Assessment of Safety and Feasibility of ExAblate Blood-Brain Barrier (BBB) Disruption for Treatment of Glioma

This is a prospective, single center, single-arm study to establish the safety, feasibility, and effectiveness of BBB disruption along the periphery of the tumor resection cavity using the ExAblate Neuro Model 4000 Type 2 (220 kHz) system and DEFINITY ultrasound contrast in patients with GBM. Adult patients with a first time diagnosis of GBM, whom have undergone maximal safe surgical resection and have safely completed the initial phase of concurrent chemo-radiation therapy, will be recruited for this study. Twenty patients will undergo up to 6 treatments with FUS coincident with their standard TMZ cycles.

Inclusion criteria

• Men or women.
• Age between 18 and 80 years, inclusive.
• Able and willing to give informed consent.
• Grade IV malignant glioma (GBM) confirmed through assessment of surgical specimens by a board-certified neuropathologist.
• Undergone maximal safe surgical resection and completed concurrent radiotherapy+oral TMZ without any complications and deemed eligible for the maintenance phase of TMZ treatment.
• Karnofsky rating 70-100.
• ASA score 1-3.
• Able to communicate during the ExAblate MRgFUS procedure.
• Able to attend all study visits (i.e., life expectancy of at least 3 months).

Exclusion criteria

• Patients presenting with the following imaging characteristics:

i. Evidence of recent intracranial hemorrhage.

• The sonication pathway to the tumour involves:

i. Extensive scalp scars, ii. Clips or other metallic implanted objects in the skull or the brain (brain implants).

• The subject presents with symptoms and signs of increased intracranial pressure (e.g., headache, nausea, vomiting, lethargy, and papilledema).
• Patients requiring increasing doses of corticosteroids.
• Patient receiving bevacizumab (Avastin) therapy.
• 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.
• Cardiac disease or unstable hemodynamics including:

i. 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.

• Severe hypertension (diastolic BP > 100 on medication).
• Anti-coagulant therapy, or medications known to increase risk of hemorrhage within washout period prior to treatment.
• History of a bleeding disorder, coagulopathy or with a history of spontaneous tumour hemorrhage.
• Documented cerebral infarction within the past 12 months.
• TIA in the last 1 month.
• Cerebral or systemic vasculopathy.
• Insulin-dependent diabetes mellitus that is not well-controlled or that in the Investigator's opinion precludes participation in the study.
• Known sensitivity to gadolinium-DTPA.
• Known sensitivity to DEFINITY ultrasound contrast agent or perflutren.
• Contraindications to MRI such as non-MRI-compatible implanted devices.
• Large subjects not fitting comfortably into the MRI scanner.
• Difficulty lying supine and still for up to 4 hours in the MRI unit or claustrophobia.
• Untreated, uncontrolled sleep apnea.
• Positive pregnancy test (for pre-menopausal women).
• Known life-threatening systemic disease.
• Severely impaired renal function.
• Cardiac shunt.
• Previous full course of chemotherapy.
• 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.
• Liver injury as indicated by liver function tests.