Blood-Brain Barrier Disruption (BBBD) for Liquid Biopsy in Subjects With GlioBlastoma Brain Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of targeted blood brain barrier disruption with Exablate Model 4000 Type 2.0/2.1 for liquid biopsy in subjects with suspected Glioblastoma brain tumors

Detailed Description
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This is a prospective, multi-center, pivotal clinical trial to evaluate the safety and efficacy of targeted blood brain barrier disruption using Exablate Model 4000 Type 2 for liquid biopsy in subjects with suspected Glioblastoma brain tumors. The study will be conducted at up to 15 centers in the US.

Official Title
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A Pivotal Study to Evaluate the Safety and Effectiveness of Exablate Model 4000 Using Microbubble Resonators to Temporarily Mediate Blood-Brain Barrier Disruption (BBBD) for Liquid Biopsy in Subjects With GlioBlastoma Brain Tumors

Conditions
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Glioblastoma, Glioma, Liquid Biopsy

Intervention / Treatment
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* Device: Focused Ultrasound (Exablate Model 4000)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female between >18-80 years of age who are able and willing to give informed consent Subjects with stereotactically-targetable suspected glioblastoma tumor on pre-operative brain imaging scans Subjects that are scheduled, or will be scheduled within 4 weeks, for surgical resection or biopsy per standard clinical tumor care Karnofsky Performance Score >70 Able to communicate sensations during the Exablate BBBD procedure Exclusion Criteria: Tumor originating from the deep midline, thalamus, midbrain, cerebellum or brainstem. Multifocal tumors Tumor morphology or other imaging findings that precludes the ability to sonicate the planned tumor volume (including significant tumor volume outside the treatment envelope or tumor volume that exceeds the maximum sonication volume allowed, i.e. currently 110 ccs at the treatment volume level). Concern for adequate tumor coverage by sonication based on tumor morphology should be discussed with the Sponsor. MRI or clinical findings of: Active or chronic infection(s) or inflammatory processes Acute or chronic hemorrhages, specifically any lobar microbleeds, and no siderosis, amyloid angiopathy, or macro-hemorrhages Intracranial thrombosis, vascular malformation, cerebral aneurysm or vasculitis MR non-compatible metallic implants in the skull or the brain or the presence of unknown MR unsafe devices Significant cardiac disease or unstable hemodynamic status Documented myocardial infarction within six months of enrollment Unstable angina on medication Unstable or worsening congestive heart failure Left ventricular ejection fraction below the lower limit of normal History of a hemodynamically unstable cardiac arrhythmia Cardiac pacemaker History of hypersensitivity to Perflutren lipid microsphere or its components, e.g., polyethylene glycol Uncontrolled hypertension (systolic > 180 and diastolic BP > 120 on medication) Unable to discontinue use of anti-coagulant/antiplatelet therapy as per local standard. History of a liver disease, bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or evidence of increased risk of bleeding Abnormal coagulation profile (Platelets < 80,000), PT (>14) or PTT (>36), and INR > 1.3 Known cerebral or systemic vasculopathy Significant depression and at potential risk of suicide Known sensitivity/allergy to gadolinium or DEFINITY, Active seizures despite medication treatment (defined as >1 seizure per week) which could be worsened by disruption of the blood brain barrier Active drug or alcohol disorder which have a higher risk for seizures, infection and/or poor executive functioning Positive HIV status, which can lead to increased entry of HIV into the brain parenchyma leading to HIV encephalitis Potential blood-borne infections which can lead to increased entry to brain parenchyma leading to meningitis or brain abscess Any contraindications to MRI scanning, including: Large subjects not fitting comfortably into the scanner Difficulty lying supine and still for up to 3 hours in the MRI unit or claustrophobia Impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2 Severe Respiratory Illness: chronic pulmonary disorders e.g. severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, subjects with a history of severe drug allergies, asthma or hay fever, and multiple allergies where the benefit/risk of administering Definity® is considered unfavorable by the study physicians in relation to the product labeling for Definity Currently in a clinical trial involving an investigational product or non-approved use of a drug or device Pregnancy or Lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exablate BBBD<br>Using Exablate Model 4000 Type 2 for liquid biopsy in subjects with Glioblastoma | Device: Focused Ultrasound (Exablate Model 4000)<br>* BBB opening via Exablate Type 2 system with microbubble resonators and drawing blood before and after opening<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | All adverse events and/or Serious Adverse Events will be documented and reported according to CTCAE | Through study completion, up to 1 year | 
| Circulating Free DNA | To demonstrate that there is at least a 2-fold increase in circulating free DNA at 1-hour post blood brain barrier disruption (BBBD) | 1 hour post BBBD | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation with Tumor Tissue | To demonstrate there is a correlation between patterns obtained in the panel of biomarkers evaluated in the resected tumor tissue and/or biopsy and blood sample collected 1-hour post BBBD | 1 hour post BBBD |