Phase I trial evaluating the tolerance of repeated opening of the bloodbrain barrier by ultrasound before chemotherapy in the treatment of recurrent primary supratentorial malignant brain tumors in children

Phase 1/2

Recruiting

• Conditions: recurrent primary supratentorial malignant brain tumors in children

• Registration Number: 2024-516169-35-00
• Lead Sponsor: Assistance Publique Hopitaux De Paris

Brief Summary

To determine the maximum tolerated ultrasound power for inducing blood-brain barrier (BBB) opening using the implantable SonoCloud®-9 (SC9) device in the treatment of recurrent or progressive malignant supratentorial brain tumors in pediatric patients receiving intravenous (IV) carboplatin.

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 Timeline

• Study First Submitted: 2022-02-09
• Study First Submitted QC: 2022-03-14
• Study First Posted: 2022-03-24
• Study Start: 2023-02-06
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-16
• Last Update Posted: 2025-07-20
• Primary Completion: 2026-10
• Study Completion: 2027-10-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Not specified
• Target Recruitment: 24

Inclusion Criteria

patient aged ≥ 5 years old and < 18 years old

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.

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 stable for the last 7 days

neutrophils > 1.5 x 109/L

Exclusion Criteria

weight <15kg

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

significant intra-tumoral bleeding (hematoma) or ipsilateral subdural effusion

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

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

radiotherapy during the last 6 weeks

patient with another malignant tumour (other than the primary brain tumour) requiring concomitant treatment.

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Absence of Dose Limiting Toxicity (DLT) directly related to the ultrasound emission from the SonoCloud-9® device (3 emitters), assessed at each cycle		Absence of Dose Limiting Toxicity (DLT) directly related to the ultrasound emission from the SonoCloud-9® device (3 emitters), assessed at each cycle

Secondary Outcome Measures

Name	Time	Method
Evaluation of the grade of blood-brain barrier (BBB) opening by ultrasound as described by Carpentier et al.		Evaluation of the grade of blood-brain barrier (BBB) opening by ultrasound as described by Carpentier et al.
overall survival (OS) at 3 months and progression-free survival (PFS) at 6 months		overall survival (OS) at 3 months and progression-free survival (PFS) at 6 months
Evaluation of the occurrence of allergic and/or cardiac complications.		Evaluation of the occurrence of allergic and/or cardiac complications.
Evaluation of complications related to implantation or sonications (excluding ultrasound effects), evaluation of implantation and connection procedures, and assessment of the device's bioavailability and resistance.		Evaluation of complications related to implantation or sonications (excluding ultrasound effects), evaluation of implantation and connection procedures, and assessment of the device's bioavailability and resistance.
Evaluation of clinical and/or radiological complications beyond the first treatment cycle.		Evaluation of clinical and/or radiological complications beyond the first treatment cycle.
Assessment of circulating tumor DNA, antigens or circulating tumor markers, and circulating tumor cells		Assessment of circulating tumor DNA, antigens or circulating tumor markers, and circulating tumor cells

Trial Locations

Locations (3)

Assistance Publique Hopitaux De Paris; 🇫🇷 Paris, France

Institut Curie; 🇫🇷 Paris, France

Institut Gustave Roussy; 🇫🇷 Villejuif, France

Assistance Publique Hopitaux De Paris

🇫🇷Paris, France

Kevin BECCARIA

Site contact

+33171396592

kevin.beccaria@aphp.fr