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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Feb 2023 → ongoing

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

DGOS - French Ministry of Health

External identifiers

EU CT number

2024-516169-35-00

EudraCT number

2021-002790-26

ClinicalTrials.gov

NCT05293197

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

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.

Secondary objectives 6

1. To evaluate the intensity of blood-brain barrier (BBB) opening using the SC9 device
2. To evaluate the effect of blood-brain barrier (BBB) opening by the SC9 device in conjunction with concomitant chemotherapy on tumor progression at 3 and 6 months
3. To assess the tolerance to the ultrasonic resonator in conjunction with the SC9 device in children
4. To evaluate the feasibility of the procedure (technical feasibility and absence of complications related to SC9 implantation and sonication procedures, excluding ultrasound effects): complications related to implantation or sonications (excluding ultrasound effects), evaluation of implantation and connection procedures, and assessment of device bioavailability and resistance.
5. To evaluate the tolerance and effect of repeated BBB openings using the SC9 device at the maximum tolerated dose.
6. To evaluate the effect of BBB opening on the circulation of tumor components in the bloodstream (ancillary study).

Conditions and MedDRA coding

recurrent primary supratentorial malignant brain tumors in children

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. patient aged ≥ 5 years old and < 18 years old
2. patient able to receive sonications and perform MRI studies without sedation
3. diagnosis of supra-tentorial primary malignant brain tumor (e.g. malignant glioma, embryonal tumor including ATRT, ependymoma)
4. recurrence or progression of brain tumor after at least a first line of standard treatment (multifocal tumors and metastatic disease allowed)
5. indication of treatment with carboplatin, validated in multidisciplinary meeting
6. 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)
7. no threat of brain herniation or uncontrolled intracranial hypertension
8. corticosteroids treatment ≤ 1mg/kg/day stable for the last 7 days
9. neutrophils > 1.5 x 109/L
10. platelets > 100 x 109/L
11. total bilirubin < 1.5x upper limit of normal, AST et ALT < 2.5x upper limit of normal
12. serum creatinin < 1.5x upper limit of normal for the age or creatinine clairance >70mL/min/1.73m2 (EDTA method or 24h urine)
13. coagulation parameters in the normal limits for age (fibrinogen, prothrombin time and activated clotting time)
14. no grade 2 or more toxicity depending on the NCI-CTCAE v5.0 criteria
15. no healed wound on the scalp
16. covered by health insurance
17. for patients of chilbearing age (15-17 years old) : a negative pregnancy test and an efficient method of birth control
18. written consent signed by the patient (if possible) and his parents or legal representatives.

Exclusion criteria 22

1. weight <15kg
2. significant intra-tumoral bleeding (hematoma) or ipsilateral subdural effusion
3. 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
4. radiotherapy during the last 6 weeks
5. patient with another malignant tumour (other than the primary brain tumour) requiring concomitant treatment.
6. any other uncontrolled disease or active infection
7. any other co-morbidity that could compromise participation to the study (in the judgement of the clinical investigator)
8. 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)
9. implanted defibrillator/pacemaker, neurostimulator, cochlear implant, intracerebral ferromagnetic vascular clip
10. any contraindication to general anesthesia
11. any contraindication to MRI or known allergy to gadolinium or other MRI contrast agent/
12. 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
13. carboplartin hypersensitivity
14. treatment with phenytoin or fosphenytoin
15. earlier vaccination with attenuated alive vaccine
16. diminished auditory acuity ≥ grade 3 on CTCAE classification
17. history of thermoregulation disorder
18. impossibility of a rigorous medical follow-up due to geographic, social or mental reasons
19. pregnant and lactating women
20. contemporaneous treatment by anticoagulant or platelet aggregation inhibiting drugs
21. 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
22. any contemporaneous treatment that, in the judgement of the clinical investigator, could induce brain toxicity after BBB disruption

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 6

1. Evaluation of the grade of blood-brain barrier (BBB) opening by ultrasound as described by Carpentier et al.
2. overall survival (OS) at 3 months and progression-free survival (PFS) at 6 months
3. Evaluation of the occurrence of allergic and/or cardiac complications.
4. 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.
5. Evaluation of clinical and/or radiological complications beyond the first treatment cycle.
6. Assessment of circulating tumor DNA, antigens or circulating tumor markers, and circulating tumor cells

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Kévin BECCARIA

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Kévin BECCARIA

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

3 submissions — initial application plus substantial / non-substantial modifications