Blood Brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Doxorubicin for Treatment of Pediatric DIPG

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 Type2.0/2.1 in combination with Doxorubicin therapy for the treatment of DIPG in pediatric patients

Detailed Description
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This is a prospective, single arm, non-randomized feasibility study to evaluate the safety, feasibility and preliminary efficacy of Blood Brain Barrier Disruption (BBBD) using the Exablate Type 2 system in pediatric patients with Diffuse Intrinsic Pontine Gliomas (DIPG)undergoing Doxorubicin chemotherapy. The study will be conducted at up to three sites in the United States. Patients will undergo 3 treatment cycles, approximately 4 -6 weeks apart. The study aims to establish feasibility and safety of Exablate BBBD in conjunction with Doxorubicin in the treatment of pediatric DIPG and assess preliminary efficacy in this patient population.

Official Title
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A Safety and Feasibility Study to Evaluate Blood Brain Barrier Disruption Using Exablate MR Guided Focused Ultrasound in Combination With Doxorubicin in Treating Pediatric Patients With Diffuse Intrinsic Pontine Gliomas (DIPG)

Conditions
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Brain Tumor

Intervention / Treatment
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* Device: Exablate
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 5 and 21 years, inclusive Patient diagnosed with DIPG At least 4-week and not greater than 12 weeks from completion of radiation therapy Post-radiation imaging does not show evidence of necrosis/ hemorrhage or other features that contraindicate MRgFUS If brain surgery occurred, at least 14 days passed since last brain surgery and the patient is fully recovered and neurologically stable If on steroids, stable or decreasing dose for at least 7 days prior to study entry Stable or improving neurologic status for 7 days prior to study entry Able and willing to give consent and/or assent or have a legal guardian who is able and willing to do so Able to attend all study visits and with life expectancy of at least 6 months Exclusion Criteria: Tumor not visible on any pre-therapy or post-radiation imaging Previous participation in other chemotherapy, molecularly targeted therapy, or immunotherapy treatment-related phase 1 or 2 trials Symptoms and signs of increased intracranial pressure Subject with metastatic disease Subject with ventricular peritoneal shunt Subject receiving bevacizumab (Avastin) therapy or increasing doses of steroids Anti-coagulant therapy, or medications known to increase risk of hemorrhage, (e.g., ASA, non-steroidal anti-inflammatory drugs [NSAIDs], statins) within washout period prior to treatment History of a bleeding disorder, coagulopathy or with a history of spontaneous tumor hemorrhage. Hypertension per age Cerebral or systemic vasculopathy, including intracranial thrombosis, vascular malformation, cerebral aneurysm, or vasculitis Immunosuppression (corticosteroids to prevent/treat brain edema are permitted). Patients with positive HIV status Active seizure disorder or epilepsy (seizures despite medical treatment) for a minimum of 4 weeks prior to first cycle/Exablate BBBD procedure captured by history Known sensitivity to gadolinium-based contrast agents Known sensitivity to DEFINITY® ultrasound contrast agent or known hypersensitivity to perflutren microsphere or its components, e.g., polyethylene glycol Contraindication to Doxorubicin Previous treatment with complete cumulative doses of Doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones Severely impaired renal function with estimated glomerular filtration rate <2 standard deviations for age Patients that may require trastuzumab during the study Patients that may require inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp during the study

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blood Brain Barrier Disruption (BBBD)<br>Exablate MR Guided Focused Ultrasound for Blood Brain Barrier Disruption with Doxorubicin for treating pediatric patients with DIPG | Device: Exablate<br>* Blood Brain Barrier Disruption (BBBD) via Exablate Type 2 system with microbubble resonators on the day of Doxorubicin infusion to treat DIPG brain tumors<br>* Other names: Exablate BBBD;Drug: Doxorubicin<br>* Doxorubicin infusion<br>* Other names: Rubex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | All adverse events from first treatment to end of study will be documented and reported according to the CTCAE terminology and severity scale | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Brain Barrier Disruption (BBBD) | BBBD will be assessed as a comparative ratio measured in pre and post-sonication contrast-enhanced MR images | immediately post BBBD sonication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DIPG, Focused Ultrasound, Chemotherapy, Phase I trial, Pediatrics