Microbubble-enhanced transcranial focused ultrasound with temozolomide for patients with high-grade glioma (BT008NA): a multicentre, open-label, phase 1/2 trial

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.

BT008NA was an open-label, single-arm, phase 1/2 trial conducted at five sites in the USA and Canada (part of the ReFOCUSED Consortium). Key eligibility criteria were participants with newly diagnosed high-grade glioma (glioblastoma as per WHO 2016 classification), aged 18–80 years, with normal organ function, a baseline Karnofsky Performance Status score of 70 or higher, who had received maximal safe resection and 6-week chemoradiotherapy and were to start standard-of-care monthly adjuvant temozolomide chemotherapy (150 mg/m2 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.

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.

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.

National Institutes of Health and Insightec.

References

1.

Weller, M ∙ Van Den Bent, M ∙ Preusser, M ∙ et al.

EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood

Nat Rev Clin Oncol. 2021; 18:170-186

Google Scholar

2.

Arvanitis, CD ∙ Ferraro, GB ∙ Jain, RK

The blood–brain barrier and blood–tumour barrier in brain tumours and metastases

Nat Rev Cancer. 2020; 20:26-41

Google Scholar

3.

McDannold, N ∙ Arvanitis, CD ∙ Vykhodtseva, N ∙ et al.

Temporary disruption of the blood–brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques

Cancer Res. 2012; 72:3652-3663

Google Scholar

4.

Meng, Y ∙ Reilly, RM ∙ Pezo, RC ∙ et al.

MR-guided focused ultrasound enhances delivery of trastuzumab to HER2-positive brain metastases

Sci Transl Med. 2021; 13, eabj4011

Google Scholar

5.

Meng, Y ∙ Pople, CB ∙ Suppiah, S ∙ et al.

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors

Neuro Oncol. 2021; 23:1789-1797

Google Scholar

6.

Yuan, J ∙ Xu, L ∙ Chien, CY ∙ et al.

First-in-human prospective trial of sonobiopsy in high-grade glioma patients using neuronavigation-guided focused ultrasound

NPJ Precis Oncol. 2023; 7:92

Google Scholar

7.

Ozair, A ∙ Moiz, B ∙ Anastasiadis, P ∙ et al.

Applications of transcranial focused ultrasound for primary brain tumors

Neurooncol Adv. 2025; 7, vdaf156

Google Scholar

8.

Anastasiadis, P ∙ Gandhi, D ∙ Guo, Y ∙ et al.

Localized blood–brain barrier opening in infiltrating gliomas with MRI-guided acoustic emissions-controlled focused ultrasound

Proc Natl Acad Sci USA. 2021; 118, e2103280118

Google Scholar

9.

Mainprize, T ∙ Lipsman, N ∙ Huang, Y ∙ et al.

Blood–brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study

Sci Rep. 2019; 9:321

Google Scholar

10.

Park, SH ∙ Kim, MJ ∙ Jung, HH ∙ et al.

Safety and feasibility of multiple blood–brain barrier disruptions for the treatment of glioblastoma in patients undergoing standard adjuvant chemotherapy

J Neurosurg. 2020; 134:475-483

Google Scholar

11.

Chen, KT ∙ Chai, WY ∙ Lin, YJ ∙ et al.

Neuronavigation-guided focused ultrasound for transcranial blood–brain barrier opening and immunostimulation in brain tumors

Sci Adv. 2021; 7, eabd0772

Google Scholar

12.

Sonabend, AM ∙ Gould, A ∙ Amidei, C ∙ et al.

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; 24:509-522

Google Scholar

13.

Bilbro, NA ∙ Hirst, A ∙ Paez, A ∙ et al.

The IDEAL Reporting Guidelines: A Delphi Consensus Statement Stage specific recommendations for reporting the evaluation of surgical innovation

Ann Surg. 2021; 273:82-85

Google Scholar

14.

Woodworth, GF ∙ Anastasiadis, P ∙ Ozair, A ∙ et al.

Acoustic emissions dose and spatial control of blood–brain barrier opening with focused ultrasound

Device. 2025; 3, 100894

Google Scholar

15.

Douville, C ∙ Cohen, JD ∙ Ptak, J ∙ et al.

Assessing aneuploidy with repetitive element sequencing

Proc Natl Acad Sci USA. 2020; 117:4858-4863

Google Scholar

16.

Cristiano, S ∙ Leal, A ∙ Phallen, J ∙ et al.

Genome-wide cell-free DNA fragmentation in patients with cancer

Nature. 2019; 570:385-389

Google Scholar

17.

US Food and Drug Administration

Guidance document: considerations for the design and conduct of externally controlled trials for drug and biological products

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-design-and-conduct-externally-controlled-trials-drug-and-biological-products

Date: 2023

Date accessed: January 10, 2025

Google Scholar

18.

Rahman, R ∙ Ventz, S ∙ McDunn, J ∙ et al.

Leveraging external data in the design and analysis of clinical trials in neuro-oncology

Lancet Oncol. 2021; 22:e456-e465

Google Scholar

19.

Iacus, SM ∙ King, G ∙ Porro, G

Causal inference without balance checking: coarsened exact matching

Polit Anal. 2012; 20:1-24

Google Scholar

20.

Ho, DE ∙ Imai, K ∙ King, G ∙ et al.

Matching as nonparametric preprocessing for reducing model dependence in parametric causal inference

Polit Anal. 2007; 15:199-236

Google Scholar

21.

VanderWeele, TJ ∙ Ding, P

Sensitivity analysis in observational research: introducing the E-value

Ann Intern Med. 2017; 167:268-274

Google Scholar

22.

Stupp, R ∙ Mason, WP ∙ van den Bent, MJ ∙ et al.

Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

N Engl J Med. 2005; 352:987-996

Google Scholar

23.

Carpentier, A ∙ Stupp, R ∙ Sonabend, AM ∙ et al.

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

Nat Commun. 2024; 15, 1650

Google Scholar

24.

Arrieta, VA ∙ Gould, A ∙ Kim, KS ∙ et al.

Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas

Nat Commun. 2024; 15, 4698

Google Scholar

25.

Idbaih, A ∙ Canney, M ∙ Belin, L ∙ et al.

Safety and feasibility of repeated and transient blood–brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma

Clin Cancer Res. 2019; 25:3793-3801

Google Scholar

26.

Carpentier, A ∙ Canney, M ∙ Vignot, A ∙ et al.

Clinical trial of blood–brain barrier disruption by pulsed ultrasound

Sci Transl Med. 2016; 8, 343re2

Google Scholar

27.

Portnow, J ∙ Badie, B ∙ Chen, M ∙ et al.

The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation

Clin Cancer Res. 2009; 15:7092-7098

Google Scholar

28.

Alnahhas, I ∙ Alsawas, M ∙ Rayi, A ∙ et al.

Characterizing benefit from temozolomide in MGMT promoter unmethylated and methylated glioblastoma: a systematic review and meta-analysis

Neurooncol Adv. 2020; 2, vdaa082

Google Scholar

29.

Mouliere, F ∙ Smith, CG ∙ Heider, K ∙ et al.

Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients

EMBO Mol Med. 2021; 13, e12881

Google Scholar

30.

Bettegowda, C ∙ Sausen, M ∙ Leary, RJ ∙ et al.

Detection of circulating tumor DNA in early- and late-stage human malignancies

Sci Transl Med. 2014; 6, 224ra24

Google Scholar

31.

Wei, KC ∙ Chu, PC ∙ Wang, HY ∙ et al.

Focused ultrasound-induced blood–brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study

PloS One. 2013; 8, e58995

Google Scholar

32.

Liu, HL ∙ Huang, CY ∙ Chen, JY ∙ et al.

Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood–brain barrier opening for enhanced temozolomide delivery in glioma treatment

PLoS One. 2014; 9, e114311

Google Scholar