SONOKID. A Phase I Trial Evaluating the Tolerability of Repeated Blood-Brain Barrier Disruption by Ultrasound Prior to Chemotherapy in the Treatment of Recurrent Supratentorial Primary Malignant Brain Tumors in Children.
Overview
- Phase
- Phase 1/2
- Intervention
- Not specified
- Conditions
- Not specified
- Sponsor
- Assistance Publique Hopitaux De Paris
- Enrollment
- 24
- Locations
- 3
- Primary Endpoint
- Absence of Dose Limiting Toxicity (DLT) directly related to the ultrasound emission from the SonoCloud-9® device (3 emitters), assessed at each cycle
- Status
- Recruiting
- Last Updated
- 5 months ago
Overview
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.
Investigators
Pr Kévin BECCARIA
Scientific
Assistance Publique Hopitaux De Paris
Eligibility Criteria
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.
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
Outcomes
Primary Outcomes
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 Outcomes
- Cardiac adverse events related to ultrasound contrast agent SonoVue®(Monthly, up to 12 months)
- BBB opening intensity with the SonoCloud® device(Monthly, up to 12 months)
- Clinical efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy(Month 6)
- Radiological efficacy of BBB disruption by the SonoCloud® device in association with systemic chemotherapy(Month 6)
- Allergic adverse events related to ultrasound contrast agent SonoVue®(Monthly, up to 12 months)
- Feasibility of the BBB disruption technique(Day 1 after implantation)
- Feasibility of the BBB disruption procedure(During surgery)
- Skin complications relation to the BBB disruption procedure(Monthly, up to 12 months)
- Biodisponibility of the SonoCloud-9® device(12 months)
- Assessment of SonoCLOUD- 9® device resistance(12 months)
- DNA and tumor cells concentrations in blood and cerebrospinal fluid(Monthly, up to 12 months)