Clinical trial NCT05902169: Sonocloud-9 in Association With Carboplatin Versus Standard-of-Care Chemotherapies (CCNU or TMZ) in Recurrent GBM
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Glioblastoma
Recurrent Glioblastoma
GBM
Keywords: carboplatin
SonoCloud
blood-brain barrier
Low Intensity Pulsed Ultrasound (LIPU)
Lead sponsor: CarThera
Sponsor class: INDUSTRY
First posted: 2023-06-13
Enrollment: 560
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 24 months
Secondary outcomes:
measure: Tumor Growth Rate
timeFrame: Up to week 24
measure: Progression Free Survival (PFS)
timeFrame: Up to 24 months
measure: Overall survival at 12 months (OS12)
timeFrame: 12 months
measure: Overall survival at 18 months (OS18)
timeFrame: 18 months
measure: Progression-free survival at 6 months (PFS6)
timeFrame: 6 months
Other outcomes:
measure: Safety and Tolerability
timeFrame: Up to week 24
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: UCHealth
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic of Jacksonville Florida
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health
state: Indiana
city: Baltimore
country: United States
facility: John Hopkins University
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: New York
country: United States
facility: NewYork-Presbyterian / Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Lennox Hill Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas Houston Health Science Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Hunstman Cancer Institute
state: Utah
city: Innsbruck
country: Austria
facility: Medizinische Universitaet Innsbruck
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Liège
country: Belgium
facility: CHU de Liège
city: Bron
country: France
facility: Hôpital Neurologique Pierre Wertheimer
city: Marseille
country: France
facility: Hôpital de La Timone
city: Paris
country: France
facility: Hôpital de la Pitié-Salpêtrière
city: Suresnes
country: France
facility: Hôpital Foch
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Essen
country: Germany
facility: Universitätsklinikum Essen Klinik für Neurologie
city: Köln
country: Germany
facility: Neurochirurgie uniklinik Köln
city: Bologna
country: Italy
facility: Ospedale Bellaria
city: Padua
country: Italy
facility: Istituto Oncologico Veneto
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum (Erasmus MC)
city: The Hague
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology (VHIO)
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
Study officials:
References:
citation: Carpentier A, Canney M, Vignot A, Reina V, Beccaria K, Horodyckid C, Karachi C, Leclercq D, Lafon C, Chapelon JY, Capelle L, Cornu P, Sanson M, Hoang-Xuan K, Delattre JY, Idbaih A. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med. 2016 Jun 15;8(343):343re2. doi: 10.1126/scitranslmed.aaf6086.
citation: Sonabend AM, Gould A, Amidei C, Ward R, Schmidt KA, Zhang DY, Gomez C, Bebawy JF, Liu BP, Bouchoux G, Desseaux C, Helenowski IB, Lukas RV, Dixit K, Kumthekar P, Arrieta VA, Lesniak MS, Carpentier A, Zhang H, Muzzio M, Canney M, Stupp R. Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Lancet Oncol. 2023 May;24(5):509-522. doi: 10.1016/S1470-2045(23)00112-2.