Microbubble-enhanced transcranial focused ultrasound with temozolomide for patients with high-grade glioma (BT008NA): a multicentre, open-label, phase 1/2 trial
Graeme F. Woodworth, Pavlos Anastasiadis, Ahmad Ozair, Jeremi Chabros, Chetan Bettegowda, Chixiang Chen, Jakob V. E. Gerstl, Christopher Douville, Rania A. Mekary, Timothy R. Smith, Ying Meng, Cynthia Hawkins, Christopher B. Pople, Agessandro Abrahão, Maheleth Llinas, Chris Heyn, Adomas Bunevičius, Ali R. Rezai, Anna Ball, Kaitlyn Henry, Arjun Sahgal, Erickson Torio, Haoyu Ren, Haroon Ahmad, Harshit Arora, Howard M. Eisenberg, James Perry, Jeffrey Carpenter, Kullervo Hynynen, Lily C Pham, Mary Beth Anketell, Mary Jane Lim-Fat, Zhiyuan Xu, Christopher P. Cifarelli, Jason P. Sheehan, Nathan J. McDannold, Dheeraj Gandhi, Alexandra J. Golby, Nir Lipsman
Abstract
BACKGROUND: Brain-infiltrating tumour cells from high-grade glioma remain shielded from drug treatments by the blood-brain barrier, leading to inevitable recurrence. Microbubble-enhanced transcranial focused ultrasound (MB-FUS) enables controlled blood-brain barrier opening (BBBO), permitting localised drug delivery. We aimed to assess safety and feasibility of MB-FUS plus standard-of-care chemotherapy for individuals with high-grade glioma. METHODS: of body surface area). MRI-guided, 220 kHz transcranial MB-FUS treatments were delivered in periresectional (tumour-infiltrative) regions, on any of the first 3 days of a 28-day temozolomide cycle, for up to six cycles. Primary outcomes were safety (adverse events) and feasibility (BBBO: new contrast enhancement on post-procedure T1-weighted MRI). Protocol-prespecified secondary outcomes were overall survival and progression-free survival. Analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03551249 (USA) and NCT03616860 (Canada), and is closed to enrolment. FINDINGS: Between Oct 16, 2018, and March 9, 2022, we enrolled 34 participants, all evaluable for prespecified primary and secondary endpoints, with a mean age of 51·5 years (SD 13·0) and median follow-up 44·5 months (95% CI 34·9-57·3). By self-reporting, 18 (53%) participants were female and 16 (47%) male, 28 (82%) were White, and 34 (100%) were non-Hispanic. 176 adverse events were captured: 54 (31%) chemotherapy-related, 10 (6%) disease-related, 87 (49%) related to undergoing MB-FUS (40 [46%] grade 1, 46 [53%] grade 2, and one [1%] grade 3), and 25 (14%) unrelated. Two (1%) of the adverse events were grade 5 (disease-related deaths), three (2%) grade 4 (temozolomide-related haematological abnormalities), and eight (5%) grade 3 (three [2%] temozolomide-related, one [1%] MB-FUS-related, three [2%] disease-related, and one [1%] unrelated); these occurred across seven (21%) of 34 participants. No treatment-related deaths occurred during the trial. BBBO was visualised in all treatments. Median overall survival was 31·3 months (95% CI 21·1-not reached) and median progression-free survival was 13·5 months (9·9-26·9) with patient-specific disease courses found concordant with trajectories of MB-FUS-enriched plasma cell-free DNA. INTERPRETATION: MB-FUS plus temozolomide is a safe combinatorial therapeutic approach for individuals with high-grade glioma, with the potential to improve survival and enable non-invasive plasma biomarker-based disease surveillance (sono-liquid biopsy), warranting randomised controlled trials. FUNDING: National Institutes of Health and Insightec.