GammaTile and Stupp in Newly Diagnosed GBM

Inclusion Criteria:

1. All patients must be ≥ 18 years of age

2. Histopathological and molecular confirmation of newly diagnosed GBM using IDHmutation testing (such as immunohistochemistry for IDH1 R132H) must be performed aspart of SOC. A central lab will perform cytogenetics testing. Note: In patientswithout prior biopsy, diagnosis will be suspected preoperatively, but must beconfirmed by molecular testing (i.e., must be IDH wild type). Patients withconfirmed pathology from biopsy prior to enrollment are able to participate if theymeet all other study requirements. Enrolled patients not ultimately confirmed tohave molecular GBM or are found to have IDH mutated tumors after resection and GTplacement (if appropriate), will be followed for safety. If tested before screening,patients known to have IDH mutated tumors should not be invited to participate orconsented/enrolled.

3. Adequate tissue for central submission to determine methylation promoter status.Patients with either methylated or unmethylated MGMT promoter status are included,and this status must be confirmed by central pathology review. Note: Patients withtissue that is insufficient or inadequate for analysis, fails MGMT testing, or hasindeterminate MGMT promoter status will receive GT (if indicated) and will be partof the ITT/safety population but will be excluded from the PP population analyses.

4. A supratentorial tumor that in the opinion of the enrolling neurosurgeon is a)amenable to attempted gross total resection (GTR) and b) has a maximum preoperativediameter of 6 cm or less when considering all tumor planned for resection (enhancingand non-enhancing). If multifocal, must be fully resectable in one operative bed.Prior diagnostic biopsy allowed. Surgical protocol will follow current institutionalstandards. If intraoperative MRI is utilized, details will be captured.

5. Able to receive 5-aminolevulinic acid (5-ALA, Gleolan) or other institutionallystandard immunofluorescent-guidance such as fluorescein, prior to surgery tooptimize GTR of enhancing tumor.

6. Patient is appropriate candidate to receive SOC treatment for newly diagnosed GBM asusually practiced (Stupp protocol with at least 6 cycles and up to 12 cycles ofTMZ).

7. Concomitant systemic or local anti-cancer medications or treatments are prohibitedin this study (with the exception of TTF) before progression.

8. Anti-angiogenic therapy (e.g., bevacizumab and its biosimilars) or steroid use isallowed for symptom management (e.g., brain edema or symptomatic pseudoprogression)as per institutional standard. Note: For both agents, utilization of the lowestuseful doses and shortest useful courses are encouraged. At failure, tumortherapeutic dose of anti-angiogenic therapy (e.g., bevacizumab and its biosimilars)or other therapies can be utilized for treatment at the investigators' discretion.

9. Karnofsky Performance Scale (KPS) score of ≥ 70.

10. Eastern Cooperative Oncology Group Performance Score (ECOG-PS) of 0-2.

11. Ability to understand and the willingness to sign (personally or by a legallyauthorized representative) the written IRB approved informed consent document priorto performance of any study-related procedures.

12. Ability to understand English or Spanish.

13. Patients must be willing and able to comply with scheduled visits, treatment plan,and laboratory tests and accessible for follow-up after treatment termination.

14. Men and women of childbearing potential must be willing to employ adequatecontraception throughout the study and for men for up to 3 months after completingtreatment.

15. Satisfactory hematology as evidenced by standard pre-surgery labs:

16. Hemoglobin ≥ 10 g/dl

17. Leukocytes ≥ 2,000/mm3

18. Absolute neutrophil count (ANC) ≥ 1,500/mm3

19. Platelets ≥ 100,000/mm3

20. Total bilirubin ≤ 2.0 x institutional/lab upper limit of normal (ULN)

21. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ≤ 2.5 x ULN

22. Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x ULN

23. Serum creatinine ≤ 1.5 x ULN OR creatinine clearance (CrCl) ≥ 50mL/min (ifusing the Cockcroft-Gault formula)

24. Absolute lymphocyte count between 1,000 and 4,800 per microliter of blood.

Exclusion Criteria:

1. Known to be IDH mutated glioma by prior biopsy.

2. Patients not appropriate for concomitant or maintenance temozolomide.

3. Previous chemotherapy or radiotherapy to the head or neck region resulting inoverlapping fields or prior surgery to the brain to resect other brain tumors.

4. Staged surgery planned (prior biopsy allowed).

5. Bilateral tumors, or multi-focal tumors that cannot be encompassed in one operativefield.

6. Enhancing extension into brainstem or thalamus, or significant invasion into thecorpus callosum that would preclude a high likelihood of GTR.

7. Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer insitu) unless disease free for a minimum of 2 years

8. Definitive clinical or radiologic evidence of cancer outside the brain (excludingnonmelanomatous skin cancer, or other types of indolent cancers) not needing activetreatment within the past 2 years. Contact the Medical Monitor to review anyinquiries on indolent cancers allowed.

9. Concomitant systemic or local anti-cancer medications or treatments in use orplanned (with the exception of TTF before progression or on protocol TMZ).

10. Planned use of adjuvant anti-angiogenic therapy (e.g., bevacizumab and itsbiosimilars) specifically for tumor treatment

11. Enrollment in another investigational study or planned use of investigationaltherapies. Note: Experimental therapies or enrollment in a subsequent study areallowed after a patient on study has a local recurrence or distant brain failure.

12. Patients with contraindication to MRI or CT

13. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to temozolomide, bovine -derived collagen, 5-ALA or otherinstitutionally standard immunofluorescent-guidance compounds, such as fluorescein.

14. Participants with severe intercurrent illness that will prohibit subsequentchemotherapy and radiotherapy including, but not limited to, unstable systemicdisease including ongoing or active infection, COVID-19, uncontrolled hypertension,serous cardiac arrythmia requiring medication, acute cardiovascular disease orclinically manifested myocardial insufficiency or history of myocardial infarctionduring the past 6 months prior to screening, severe psychiatric illness or otherillness that, in the judgment of the investigator, would make the patientinappropriate for entry into this study or interfere significantly with properassessment of safety and adverse events of the prescribed regimens.

15. Women who are pregnant or lactating. Women of child-bearing potential must have anegative urine test or serum beta human chorionic gonadotrophin (b-HCG) documentedno greater than 14 days prior to study registration unless they are surgicallysterile (e.g. oophorectomy, hysterectomy, tubal ligation) or menopausal. Menopauseis defined as 12 months of amenorrhea in a woman over 45 in the absence of possiblecauses for amenorrhea (e.g., low body fat, hormonal imbalances, etc.)

16. Any concomitant therapy (e.g., strict ketogenic diet, high dose vitamin C) that, inthe investigator's opinion, would interfere with the evaluation of the safety orefficacy of any of the study treatments.

17. History of any psychiatric condition that might impair patient's ability tounderstand or comply with the requirements of the study or to provide consent.

18. Participants who, in the investigator's opinion, are unable to understand theprotocol or to give informed consent (personally or by a legally authorizedrepresentative), have a history of poor cooperation, noncompliance with medicaltreatment, or difficulty in returning for follow up care.