Repeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial

• Published in: Nature communications Vol. 15; no. 1; pp. 1650 - 12
• Main Authors: Carpentier, Alexandre, Stupp, Roger, Sonabend, Adam M., Dufour, Henry, Chinot, Olivier, Mathon, Bertrand, Ducray, François, Guyotat, Jacques, Baize, Nathalie, Menei, Philippe, de Groot, John, Weinberg, Jeffrey S., Liu, Benjamin P., Guemas, Eric, Desseaux, Carole, Schmitt, Charlotte, Bouchoux, Guillaume, Canney, Michael, Idbaih, Ahmed
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378/1341; 692/4028/67/1922; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bioengineering; Biological Transport; Blood-Brain Barrier; Blood-Brain Barrier - pathology; Bone surgery; Brain cancer; Cancer; Carboplatin; Carboplatin - adverse effects; Clinical trials; Disruption; Drug delivery; Effectiveness; Emitters; Glioblastoma; Glioblastoma - diagnostic imaging; Glioblastoma - drug therapy; Humanities and Social Sciences; Humans; Life Sciences; Magnetic resonance imaging; multidisciplinary; Neuroimaging; Neurons and Cognition; Patients; Pharmaceutical sciences; Pharmacology; Safety; Science; Science (multidisciplinary); Sonication; Surgery; Survival; Syncope; Ultrasonic imaging; Ultrasonography; Ultrasound; Wound infection
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45818-7

Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope ( n  = 3), fatigue ( n  = 1), wound infection ( n  = 2), and pain at time of device connection ( n  = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery. Recent work indicates that drug delivery to the brain can be improved through disruption of the blood brain barrier using low intensity pulsed ultrasound. Here, the authors report a phase I/II clinical trial investigating the combination of a nine-emitter implantable ultrasound device and carboplatin in patients with recurrent glioblastoma.