Phase 3 Randomized Study of Niraparib Tosilate Monohydrate vs. Temozolomide in Newly Diagnosed MGMT Unmethylated Glioblastoma

The primary objective of this Phase 3, open-label, randomized study is to evaluate whether **niraparib** significantly extends progression-free survival and overall survival compared to **temozolomide** in adult participants with newly-diagnosed, MGMT unmethylated glioblastoma. This is clinically relevant as extending survival in this patient population could represent a significant advancement in the treatment of this aggressive brain tumor.

Secondary objectives include:

• Testing whether niraparib improves objective tumor response compared with temozolomide.
• Evaluating the impact of niraparib compared to temozolomide on symptoms, function domains, and global health-related quality of life (HRQoL).
• Assessing whether treatment with niraparib is associated with better neurocognitive function over time versus temozolomide.
• Evaluating safety and tolerability in participants treated with niraparib versus temozolomide.

The clinical trial involves a total of **219 participants** diagnosed with **O6-methylguanine methyltransferase (MGMT) unmethylated glioblastoma**. The study population includes both male and female subjects, aged 18 years and older, who have been newly diagnosed with this condition. Participants were selected based on specific criteria, including a histologic confirmation of glioblastoma, a **Karnofsky performance status** of 70 or higher, and adequate organ function. The trial population is required to have normal or controlled blood pressure and must be able to swallow oral medications. Lifestyle considerations such as the use of corticosteroids are controlled, with participants needing to maintain a stable or decreased dose of dexamethasone. The trial includes individuals who have not received prior treatment for glioblastoma, except for surgical resection or biopsy. Both male and female participants must adhere to specific contraceptive guidelines to prevent pregnancy during and after the study period. The trial also involves a vulnerable population, as indicated by the inclusion of individuals who may require additional protections. The selection process ensures that participants meet all necessary health and safety standards to participate in the study.

The clinical trial is a **Phase 3**, open-label, randomized, two-arm study designed to evaluate the clinical efficacy and safety of **niraparib** compared to **temozolomide** in adult participants with newly-diagnosed, **MGMT unmethylated glioblastoma**. The trial aims to determine whether niraparib significantly extends progression-free survival and overall survival compared to temozolomide. The study is expected to commence recruitment on December 4, 2024, and conclude by April 5, 2028. Participants will be randomly assigned to receive either niraparib or temozolomide, with both medications administered orally. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as histologic documentation of glioblastoma, adequate organ function, and the ability to swallow oral medications. Participants must also have a **Karnofsky performance status** of 70 or higher and meet specific reproductive health criteria.

Following the screening, participants will undergo randomization and commence treatment, with regular follow-up visits scheduled to monitor safety, efficacy, and any adverse events. These visits will include assessments of progression-free survival, overall survival, and secondary endpoints such as overall response rate and changes in neurocognitive function. The trial will also evaluate the incidence of adverse events, treatment discontinuations, and changes in clinical laboratory results. The expected length of participant involvement is up to 63 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The end-of-study visit will occur after the completion of the treatment period or upon early termination, during which final assessments will be conducted to gather comprehensive data on the trial's primary and secondary endpoints.

The clinical trial involves the administration of **TEMOZOLOMIDE**, a chemotherapeutic agent, in the form of a hard capsule. The active substance, **temozolomide**, is of chemical origin. The medication is administered orally with a maximum daily dose of 200 mg/m². The total maximum dose is 9675 mg/m² over a treatment period of up to 8 weeks. The role of temozolomide in this study is as a comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

**NIRAPARIB TOSILATE MONOHYDRATE** is the experimental medication in this study, provided in tablet form. The active substance, **niraparib tosilate monohydrate**, is also of chemical origin. This medication is administered orally with a maximum daily dose of 200 mg. The total maximum dose is 344.40 mg over a treatment period of up to 63 weeks. Niraparib is designated as an orphan drug, with the designation number EU/3/10/760, and is being tested for its efficacy in extending progression-free and overall survival in participants with newly-diagnosed, MGMT promoter unmethylated glioblastoma. Compliance with the dosing schedule will be closely monitored to ensure accurate assessment of the drug's efficacy and safety.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include **progression-free survival** and **overall survival**. Progression-free survival is defined as the time from the date of randomization to the date of first disease progression per RANO 2.0 by BICR assessment or death from any cause, whichever occurs first. Overall survival is defined as the time from the date of randomization to the date of death due to any cause.

Secondary endpoints will evaluate the overall response rate, which is defined as confirmed complete response or confirmed partial response, as per RANO 2.0 by BICR assessment. Additionally, the trial will compare symptoms, function, and health-related quality of life (HRQoL) at baseline to specified timepoints in the schedule of assessments. Changes from baseline in neurocognitive function will be assessed using the Hopkins Verbal Learning Test, Controlled Oral Word Association, and Trail Making Test Parts A and B. The incidence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will also be monitored, along with treatment discontinuations, dose interruptions, and dose reductions due to these events. Changes in Karnofsky performance status, clinical laboratory results, and vital sign measurements will be recorded. The frequency and severity of symptomatic AEs will be evaluated based on the PRO-CTCAE.