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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Malignant Glioma; Embryonal Tumor; Malignant Brain Tumor
• Intervention / Treatment: Device: SonoCloud® (9 transducers)

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 Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kevin BECCARIA, MD, PhD; Phone Number: +33 1 71 39 65 92; Email: kevin.beccaria@aphp.fr
• Study Contact Backup: Name: Nelly BRIAND, MD, PhD; Phone Number: +33 1 44 38 18 62; Email: nelly.briand@aphp.fr

Study Locations

• France
  • Paris, France, 75005
    • Recruiting
    • Institut Curie
    • Contact: Franck BOURDEAUT, MD, PhD; Phone Number: +33 1 4432 44 71; Email: franck.bourdeaut@curie.fr
    • Principal Investigator: Franck BOURDEAUT
  • Paris, France, 75015
    • Recruiting
    • Service de neurochirugie Pédiatrique - Hôpital Necker- Enfants Malades
    • Contact: Kevin BECCARIA, MD, PhD; Phone Number: +33 1 71 39 65 92; Email: kevin.beccaria@aphp.fr
    • Principal Investigator: Kevin BECCARIA
  • Villejuif, France, 94800
    • Recruiting
    • Institut Gustave Roussy
    • Contact: Jacques GRILL, MD, PhD; Phone Number: +33 142116209; Email: jacques.grill@gustaveroussy.fr
    • Principal Investigator: Jacques GRILL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Gustave Roussy, Cancer Campus, Grand Paris; Institut Curie; CarThera
• Investigators: Principal Investigator: Kevin BECCARIA, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Carpentier A, Canney M, Vignot A, Reina V, Beccaria K, Horodyckid C, Karachi C, Leclercq D, Lafon C, Chapelon JY, Capelle L, Cornu P, Sanson M, Hoang-Xuan K, Delattre JY, Idbaih A. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med. 2016 Jun 15;8(343):343re2. doi: 10.1126/scitranslmed.aaf6086.
• Idbaih A, Canney M, Belin L, Desseaux C, Vignot A, Bouchoux G, Asquier N, Law-Ye B, Leclercq D, Bissery A, De Rycke Y, Trosch C, Capelle L, Sanson M, Hoang-Xuan K, Dehais C, Houillier C, Laigle-Donadey F, Mathon B, Andre A, Lafon C, Chapelon JY, Delattre JY, Carpentier A. Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Clin Cancer Res. 2019 Jul 1;25(13):3793-3801. doi: 10.1158/1078-0432.CCR-18-3643. Epub 2019 Mar 19.

Helpful Links

• more information about the SonoCloud® device and related clinical trials

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: February 9, 2022
• First Submitted That Met QC Criteria: March 14, 2022
• First Posted (Actual): March 24, 2022

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 13, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Adolescents; Children; Carboplatin; Malignant brain tumor; Brain cancer; Therapeutic ultrasound; Low intensity pulsed ultrasound (LIPU); Blood-brain barrier (BBB)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms; Glioma; Brain Neoplasms
• Other Study ID Numbers: D20181321; 2021-002790-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No