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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05293197

Collaborator

CarThera (Industry), Gustave Roussy, Cancer Campus, Grand Paris (Other), Institut Curie (Other)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Brain Tumor Malignant Glioma Embryonal Tumor	Device: SonoCloud® (9 transducers)	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Mar 1, 2022

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SonoCloud® SonoCloud® : dose escalation 6 cycles of sonication	Device: SonoCloud® (9 transducers) SonoCloud®, sonication: dose escalation 6 cycles of sonication

Arm

Intervention/Treatment

Experimental: SonoCloud®

SonoCloud® : dose escalation 6 cycles of sonication

Device: SonoCloud® (9 transducers)

SonoCloud®, sonication: dose escalation 6 cycles of sonication

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

BBB opening intensity with the SonoCloud® device [Monthly, up to 12 months]
Grading of BBB disruption using the scale previously described (Carpentier et al 2016), after each sonication
Clinical efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy [Month 3]
Overall Survival (OS)
Clinical efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy [Month 6]
Overall Survival (OS)
Radiological efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy [Month 3]
Progression Free Survival (PFS) using RANO Criteria
Radiological efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy [Month 6]
Progression Free Survival (PFS) using RANO Criteria
Allergic adverse events related to ultrasound contrast agent SonoVue® [Monthly, up to 12 months]
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
Cardiac adverse events related to ultrasound contrast agent SonoVue® [Monthly, up to 12 months]
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
Feasibility of the BBB disruption technique [Monthly, up to 12 months]
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
Feasibility of the BBB disruption technique [Monthly, up to 12 months]
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
Feasibility of the BBB disruption technique [Monthly, up to 12 months]
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
Feasibility of the BBB disruption technique [Day 1 after implantation]
Complications associated with the implantation of the SonoCloud® device using radiological examination : device position and post-operative complication (hematoma), one day after implantation
Feasibility of the BBB disruption procedure [Monthly, up to 12 months]
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
Feasibility of the BBB disruption procedure [Monthly, up to 12 months]
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
Skin complications relation to the BBB disruption procedure [Monthly, up to 12 months]
Assessment of skin complications associated with sonications : eschar and/or infection, before each cycle of treatment
Feasibility of the BBB disruption procedure [Monthly, up to 12 months]
Process evaluated by the surgeon: number of tests necessary for needle connexion to the device, at each sonication
Feasibility of the BBB disruption procedure [Monthly, up to 12 months]
Process evaluated by the surgeon : duration from needle connexion to the end of sonication, at each sonication
Feasibility of the BBB disruption procedure [During surgery]
Process evaluated by the surgeon : duration for device implantation
Biodisponibility of the SonoCloud-9® device [12 months]
Histological analysis of tissue around the device : thickness, inflammation, biocompatibility, at explantation
Assessment of SonoCLOUD- 9® device resistance [12 months]
Physical analysis of the device, at explantation
DNA and tumor cells concentrations in blood and cerebrospinal fluid [Monthly, up to 12 months]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 <10kg
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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Institut Curie	Paris	France	75005
2	Service de neurochirugie Pédiatrique - Hôpital Necker- Enfants Malades	Paris	France	75015
3	Institut Gustave Roussy	Villejuif	France	94800