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

Phase 3

Recruiting

• Conditions: Glioblastoma; Recurrent Glioblastoma; GBM
• Interventions: Device: SonoCloud-9 (SC9); Drug: Lomustine; Drug: Temozolomide; Drug: Carboplatin

• Registration Number: NCT05902169
• Lead Sponsor: CarThera

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-06-05
• Study First Submitted QC: 2023-06-05
• Study First Posted: 2023-06-13
• Study Start: 2024-01-29
• Status Verified: 2024-07
• Last Update Submitted: 2025-04-25
• Last Update Posted: 2025-04-27
• Primary Completion: 2028-01-28
• Study Completion: 2028-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 560

Inclusion Criteria

1. Histologically proven glioblastoma (WHO criteria 2021), absence of IDH mutation demonstrated by negative IDH1 R132H staining on Immunohistochemistry.

2. Patient must have received prior first line therapy that must have contained both:

   1. Prior surgery or biopsy and standard fractionated radiotherapy (1.8-2 Gy/fraction, >56 Gy<66 Gy) or hypofractionated radiotherapy (15 x 2.66 Gy or similar regimen)
   2. One line of maintenance chemotherapy and/or immune- or biological therapy, (with or without Tumor-Treating Fields)

3. First, unequivocal disease progression with

   1. measurable tumor (>100 mm2 or 1 cm3, based on RANO criteria) documented (e.g., increase of 25% in tumor diameter) on MRI performed within 14 days of inclusion and,
   2. interval of a minimum of 12 weeks since the completion of prior radiotherapy, unless there is a new lesion outside the radiation field or unequivocal evidence of viable tumor on histopathological sampling

4. Patient is candidate for craniotomy and at least 50% resection of enhancing region

5. Maximal enhancing tumor diameter prior to inclusion ≤ 5 cm on T1w. (In case of planned lobectomy, post operative peritumoral brain or residual size ≤5 cm)

6. WHO performance status ≤ 2 (equivalent to Karnofsky Performance Status (KPS) ≥ 70)

7. Age ≥ 18 years

8. Participant must be recovered from acute toxic effects (<grade 2) of all prior anticancer therapy. Interval since last therapy to presumed date of surgery of at least:

   1. ≥ 4 weeks or 5 half-lives (whichever is shorter) for

      • Cytotoxic
      • Other small chemical entity (e.g., targeted therapy)
      • For biologics (e.g., antibodies, except bevacizumab)

   2. ≥ 6 weeks of prior bevacizumab

9. Adequate hematologic, hepatic, and renal laboratory values within 14 days of inclusion i.e.:

   1. Hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/mm3, neutrophils ≥ 1500/mm3.
   2. Liver function test with ≤ grade 1 alterations, except if due to antiepileptic drug therapy or isolated increased bilirubin due to Gilbert syndrome
   3. Estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2 using Cockcroft Gault formula

10. Patient able to understand clinical trial information and willing to provide signed and informed consent

11. Patient of childbearing potential must have a negative pregnancy test within 14 days of inclusion and must agree to use a medically-acceptable method of birth control during the treatment period and, if randomized in the experimental arm, for at least 1 month after the last cycle of carboplatin

12. A male patient must agree to use condoms during the treatment period and, if randomized in the experimental arm, for at least 3 months after the last cycle of carboplatin; the patient must also refrain from donating sperm during this period.

13. Patient must be a beneficiary of a health plan that covers routine patient care costs. Patient must be a beneficiary of or affiliated with a social security scheme (according to country-specific requirements)

Non-Inclusion Criteria:

1. Multifocal enhancing tumor on T1w (unless all localized in a 5 cm diameter area)
2. Posterior fossa tumor
3. Known BRAF/ NTKR mutated patients
4. Patient at risk of surgery site infection (e.g., 2 or more previous craniotomies/neurosurgery within the last 3 months, poor skin condition, and/or previously infected surgical field, or any other condition that is of increased infectious risk in the opinion of the neurosurgeon)
5. Patient treated at high, stable -or average- dose of corticosteroids (≥ 6 mg/day dexamethasone or equivalent) in the 7 days prior to inclusion. Patients on dexamethasone for reasons other than mass effect may still be enrolled.
6. Contra-indication to carboplatin, CCNU or TMZ
7. Known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in ultrasound resonator
8. Patient has received bevacizumab for other reasons (such as tumor progression) than treating edema
9. Peripheral neuropathy or neuropathy ≥ grade 2
10. Uncontrolled epilepsy or evidence of intracranial pressure
11. Patient with known intracranial aneurism or having presented intra-tumor significant spontaneous hemorrhage
12. Patient with unremovable coils, clips, shunts, intravascular stents, and/or wafer, or reservoirs
13. Patient with medical need to be on continued anti-platelet aggregation therapy and/or anticoagulation. Patients for whom anticoagulation/platelet aggregation can be temporarily interrupted may be eligible after discussion and prior authorization by the sponsor.
14. Patient receiving enzyme-inducing antiepileptic drugs (namely phenytoin, carbamazepine and derivatives, phenobarbital), unless switched on another antiepileptic regimen
15. History of other malignancy within 3 years prior to study start with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma, non-melanomatous skin cancer or carcinoma in situ of the uterine cervix
16. Patient with known or suspected active or chronic infections
17. Patient with known significant cardiac disease, known to have right-to-left shunts, severe pulmonary hypertension (pulmonary artery pressure > 90 mm Hg), uncontrolled systemic hypertension, or acute respiratory distress syndrome
18. Known sensitivity/allergy to gadolinium, or other intravascular contrast agents
19. Patient with impaired thermo-regulation or temperature sensation
20. Pregnant, or breastfeeding patient
21. Any other serious patient medical or psychological condition that may interfere with adequate and safe delivery of treatment and care (e.g., positive human immunodeficiency virus [HIV] status, potential blood-borne infections,...), circumstance (e.g., sinus opening during surgery), psychological, morphological characteristics (e.g., skin characteristics, bone thickness), or any pre-existing comorbidities that in the investigator's opinion may prevent the implantation of the device, may impair the ability of the patient to receive treatment with SonoCloud-9 or may be confounding for evaluation of the clinical trial endpoints
22. Patients under guardianship, curatorship, under legal protection or deprived of liberty by an administrative or judicial decision

Exclusion Criterion:

Occurrence of any major medical illnesses or impairments that in the Investigator's opinion may hampered the ability of the patient to receive treatment with SonoCloud-9 or may be confounding for evaluation of the clinical endpoints.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental Arm: SonoCloud-9 Ultrasound + Carboplatin	SonoCloud-9 (SC9)	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.
Control Arm: SoC single agent chemotherapy TMZ or CCNU	Temozolomide	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.
Experimental Arm: SonoCloud-9 Ultrasound + Carboplatin	Carboplatin	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.
Control Arm: SoC single agent chemotherapy TMZ or CCNU	Lomustine	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.

Primary Outcome Measures

Name	Time	Method
Overall survival (OS)	Up to 24 months	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).

Secondary Outcome Measures

Name	Time	Method
Overall survival at 12 months (OS12)	12 months	Defined as the proportion of participants alive at 12 months
Progression-free survival at 6 months (PFS6)	6 months	Defined as the proportion of participants without disease progression or death due to any cause at 6 months.
Tumor Growth Rate	Up to week 24	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).
Progression Free Survival (PFS)	Up to 24 months	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.
Overall survival at 18 months (OS18)	18 months	Defined as the proportion of participants alive at 18 months

Trial Locations

Locations (39)

John Hopkins University; 🇺🇸 Baltimore, Maryland, United States

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Medizinische Universitaet Innsbruck; 🇦🇹 Innsbruck, Austria

Mayo Clinic Arizona; 🇺🇸 Phoenix, Arizona, United States

UCHealth; 🇺🇸 Aurora, Colorado, United States

Mayo Clinic of Jacksonville Florida; 🇺🇸 Jacksonville, Florida, United States

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Indiana University Health; 🇺🇸 Indianapolis, Indiana, United States

Mayo Clinic Rochester; 🇺🇸 Rochester, Minnesota, United States

Weill Cornell Medicine; 🇺🇸 New York, New York, United States

NewYork-Presbyterian / Columbia University Irving Medical Center; 🇺🇸 New York, New York, United States

Lennox Hill Hospital; 🇺🇸 New York, New York, United States

University of North Carolina; 🇺🇸 Chapel Hill, North Carolina, United States

Penn State Health Milton S. Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

University of Texas Houston Health Science Center; 🇺🇸 Houston, Texas, United States

University of Utah, Hunstman Cancer Institute; 🇺🇸 Salt Lake City, Utah, United States

Universitair Ziekenhuis Brussel; 🇧🇪 Brussel, Belgium

Universitair Ziekenhuis Leuven; 🇧🇪 Leuven, Belgium

CHU de Liège; 🇧🇪 Liège, Belgium

Hôpital Neurologique Pierre Wertheimer; 🇫🇷 Bron, France

Hôpital de La Timone; 🇫🇷 Marseille, France

Hôpital de la Pitié-Salpêtrière; 🇫🇷 Paris, France

Hôpital Foch; 🇫🇷 Suresnes, France

Klinikum Chemnitz gGmbH; 🇩🇪 Chemnitz, Germany

Universitätsklinikum Carl Gustav Carus Dresden; 🇩🇪 Dresden, Germany

Universitätsklinikum Essen Klinik für Neurologie; 🇩🇪 Essen, Germany

Neurochirurgie uniklinik Köln; 🇩🇪 Köln, Germany

Istituto Oncologico Veneto; 🇮🇹 Padua, Italy

Erasmus Medisch Centrum (Erasmus MC); 🇳🇱 Rotterdam, Netherlands

Haaglanden Medisch Centrum; 🇳🇱 The Hague, Netherlands

Vall d'Hebron Institute of Oncology (VHIO); 🇪🇸 Barcelona, Spain

Hospital Universitario HM Sanchinarro; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Universitario Virgen del Rocío; 🇪🇸 Sevilla, Spain

Inselspital Bern; 🇨🇭 Bern, Switzerland

Centre Hospitalier Universitaire Vaudois (CHUV); 🇨🇭 Lausanne, Switzerland