This is a Phase 3 prospective, randomized, superiority, open-label, multi-site study. The overview of this study is as follows:

• A Screening/Baseline Period of 21 days. During this time, patients will be randomized into a 1:2 allocation of Arm A:Arm B.
• A Perioperative/Operative Phase where patients will undergo tumor resection (Arm A) or tumor resection plus GammaTile implantation (Arm B).
• An EBRT Prior to Start Period. This occurs within 10 business days prior to EBRT and Concurrent TMZ Phase.
• An EBRT and Concurrent TMZ Phase, which will begin 30 ±10 days post-surgery. EBRT (30 fractions) and TMZ will be administered up to 5 days a week for 6 weeks in Arm A, and EBRT (20 fractions) and TMZ will be administered for up to 5 days a week for 4 weeks in Arm B. TMZ will be administered at a dose of 75 mg/m2/day orally for each Arm.
• An Adjuvant TMZ Phase, which begins 28 ±7 days following the EBRT and Concurrent TMZ Phase, and is comprised of six 28-day cycles. TMZ (150-200 mg/m2/day orally) will be administered for the first 5 days of each 28-day cycle for each Arm. Tumor treating fields are allowed but are not mandated during this phase. Up to 6 additional cycles (for a total of 12) can be completed at the discretion of the Investigator.
• An Early Discontinuation/Follow-Up Phase will occur 28 ±7 days after completion of Cycle 6 of the Adjuvant TMZ Phase, regardless of the total number of cycles completed or any delays in cycle start. If fewer than six cycles are completed, the first follow-up assessment will occur 28 ±7 days after the last administered dose of adjuvant TMZ. If patient has a qualifying event requiring entrance to Early Discontinuation Phase, the first follow-up assessment will occur as soon as feasible, but within 28 days.

For any unscheduled visits, data collected should be documented in the case report form (CRF) and must include, but are not limited to, safety evaluations, survival status, and disease status.

Major Criteria Includes the Following:

Inclusion Criteria

• Patients must be ≥18 years of age.

• Have radiographic suspicion of newly diagnosed glioblastoma (GBM).

  o If final pathology reports IDH mutant glioma, then the patients found to have an IDH mutation will be followed for safety and QoL measures but will not be included in the primary and secondary comparative survival and efficacy analyses.

• Are medically and surgically appropriate for resection.

• Have an estimated Karnofsky Performance Scale (KPS) score of ≥70.

• Are able to receive standard of care treatment.

Exclusion Criteria

• A previous biopsy diagnosis other than IDH wild-type GBM.
• Have contraindications to TMZ, magnetic resonance imaging, gadolinium, or non-contrast computed tomography.
• Have multi-focal enhancing tumors that cannot be encompassed in one operative field.