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

Trial ID: NCT05293197

Interventional - Phase 1 - Recruiting

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.

Conditions

• Malignant Brain Tumor
• Malignant Glioma
• Embryonal Tumor

Interventions

• SonoCloud® (9 transducers)

Eligibility

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

Sponsor

Assistance Publique - Hôpitaux de Paris, CarThera, Gustave Roussy, Cancer Campus, Grand Paris, Institut Curie, URC-CIC Paris Descartes Necker Cochin

Source: ClinicalTrials.gov

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