determined progression or death from any cause, and **Tumor Response**, categorized as complete response, partial response, progressive disease, or stable disease. Additionally, the **Duration of Response** will be evaluated, defined as the time from the date of response to the date of clinically determined disease progression or death from any cause.

The trial is structured in two stages: a Screening stage (Stage 1) to identify experimental therapies that improve OS, and an Expansion stage (Stage 2) to confirm the efficacy of these therapies and associated biomarker signatures. The trial will utilize a response adaptive randomization platform to evaluate multiple regimens in newly diagnosed and recurrent GBM. The efficacy parameters will be collected and analyzed at predefined timepoints throughout the trial duration, which is estimated to conclude by December 2026.