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

Prior treatment

• Patients requiring increasing doses of corticosteroids.
• Patient receiving bevacizumab (Avastin) therapy.
• Patients with ≥25% increase in volume of contrast enhancement at time of assessment for study enrollment, compared with their first postoperative MRI. This cut-off is used to differentiate between pseudoprogression (which can occur following both radiation and TMZ therapy) and true tumor progression. This will be further ascertained through a discussion between the study neurosurgeons and radiologists.
• Patients undergoing other concurrent therapies such as chemotherapy wafers, immunotoxins delivered by convection-enhanced delivery, regionally administered gene and viral therapies, immunotherapies, and focal irradiation with brachytherapy, stereotactic radiosurgery, and laser interstitial thermotherapy. These regimens have been shown to cause contrast enhancement in the resection cavity boundary, which can be difficult to differentiate from true tumor recurrence.
• Anti-coagulant therapy, or medications known to increase risk of hemorrhage within washout period prior to treatment (i.e., antiplatelet or vitamin K inhibitor anticoagulants within 7 days, non-vitamin K inhibitor anticoagulants within 72 hours, or heparin-derived compounds within 48 hours of treatment).
• Previous full course of chemotherapy for GBM (at the discretion of investigator).
• Previous radiotherapy.

Other illness

• Patients presenting with the following imaging characteristics:
  • Following steroid treatment, brain edema and/or mass effect that causes midline shift or shift in wall of the third ventricle of more than 10 mm.
  • Evidence of recent (less than 2 weeks) intracranial hemorrhage. iii. Calcifications in the FUS sonication beam path in the event system tools cannot tailor the treatment around these calcification spots.
• The sonication pathway to the tumor involves:
  • More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp.
  • Clips or other metallic implanted objects in the skull or the brain, except shunts.
• Severe hypertension (diastolic blood pressure (DBP) \> 100 on medication).
• History of a bleeding disorder, coagulopathy or with a history of spontaneous tumor hemorrhage.
• Insulin-dependent diabetes mellitus that is not well-controlled or that in the Investigator's opinion precludes participation in the study.
• Known life-threatening systemic disease.
• Right to left or bi-directional cardiac shunt.
• Allergy to eggs or egg products.
• Subjects with evidence of cranial or systemic infection.
• Subjects with chronic pulmonary disorders.
• Subjects with a history of drug allergies, asthma or hay fever, and multiple allergies, in particular subjects with a history of anaphylaxis.
• Subjects with evidence of Hepatitis B virus infection/carrier state.

Lab values

• Cardiac disease or unstable hemodynamics including:
  • Documented myocardial infarction within six months of enrollment. ii. Unstable angina on medication. iii. Congestive heart failure. iv. Left ventricular ejection fraction \<50%. v. History of a hemodynamically unstable cardiac arrhythmia. vi. Cardiac pacemaker.
• Abnormal level of platelets (\< 100,000) or INR \> 1.3.
• Subjects with a family or personal history of QT prolongation or taking concomitant medications known to cause QTc prolongation, or QT prolongation observed on screening ECG (QTc \> 450 for men and \>470 for women).

Other

• The subject presents with symptoms and signs of increased intracranial pressure (e.g., headache, nausea, vomiting, lethargy, and papilledema).
• Documented cerebral infarction within the past 12 months.
• TIA in the last 1 month.
• Cerebral or systemic vasculopathy.
• Known sensitivity to gadolinium-DTPA.
• Known sensitivity to DEFINITY® ultrasound contrast agent or perflutren.
• Contraindications to MRI such as non-MRI-compatible implanted devices, unable to tolerate an MRI due to for instance pain or claustrophobia, untreated, uncontrolled sleep apnea.
• Positive pregnancy test (for pre-menopausal women).
• Severely impaired renal function with estimated glomerular filtration rate \<30 mL/min/1.73m2 and/or on dialysis.
• Liver injury as indicated by liver function tests that in the Investigator's opinion precludes participation in the study.

• Age between 18 and 85 years, inclusive.
• Able and willing to provide written informed consent.
• Diagnosis of Glioblastoma by histology or molecular markers based on WHO 2021 classification.
• Previously undergone a maximal safe surgical resection and completed concurrent, standard-of-care RT and TMZ without any complications and deemed eligible for the maintenance phase of TMZ treatment.
• Tumor or tumor resection cavity is clearly defined on screening MRI scans.
• Karnofsky Performance Score rating 70-100.
• American Society of Anesthesiologists (ASA) physical status score of 1-3.
• Life expectancy of at least 3 months and able to attend all study visits.