Safety of BBB Opening With the SonoCloud

Study Overview
=================
Brief Summary
-----------------
PURPOSE: The purpose of this study is to determine whether transient opening of the blood-brain barrier by pulsed ultrasound using the SonoCloud implantable ultrasound device is safely tolerated in patients with recurrent glioblastoma immediately before systemic delivery of carboplatin-based chemotherapy. STUDY HYPOTHESIS: The blood-brain barrier can be safely opened using pulsed ultrasound prior to chemotherapy administration in patients with recurrent glioblastoma. Transient opening of the blood-brain barrier by pulsed ultrasound will increase the glioblastoma exposure to carboplatin-based chemotherapy and increase progression-free and overall survival in patients with recurrent glioblastoma.

Detailed Description
-----------------
For patients with recurrent malignant gliomas, who have already been treated by a combination of surgery, radiation therapy and/or chemotherapy, few treatment options currently exist. Salvage therapies typically consist of systemic administration of chemotherapy agents, which have been shown to have limited effectiveness as median survival in this patient group is currently only 6 months. One limitation to the efficacy of systemic chemotherapy in the treatment of brain tumors is the blood-brain barrier (BBB). To enhance the delivery of systemically administered chemotherapy agents to brain tumors, an implantable ultrasound device was developed that can be used to temporarily disrupt the BBB. Delivery of pulsed ultrasound, in combination with an ultrasound contrast agent, has been shown to temporarily disrupt the BBB for a duration of more than 6 hours and allow for a significantly increased penetration of systemically administered chemotherapy drugs in pre-clinical studies. This study will evaluate the safety of temporary disruption of the BBB during carboplatin chemotherapy delivery in patients with recurrent glioblastoma. This study will also evaluate the maximum tolerated dose of ultrasound that can be used to disrupt the BBB. The use of dynamic contrast-enhanced MRI will be evaluated for determining the extent and magnitude of BBB opening. Clinical efficacy (Survival) and radiological efficacy (Progression Free Survival) will also be evaluated as secondary endpoints.

Official Title
-----------------
A Study to Evaluate the Safety of Transient Opening of the Blood-Brain Barrier by Low Intensity Pulsed Ultrasound With the SonoCloud Implantable Device in Patients With Recurrent Glioblastoma Before Chemotherapy Administration

Conditions
-----------------
Glioblastoma, Glioma, Brain Tumor

Intervention / Treatment
-----------------
* Device: SonoCloud
* Drug: Carboplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Age greater than 18 years. Subjects with recurrent glioma who have failed standard therapy with surgery and/or treatment with radiation and temozolomide. Patient eligible for Carboplatin-based chemotherapy Contrast-enhanced tumor less than 35 mm in diameter No risk of cerebral herniation Able to tolerate pre/post procedure steroid treatment Social security affiliated (in France) Able and willing to give signed and informed consent Normal biological status Hemoglobin ≥ 10 g/dl Platelets ≥ 100000/mm3 Neutrophils ≥ 1500/mm3 Normal creatine clearance ≥ 60ml/mn ASAT < 3 N ALAT < 3 N Normal Bilirubin Level < 1.5 N Alkaline Phosphatase < 3 N INR < 1.5 Prothrombin Level ≥ 70% Exclusion criteria: Allergic to Iodine, Gadolinium, Xylocain Contra-indications to echographic contrast agent (microbubbles) Severe Renal insufficiency Hepatic insufficiency Possible toxic treatment for CNS Previously infected surgical field Uncontrolled epilepsy MRI contra-indications Hemostasis troubles thrombopenia <75.000, TP <60%, INR >1.5, anti-platelet or anticoagulant therapy on-going) Active phlebitis or active pulmonary embolism Pregnant or currently breast-feeding Patients under judicial protection

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SonoCloud + carboplatin<br>SonoCloud : dose escalation Carboplatin : min 6 cycles - individual dose determination according to renal function and AUC | Device: SonoCloud<br>* SonoCloud : dose escalation<br>Drug: Carboplatin<br>* Carboplatin : min 6 cycles - individual dose determination according to renal function and AUC<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of transient disruption of the blood-brain barrier using the SonoCloud system in patients with recurrent glioblastoma. |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of ultrasound with the SonoCloud system for transient disruption of the BBB. |  | 12 months | 
| Quantification of the disruption of the BBB by the SonoCloud system using dynamic T1 contrast-enhanced MRI. |  | 12 months | 
| Progression-free survival in patients treated with the SonoCloud system in combination with carboplatin chemotherapy. |  | 12 months | 
| Overall survival in patients treated with the SonoCloud system in combination with carboplatin chemotherapy. |  | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Blood brain barrier (BBB), Disruption, Low intensity pulsed ultrasound (LIPU), Sonocloud device, Glioblastoma (GBM), Brain Cancer, Carboplatin, Therapeutic Ultrasound