Focused Ultrasound Blood-Brain Barrier Disruption for the Treatment of High-Grade Glioma in Patients Undergoing Standard Chemotherapy

Inclusion Criteria:

1. Age between 18 and 85 years, inclusive.

2. Able and willing to provide written informed consent.

3. Diagnosis of Glioblastoma by histology or molecular markers based on WHO 2021classification.

4. Previously undergone a maximal safe surgical resection and completed concurrent,standard-of-care RT and TMZ without any complications and deemed eligible for themaintenance phase of TMZ treatment.

5. Tumor or tumor resection cavity is clearly defined on screening MRI scans.

6. Karnofsky Performance Score rating 70-100.

7. American Society of Anesthesiologists (ASA) physical status score of 1-3.

8. Life expectancy of at least 3 months and able to attend all study visits.

Exclusion Criteria:

1. Patients presenting with the following imaging characteristics: i. Following steroid treatment, brain edema and/or mass effect that causes midlineshift or shift in wall of the third ventricle of more than 10 mm. ii. Evidence of recent (less than 2 weeks) intracranial hemorrhage. iii.Calcifications in the FUS sonication beam path in the event system tools cannottailor the treatment around these calcification spots.

2. The sonication pathway to the tumor involves: i. More than 30% of the skull area traversed by the sonication pathway is covered byscars, scalp disorders (e.g., eczema), or atrophy of the scalp. ii. Clips or other metallic implanted objects in the skull or the brain, exceptshunts.

3. The subject presents with symptoms and signs of increased intracranial pressure (e.g., headache, nausea, vomiting, lethargy, and papilledema).

4. Patients requiring increasing doses of corticosteroids.

5. Patient receiving bevacizumab (Avastin) therapy.

6. Patients with ≥25% increase in volume of contrast enhancement at time of assessmentfor study enrollment, compared with their first postoperative MRI. This cut-off isused to differentiate between pseudoprogression (which can occur following bothradiation and TMZ therapy) and true tumor progression. This will be furtherascertained through a discussion between the study neurosurgeons and radiologists.

7. Patients undergoing other concurrent therapies such as chemotherapy wafers,immunotoxins delivered by convection-enhanced delivery, regionally administered geneand viral therapies, immunotherapies, and focal irradiation with brachytherapy,stereotactic radiosurgery, and laser interstitial thermotherapy. These regimens havebeen shown to cause contrast enhancement in the resection cavity boundary, which canbe difficult to differentiate from true tumor recurrence.

8. Cardiac disease or unstable hemodynamics including: i. Documented myocardial infarction within six months of enrollment. ii. Unstableangina on medication. iii. Congestive heart failure. iv. Left ventricular ejectionfraction <50%. v. History of a hemodynamically unstable cardiac arrhythmia. vi.Cardiac pacemaker.

9. Severe hypertension (diastolic blood pressure (DBP) > 100 on medication).

10. Anti-coagulant therapy, or medications known to increase risk of hemorrhage withinwashout period prior to treatment (i.e., antiplatelet or vitamin K inhibitoranticoagulants within 7 days, non-vitamin K inhibitor anticoagulants within 72hours, or heparin-derived compounds within 48 hours of treatment).

11. History of a bleeding disorder, coagulopathy or with a history of spontaneous tumorhemorrhage.

12. Abnormal level of platelets (< 100,000) or INR > 1.3.

13. Documented cerebral infarction within the past 12 months.

14. TIA in the last 1 month.

15. Cerebral or systemic vasculopathy.

16. Insulin-dependent diabetes mellitus that is not well-controlled or that in theInvestigator's opinion precludes participation in the study.

17. Known sensitivity to gadolinium-DTPA.

18. Known sensitivity to DEFINITY® ultrasound contrast agent or perflutren.

19. Contraindications to MRI such as non-MRI-compatible implanted devices, unable totolerate an MRI due to for instance pain or claustrophobia, untreated, uncontrolledsleep apnea.

20. Positive pregnancy test (for pre-menopausal women).

21. Known life-threatening systemic disease.

22. Severely impaired renal function with estimated glomerular filtration rate <30mL/min/1.73m2 and/or on dialysis.

23. Right to left or bi-directional cardiac shunt.

24. Previous full course of chemotherapy for GBM (at the discretion of investigator).

25. Previous radiotherapy.

26. Allergy to eggs or egg products.

27. Subjects with evidence of cranial or systemic infection.

28. Subjects with chronic pulmonary disorders.

29. Subjects with a history of drug allergies, asthma or hay fever, and multipleallergies, in particular subjects with a history of anaphylaxis.

30. Subjects with a family or personal history of QT prolongation or taking concomitantmedications known to cause QTc prolongation, or QT prolongation observed onscreening ECG (QTc > 450 for men and >470 for women).

31. Subjects with evidence of Hepatitis B virus infection/carrier state.

32. Liver injury as indicated by liver function tests that in the Investigator's opinionprecludes participation in the study.