Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Temozolomide

Lomustine

Antineoplastic Agents, Alkylating

Alkylating Agents

The SonoCloud-9 (SC9) device will be implanted in the skull bone window upon completion of tumor resection and routine craniotomy. Carboplatin (CBDCA) will be administered intravenously prior to sonication. The CBDCA/SC9 treatment will be repeated every 3 weeks (depending on patient's tolerability) until disease progression or as clinically indicated. Administration of up to 7 cycles is planned.

Standard of Care (SoC) treatment with either temozolomide (TMZ) or lomustine (CCNU).

Standard TMZ chemotherapy as a single oral dose every 4 weeks for up to 6 cycles.

Standard CCNU chemotherapy as a single oral dose every 6 weeks for up to 4 cycles.

Implantation of SC9 device and repeat activation at constant acoustic pressure

SonoCloud-9 (SC9)

Dose of carboplatin AUC 5 mg/ml.min-1 calculated using Calvert's formula:

Dose (mg) = target AUC (mg/mL x minute) x \[glomerular filtration rate (GFR) mL/minute + 25\].

Carole Desseaux

Rimas Lukas, MD

Kathryn Nevel

Brian JA Gill, MD

Dominique Higgins, MD

Duerinck Johnny, MD

Steven de Vleeschouwer, MD

Pierre Frères, MD

François Ducray, MD

Olivier Chinot, MD

Ahmed Idbaih, MD

Roland Goldbrunner, MD

Giuseppe Lombardi, MD

Martin van den Bent, MD

Angel Perez-Nunez, MD

The brain is protected from any toxic or inflammatory molecule by the blood-brain barrier (BBB). This physical barrier is located at the level of the blood vessel walls. Because of these barrier properties, the blood vessels are also impermeable to the passage of therapeutic molecules from the blood to the brain. The development of effective treatments against glioblastoma is thus limited due to the BBB that prevents most drugs injected in the bloodstream from getting into brain tissue where the tumour is seated. The SonoCloud-9 (SC9) is an investigational device using ultrasound technology and specially developed to open the BBB in the area of and surrounding the tumour. The transient opening of the BBB allows more drugs to reach the brain tumour tissue. Carboplatin is a chemotherapy that is approved to treat different cancer types alone or in combination with other drugs, and has been used in the treatment of glioblastoma. Despite its proven efficacy in the laboratory on glioblastoma cells, carboplatin does not readily cross the BBB in humans. A clinical trial has shown that in combination with the SonoCloud-9, more carboplatin can reach the brain tumour tissue. The objective of the proposed trial is to show that the association - carboplatin with the SonoCloud-9 - will increase efficacy of the drug in patients with recurrent glioblastoma.

Sonocloud-9 in Association With Carboplatin Versus Standard-of-Care Chemotherapies (CCNU or TMZ) in Recurrent GBM

A Randomized, Open-label, Multicentric, Two-arm Pivotal Trial of SonoCloud-9 Combined With Carboplatin (CBDCA) vs Standard of Care Lomustine (CCNU) or Temozolomide (TMZ) in Patients Undergoing Planned Resection for First Recurrence Glioblastoma.

Frequency and severity of adverse events scored according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, from surgery to End-of-Trial Intervention visit

Survival status will be collected during the treatment period, for up to 7 months (short-term follow-up) and then every 3 months as standard of care follow-up (long-term follow-up) until participant's 'End of Study', defined as end of survival follow-up period, death, withdrawal of consent for the collection of data, or 'lost to follow-up' (whichever comes first).

Tumor Growth Rate will be determined by measuring hyperintense tumor volume using T1w contrast-enhancing tumor-related region from post-surgery MRI baseline to unequivocal progression MRI (i.e., suspected radiologic progression confirmed by repeat scan).

Defined as the time from date of randomization to the earlier of the following events: unequivocal tumor progression as determined by IRC per RANO criteria or death due to any cause.

Defined as the proportion of participants alive at 12 months

Defined as the proportion of participants alive at 18 months

Defined as the proportion of participants without disease progression or death due to any cause at 6 months.

CarThera

Nervous System Diseases

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

SonoCloud® : dose escalation 6 cycles of sonication

SonoCloud®, sonication: dose escalation 6 cycles of sonication

SonoCloud® (9 transducers)

Kevin BECCARIA, MD, PhD

Nelly BRIAND, MD, PhD

Franck BOURDEAUT, MD, PhD

Franck BOURDEAUT

Kevin BECCARIA

Jacques GRILL, MD, PhD

Jacques GRILL

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.

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.

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

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

Clinical evaluation (neurological deficit, intracranial hypertension, epilepsy) during acoustic pressure dose escalation, after each sonication (48h)

Radiological evaluation (hemorrage, ischemia, brain swelling) during acoustic pressure dose escalation, after each sonication

Grading of BBB disruption using the scale previously described (Carpentier et al 2016), after each sonication

Progression Free Survival (PFS) using RANO Criteria

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

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

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

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

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

Complications associated with the implantation of the SonoCloud® device using radiological examination : device position and post-operative complication (hematoma), one day after implantation

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

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

Assessment of skin complications associated with sonications : eschar and/or infection, before each cycle of treatment

Process evaluated by the surgeon: number of tests necessary for needle connexion to the device, at each sonication

Process evaluated by the surgeon : duration from needle connexion to the end of sonication, at each sonication

Process evaluated by the surgeon : duration for device implantation

Histological analysis of tissue around the device : thickness, inflammation, biocompatibility, at explantation

Physical analysis of the device, at explantation

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

Gustave Roussy, Cancer Campus, Grand Paris

Institut Curie

Assistance Publique - Hôpitaux de Paris

SonoCloud-9 Carboplatin: 6 cycles (every 4 weeks)

Escalating numbers of ultrasound beams at constant acoustic pressure

SonoCloud-9

Ahmed IDBAIH, MD

Recurrent glioblastoma (GBM) is a disease with high unmet clinical need. The standard of care for patients with GBM includes surgery, radiotherapy and chemotherapy. Despite this aggressive treatment, the overall median survival of patients with GBM remains at 15-20 months.

In more than 95% of cases, tumor recurrence is observed within 2 cm to 3 cm of the resection cavity within 4-7 months after initial treatments. One of the main causes of recurrence is the inability of chemotherapies to enter the brain from the systemic circulation due to the blood-brain barrier (BBB). The BBB is unique to cerebral blood vessels and blocks most drugs from entering the brain in sufficient concentrations.

The SonoCloud-9 (SC9) System delivers ultrasound to locally and transiently increase the permeability of the BBB to allow the passage of drugs into the cerebral parenchyma. The SC9 is dimensioned to cover the resection area and surrounding tissues in patients with recurrent GBM. The large sonicated volume covered by the SC9 device allows for broad BBB disruption and should allow for carboplatin chemotherapy to penetrate the surrounding tumor infiltrative area. By enhancing drug concentrations, it is hypothesized that further disease progression will be prevented.

This will be an open-label, Phase 1/2a, multicenter, single-arm, interventional trial that will first evaluate the dose limiting toxicity (DLT) of escalating numbers of ultrasound beams at constant acoustic pressure using a standard escalation (Phase 1) and then confirm the safety and efficacy of BBB opening (Phase 2a expansion).

Safety and Efficacy of Transient Opening of the Blood-brain Barrier (BBB) With the SonoCloud-9

A Study to Evaluate the Safety and the Efficacy of Transient Opening of the Blood-brain Barrier (BBB) by Low Intensity Pulsed Ultrasound With the SonoCloud-9 Implantable Device in Recurrent Glioblastoma Patients Eligible for Surgery and for Carboplatin Chemotherapy

DLT will be evaluated using imaging (MRI) and clinical examination, as CTCAE that occurs within 2 weeks of the first sonication and that does not respond to optimal medical management (including steroids) within 7 days.

BBB opening will be evaluated by contrast-enhanced T1w magnetic resonance imaging (MRI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Sonocloud-9 in Association With Carboplatin Versus Standard-of-Care Chemotherapies (CCNU or TMZ) in Recurrent GBM	NCT05902169	Glioblastoma Recurrent Gliob... GBM	SonoCloud-9 (SC... Carboplatin Lomustine Temozolomide	18 Years -	CarThera
Sonocloud-9 in Association With Carboplatin Versus Standard-of-Care Chemotherapies (CCNU or TMZ) in Recurrent GBM	NCT05902169	Glioblastoma Recurrent Gliob... GBM	SonoCloud-9 (SC... Carboplatin Lomustine Temozolomide	18 Years -	CarThera
Safety Study of the Repeated Opening of the Blood-brain Barrier With the SonoCloud® Device to Treat Malignant Brain Tumors in Pediatric Patients	NCT05293197	Malignant Brain... Malignant Gliom... Embryonal Tumor	SonoCloud® (9 t...	5 Years - 17 Years	Assistance Publique - Hôpitaux de Paris
Safety and Efficacy of Transient Opening of the Blood-brain Barrier (BBB) With the SonoCloud-9	NCT03744026	Glioblastoma, A...	SonoCloud-9 Carboplatin	18 Years -	CarThera

Spots Global Cancer Trial Database for low intensity pulsed ultrasound (lipu)