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

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)
• •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.