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.

Overview

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.

Interventions

• Device SonoCloud-9 (SC9)
  Implantation of SC9 device and repeat activation at constant acoustic pressure
• Drug Carboplatin
  Dose of carboplatin AUC 5 mg/ml.min-1 calculated using Calvert's formula: Dose (mg) = target AUC (mg/mL x minute) x \[glomerular filtration rate (GFR) mL/minute + 25\].
• Drug Lomustine
  Dosed and administered per labelling.
• Drug Temozolomide
  Dosed and administered per labelling.

Primary outcome measures

• Overall survival (OS) [Time frame: Up to 24 months]

Secondary outcome measures (5)

• Tumor Growth Rate [Time frame: Up to week 24]
• Progression Free Survival (PFS) [Time frame: Up to 24 months]
• Overall survival at 12 months (OS12) [Time frame: 12 months]
• Overall survival at 18 months (OS18) [Time frame: 18 months]
• Progression-free survival at 6 months (PFS6) [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Histologically proven glioblastoma (WHO criteria 2021), absence of IDH mutation demonstrated by negative IDH1 R132H staining on Immunohistochemistry.
• Patient must have received prior first line therapy that must have contained both:

• 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)
• One line of maintenance chemotherapy and/or immune- or biological therapy, (with or without Tumor-Treating Fields)
• First, unequivocal disease progression with

• measurable tumor (>100 mm2 or 1 cm3, based on RANO criteria) documented (e.g., increase of 25% in tumor diameter) on MRI and,
• 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
• Patient is a candidate for craniotomy and at least 50% resection of enhancing region
• Maximal enhancing tumor diameter prior to inclusion ≤ 5 (+7%) cm on T1w on MRI performed within 14 days prior to inclusion§. (In case of planned lobectomy, post operative peritumoral brain or residual size ≤5 cm)
• WHO performance status ≤ 2 (equivalent to Karnofsky Performance Status (KPS) ≥ 70)
• Age ≥ 18 years
• 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:

• ≥ 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)
• ≥ 6 weeks of prior bevacizumab
• Adequate hematologic, hepatic, and renal laboratory values within 14 days prior to inclusion§ i.e.:

• Hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/mm3, neutrophils ≥ 1500/mm3.
• Liver function test with ≤ grade 1 alterations, except if due to antiepileptic drug therapy or isolated increased bilirubin due to Gilbert syndrome
• Estimated glomerular filtration rate (eGFR) of at least 60 mL/min/m2 using Appendix 12.4 formula
• AST(SGOT)/ALT(SPGT) ≤ 3 X institutional ULN (upper Limit of Normal)
• Patient able to understand clinical trial information and willing to provide signed and informed consent
• Patient of childbearing potential must have a negative pregnancy test within 14 days prior to 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
• 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.
• 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)

(§) These exam/lab tests could be (re)evaluated before randomization if the corresponding selection criteria could not be fully met at time of inclusion. If not met before randomization, the patient will be considered as screen failure.

Non-Inclusion Criteria:

• Multifocal enhancing tumor on T1w (unless all localized in a 5 cm diameter area)
• Posterior fossa tumor
• Known BRAF/ NTKR mutated patients
• Patient at risk of surgery site infection (e.g., 2 or more previous craniotomies/neurosurgery within the last 3 months, poor skin condition, known impaired wound healing and/or previously infected surgical field, uncontrolled diabetes or any other condition that is of increased infectious risk in the opinion of the neurosurgeon)
• 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.
• Contra-indication to carboplatin, CCNU or TMZ
• Known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in ultrasound resonator
• Patient has received bevacizumab for other reasons (such as tumor progression) than treating edema
• Peripheral neuropathy or neuropathy ≥ grade 2
• Uncontrolled epilepsy or evidence of intracranial pressure
• Patient with known intracranial aneurism or having presented intra-tumor significant spontaneous hemorrhage
• Patient with unremovable coils, clips, shunts, intravascular stents, and/or wafer, or reservoirs
• 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.
• Patient receiving enzyme-inducing antiepileptic drugs (namely phenytoin, carbamazepine and derivatives, phenobarbital), unless switched on another antiepileptic regimen
• 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
• Patient with known or suspected active or chronic infections
• 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
• Known sensitivity/allergy to gadolinium, or other intravascular contrast agents
• Patient with impaired thermo-regulation or temperature sensation
• Pregnant, or breastfeeding patient
• 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, malnutrition…), 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
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 20 centers

• Mayo Clinic Arizona — Phoenix
• University of California, San Francisco — San Francisco
• UCHealth — Aurora
• Mayo Clinic of Jacksonville Florida — Jacksonville
• Miami Cancer Institute — Miami
• Moffitt Cancer Center — Tampa
• Winship Cancer Institute at Emory University — Atlanta
• Northwestern University — Chicago
• … and 12 more centers

Italy · 6 centers

• Ospedale Bellaria — Bologna
• Ospedale Civile di Livorno — Livorno
• Istituto Oncologico Veneto — Padua
• IFO - Istituto Nazionale Tumori Regina Elena — Roma
• Irccs Istituto Clinico Humanitas — Rozzano
• Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino — Torino

Germany · 5 centers

• Charité Universitätsmedizin Berlin — Berlin
• Klinikum Chemnitz gGmbH — Chemnitz
• Neurochirurgie uniklinik Köln — Cologne
• Universitätsklinikum Carl Gustav Carus Dresden — Dresden
• Universitätsklinikum Essen Klinik für Neurologie — Essen

Spain · 5 centers

• Vall d'Hebron Institute of Oncology (VHIO) — Barcelona
• Hospital Clinic de Barcelona — Barcelona
• Hospital Universitario HM Sanchinarro — Madrid
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario Virgen del Rocío — Seville

France · 4 centers

• Hôpital Neurologique Pierre Wertheimer — Bron
• Hôpital de La Timone — Marseille
• Hôpital de la Pitié-Salpêtrière — Paris
• Hôpital Foch — Suresnes

Belgium · 3 centers

• Universitair Ziekenhuis Brussel — Brussels
• Universitair Ziekenhuis Leuven — Leuven
• CHU de Liège — Liège

Denmark · 2 centers

• Rigshospitalet — Copenhagen
• Odense University Hospital — Odense

Netherlands · 2 centers

• Erasmus Medisch Centrum (Erasmus MC) — Rotterdam
• Haaglanden Medisch Centrum — The Hague

Switzerland · 2 centers

• Inselspital Bern — Bern
• Centre Hospitalier Universitaire Vaudois (CHUV) — Lausanne

Austria · 1 center

• Medizinische Universitaet Innsbruck — Innsbruck

Sweden · 1 center

• Akademiska sjukhuset — Uppsala

Publications

• 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. PMID 27306666
• 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 phas PMID 37142373

Identifiers

NCT: NCT05902169 · SC9-GBM-03 · 2023-505829-14-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗