Safety Study of the Repeated Opening of the Blood-brain Barrier With the SonoCloud® Device to Treat Malignant Brain Tumors in Pediatric Patients

Study Overview
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Brief Summary
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Purpose : the aim of this study is to assess the feasibility and safety of ultrasound-induced opening of the blood-brain barrier (BBB) with the SonoCloud-9 implantable ultrasound device in pediatric patients treated for a recurrent malignant supra-tentorial brain tumor treated with carboplatin. Study hypothesis : the blood-brain barrier can be transiently and safely opened with pulsed low intensity ultrasound immediately prior to intravenously delivered chemotherapy. The opening of the BBB with the SonoCloud-9 system will increase the tumor exposure to carboplatin and increase progression-free and overall survival in pediatric patients treated for a recurrent malignant supra-tentorial brain tumor.

Detailed Description
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Malignant brain tumors are the first cause of death by cancer in children and adolescents. The dismal prognosis of malignant brain tumors is partially due to the existence of the blood brain barrier (BBB), a physiological barrier that limits the penetration of almost all molecules from the blood stream to the brain, including antineoplastic drugs. It has been shown that the application of low intensity ultrasound on the brain in association with intravenous microbubbles leads to transient and safe opening of the BBB. Many preclinical studies have demonstrated that ultrasound-induced opening of the BBB increases the distribution of therapeutic molecules into the brain and allows tumor control and increases survival in animal models (mice, rabbits, pigs, primates). An innovative implantable ultrasound system, the SonoCloud device, has been developed in order to repeatedly open the BBB in synchronization with chemotherapy protocols. This intracranial and subcutaneous device is not visible and MRI compatible and allows repeatable and ambulatory treatments. Moreover, such a device allows the delivery of low intensity ultrasound in a controlled and reproductible manner. A phase I/IIa trial has confirmed the feasibility and safety of this technique in adult patients treated for recurrent glioblastoma with carboplatin-based chemotherapy. This study will assess the feasibility and safety of ultrasound-induced opening of the BBB with the SonoCloud device in pediatric patients treated with carboplatin chemotherapy for a recurrent supra-tentorial malignant brain tumor. The study will determine the maximum tolerated ultrasound acoustic pressure that can be used for BBB opening and the safety of the activation of 3, then 9 transducers with the SonoCloud-9® device. Patients will follow 6 months cycles of treatment. If the treatment is well tolerated, patients will be able to be treated for 6 more cycles. The magnitude and intensity of the BBB opening, its clinical (overall survival) and radiological (progression-free survival) efficacy will be assessed as secondary endpoints. Safety of the ultrasound contrast agent SonoVue will also be evaluated in this indication in the pediatric population. An ancillary study will assess circulating tumor DNA (ctDNA) concentrations in patients with recurrence of a supra-tentorial malignant brain tumor, at diagnosis and during repeated opening of the BBB. The study will assess the correlation between ctDNA concentrations and tumor evolution.

Official Title
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Phase I Trial Assessing the Safety of the Repeated Ultrasound-induced Opening of the Blood-brain Barrier in Pediatric Patients With Refractory Supra-tentorial Malignant Brain Tumors Before Chemotherapy Administration

Conditions
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Malignant Brain Tumor, Malignant Glioma, Embryonal Tumor

Intervention / Treatment
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* Device: SonoCloud® (9 transducers)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patient aged ≥ 5 years old and < 18 years old patient able to receive sonications and perform MRI studies without sedation diagnosis of supra-tentorial primary malignant brain tumor (e.g. malignant glioma, embryonal tumor including ATRT, ependymoma) recurrence or progression of brain tumor after at least a first line of standard treatment (multifocal tumors and metastatic disease allowed) indication of treatment with carboplatin, validated in multidisciplinary meeting Karnofsky performance scale index (patients ≥ 16 years old) or Lansky performance status (patients < 16 years old) > 50% (a patient with a performance status score altered by a motor deficit due to tumor infiltration will be allowed to be included) no threat of brain herniation or uncontrolled intracranial hypertension corticosteroids treatment ≤ 1mg/kg/day neutrophils > 1.5 x 109/L platelets > 100 x 109/L total bilirubin < 1.5x upper limit of normal, AST et ALT < 2.5x upper limit of normal serum creatinin < 1.5x upper limit of normal for the age or creatinine clairance >70mL/min/1.73m2 (EDTA method or 24h urine) coagulation parameters in the normal limits for age (fibrinogen, prothrombin time and activated clotting time) no grade 2 or more toxicity depending on the NCI-CTCAE v5.0 criteria no healed wound on the scalp covered by health insurance for patients of chilbearing age (15-17 years old) : a negative pregnancy test and an efficient method of birth control written consent signed by the patient (if possible) and his parents or legal representatives. Exclusion Criteria: weight <15kg significant intra-tumoral bleeding (hematoma) or ipsilateral subdural effusion antineoplastic treatment other than carboplatin taken at the same time or stopped since less than: 6 weeks for nitrosoureas 1 month for temozolomide 1 month for bevacizumab 5 half-lives for tyrosin kinase inhibitors 3 weeks for any other chemotherapy for the first sonication session radiotherapy during the last 6 weeks any other cancer treated during the last 5 years any other uncontrolled disease or active infection any other co-morbidity that could compromise participation to the study (in the judgement of the clinical investigator) any anatomical particularity (skull thickness, thin skin) that could compromise a safe implantation of the device and/or compromise the quality of the treatment (in the judgement of the clinical investigator) implanted defibrillator/pacemaker, neurostimulator, cochlear implant, intracerebral ferromagnetic vascular clip any contraindication to general anesthesia any contraindication to MRI or known allergy to gadolinium or other MRI contrast agent/ any contraindication to ultrasound contrast agent: allergy to the active substance or any excipient acute coronary syndrome or uncontrolled ischemic heart disease chronic heart failure or history of acute heart failure or heart failure grade III or IV treatment with dobutamine severe pulmonary arterial hypertension uncontrolled systemic hypertension respiratory distress syndrome carboplartin hypersensitivity treatment with phenytoin or fosphenytoin earlier vaccination with attenuated alive vaccine diminished auditory acuity ≥ grade 3 on CTCAE classification history of thermoregulation disorder impossibility of a rigorous medical follow-up due to geographic, social or mental reasons pregnant and lactating women contemporaneous treatment by anticoagulant or platelet aggregation inhibiting drugs contemporaneous treatment possibly toxic for the central nervous system. The following treatments are excluded if taken less than 5 half-lives before the ultrasound session (unknown toxicity in case of BBB disruption) : benzodiazepine (or any sedative or hypnotique drug) antihistamine proconvulsant drugs butyrophenone, phenothiazine, or any conventional antipsychotic drug barbiturate MAO inhibitor anticholinergic anticoagulant any contemporaneous treatment that, in the judgement of the clinical investigator, could induce brain toxicity after BBB disruption

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SonoCloud®<br>SonoCloud® : dose escalation 6 cycles of sonication | Device: SonoCloud® (9 transducers)<br>* SonoCloud®, sonication: dose escalation 6 cycles of sonication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity directly linked to US emissions by the SonoCloud-9® (3 transducers) | Clinical evaluation (neurological deficit, intracranial hypertension, epilepsy) during acoustic pressure dose escalation, after each sonication (48h) | Monthly up to 12 months | 
| Dose limiting toxicity directly linked to US emissions by the SonoCloud-9®(3 transducers) | Radiological evaluation (hemorrage, ischemia, brain swelling) during acoustic pressure dose escalation, after each sonication | Monthly up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BBB opening intensity with the SonoCloud® device | Grading of BBB disruption using the scale previously described (Carpentier et al 2016), after each sonication | Monthly, up to 12 months | 
| Clinical efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy | Overall Survival (OS) | Month 3 | 
| Clinical efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy | Overall Survival (OS) | Month 6 | 
| Radiological efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy | Progression Free Survival (PFS) using RANO Criteria | Month 3 | 
| Radiological efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy | Progression Free Survival (PFS) using RANO Criteria | Month 6 | 
| Allergic adverse events related to ultrasound contrast agent SonoVue® | Allergic reactions (cutaneous eruption, oedema, respiratory failure) in relation to the use of the ultrasound contrast agent SonoVue® for BBB disruption in the pediatric population, during and after each sonication | Monthly, up to 12 months | 
| Cardiac adverse events related to ultrasound contrast agent SonoVue® | Cardiac reactions (thoracic pain, cardiac failure, EKG modification) in relation with the use of the ultrasound contrast agent SonoVue® for BBB disruption in the pediatric population, during and after each sonication | Monthly, up to 12 months | 
| Feasibility of the BBB disruption technique | Complications associated with the implantation of the SonoCloud® device : acute pain evaluation using VAS (Visual Analogue Scale) for patients >_ 7 years old or using behavioral pain scale EVENDOL for patients <7 years old, immediately after implantation | Monthly, up to 12 months | 
| Feasibility of the BBB disruption technique | Complications associated with the implantation of the SonoCloud® device : acute pain evaluation using VAS (Visual Analogue Scale) for patients >_ 7 years old or using behavioral pain scale EVENDOL for patients <7 years old, at day 1 after implantation | Monthly, up to 12 months | 
| Feasibility of the BBB disruption technique | Complications associated with the implantation of the SonoCloud® device : chronic pain evaluation using VAS (Visual Analogue Scale) for patients >_7 years old or using behavioral pain scale EVENDOL for patients <7 years old, monthly, before each new cycle of treatment | Monthly, up to 12 months | 
| Feasibility of the BBB disruption technique | Complications associated with the implantation of the SonoCloud® device using radiological examination : device position and post-operative complication (hematoma), one day after implantation | Day 1 after implantation | 
| Feasibility of the BBB disruption procedure | Assessment of complications associated with the sonications : pain evaluation using VAS (Visual Analogue Scale) for patients >_ 7 years old or using behavioral pain scale EVENDOL for patients <7 years old at needle connexion | Monthly, up to 12 months | 
| Feasibility of the BBB disruption procedure | Complications associated with the implantation of the SonoCloud® device : pain evaluation using VAS (Visual Analogue Scale) for patients >_ 7 years old or using behavioral pain scale EVENDOL for patients <7 years old, during sonication | Monthly, up to 12 months | 
| Skin complications relation to the BBB disruption procedure | Assessment of skin complications associated with sonications : eschar and/or infection, before each cycle of treatment | Monthly, up to 12 months | 
| Feasibility of the BBB disruption procedure | Process evaluated by the surgeon: number of tests necessary for needle connexion to the device, at each sonication | Monthly, up to 12 months | 
| Feasibility of the BBB disruption procedure | Process evaluated by the surgeon : duration from needle connexion to the end of sonication, at each sonication | Monthly, up to 12 months | 
| Feasibility of the BBB disruption procedure | Process evaluated by the surgeon : duration for device implantation | During surgery | 
| Biodisponibility of the SonoCloud-9® device | Histological analysis of tissue around the device : thickness, inflammation, biocompatibility, at explantation | 12 months | 
| Assessment of SonoCLOUD- 9® device resistance | Physical analysis of the device, at explantation | 12 months | 
| DNA and tumor cells concentrations in blood and cerebrospinal fluid | Evaluation of the effect of BBB disruption with the SonoCloud-9® device on the circulation of tumoral components in the blood flow, at each cycle of treatment | Monthly, up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low intensity pulsed ultrasound (LIPU), Therapeutic ultrasound, Blood-brain barrier (BBB), Malignant brain tumor, Brain cancer, Carboplatin, Children, Adolescents