Key Points
- Data from a proof-of-concept study show that it is safe to use focused ultrasound blood-brain barrier opening before chemotherapy in patients with newly diagnosed glioblastoma.
- When compared with a matched control group, this clinical trial is the first to report a likely survival benefit.
The results from a preliminary open-label, phase 1/2, Insightec-sponsored clinical trial in patients with glioblastoma (GBM) have now been published in Lancet Oncology. GBM is the most aggressive primary brain tumor, and patients typically only survive an average of 16 months – even with the current standard of care therapies, which include surgical resection, radiation, and chemotherapy.
The study was led by Graeme Woodworth, MD, FACS, at the University of Maryland and Nir Lipsman, MD, PhD, at Sunnybrook Health Sciences Centre and the University of Toronto (NCT03616860) in collaboration with three additional sites in the US (NCT03551249). It was preceded by pioneering work done in Korea by Jin Woo Chang, MD, PhD.
Overview
Thirty-four participants with a mean age of 51.5 years (range 25-79) were enrolled. Each had newly diagnosed GBM and had previously undergone surgical resection and initial chemoradiotherapy. The goal of the clinical trial was to assess the safety and feasibility of using microbubble-enhanced transcranial focused ultrasound (MB-FUS) to disrupt the blood-brain barrier (BBB) before administering the standard-of-care chemotherapy temozolomide (TMZ).
The BBB’s protective layer of tightly joined cells that keeps toxins and infectious agents from entering the brain also prevents TMZ from reaching GBMs in higher concentrations. Researchers sought to use MB-FUS to increase the amount of TMZ that reached the GBM site. While the primary outcome measure was safety, the team also measured overall survival (OS), progression-free survival (PFS), and blood biomarker changes.*
Treatment Details
At the beginning of each 28-day TMZ cycle, the 18 female (53%) and 16 male (47%) participants underwent MB-FUS BBB opening using Insightec’s Exabate Neuro low-intensity focused ultrasound system (a noninvasive device) and intravenously delivered Definity® (perflutren lipid microsphere) microbubbles. The chemotherapy cycle could be repeated up to six times.
Liquid Biopsy Data Collection
In a subset study, investigators collected blood plasma at key times before and after the MB-FUS BBB opening procedure then used liquid biopsy analysis to assess the levels of DNA released from the tumors. They were interested in whether the MB-FUS BBB opening procedure would allow the tumor levels to be more precisely measured.
Results
The procedure was deemed to be safe and feasible, with no serious procedure- or device-related adverse events. A total of 144 MB-FUS BBB opening treatments (65 cubic centimeters or less) were successfully performed in the margins surrounding the tumor resection cavity, and BBB opening was visualized in all treatments. The median follow-up time per patient was 44.5 months.
Importantly, 41% of trial participants were still alive at the end of the follow-up period (3.7 years). When compared with the matched control group, the researchers found a 40% increase in overall survival. This clinical trial is the first to report a likely survival benefit from performing MB-FUS BBB opening before TMZ chemotherapy in patients with newly diagnosed GBM.
“Our results are very encouraging,” said Dr. Woodworth. “Using focused ultrasound to open the blood-brain barrier and deliver chemotherapy could significantly improve patient survival, which other ongoing studies are seeking to confirm and expand. In addition, the demonstration of repeated monthly focused ultrasound treatments with enhanced liquid biopsy for longitudinal monitoring of brain tumors could be transformative.”
“One of the frustrating realities for individuals with these devastating brain tumors, and for us as clinicians, is knowing there may be promising drugs, but they can’t get through the BBB effectively to make a significant or lasting impact,” added Dr. Lipsman.
In the subset study, liquid biopsy showed a relationship between the tumor DNA levels and survival, suggesting its ongoing use for longitudinal, noninvasive disease surveillance.
Funding and Enrollment Sites
This investigator-initiated clinical trial was funded by the National Institutes of Health and Insightec.
The five enrollment sites, which are all part of the Research for FOCused UltraSound-Enabled Drug Delivery & Diagnostics (ReFOCUSED) Consortium, are the University of Maryland, the University of Virginia, West Virginia University, Brigham and Women’s Hospital, and Sunnybrook Health Sciences Centre. ReFOCUSED joins researchers with low-frequency Exablate Neuro brain systems from more than 20 sites in North America to advance MRI-guided focused ultrasound for improving clinical outcomes for brain diseases.
Next Steps
“This clinical trial offers encouraging early evidence that focused ultrasound can safely improve chemotherapy delivery across the blood-brain barrier and may extend survival in glioblastoma patients,” said Foundation Chairman Neal F. Kassell, MD. “However, these findings come from a small cohort, so confirmation in a larger study is crucial. The next logical step is a prospective, multicenter observational study with standardized data collection, which should be fast-tracked to clarify the therapy’s real-world benefit and accelerate regulatory approval.”
Dr. Lipsman is leading a current clinical trial (NCT07179328) evaluating the safety and feasibility of MB-FUS BBB opening in adults with GBM during the maintenance phase of standard-of-care TMZ chemotherapy.
Until next-phase clinical trials can begin, MB-FUS BBB opening plus TMZ treatments may be made available to patients through expanded access options set forth by the sponsor, Insightec, and the US Food and Drug Administration.
“Insightec is committed to ensuring our patients are able to obtain access to our technology through our groundbreaking trials, especially when there are no other treatment options available to them,” said Maurice R. Ferré, MD, CEO and Chairman of Insightec. “We are actively working on this field, preparing a new clinical trial for this indication.”
For liquid biopsy, a pivotal clinical trial called LIBERATE (NCT05383872) is collecting additional data in patients with GBM at more than 15 sites in the ReFOCUSED group.
Using a different MB-FUS BBB opening technique, Carthera’s SONOBIRD clinical trial is implanting the SonoCloud device to enhance the delivery of TMZ in patients with recurrent GBM. See the January 2025 Q&A.
See the University of Maryland School of Medicine Release
See the Sunnybrook Research Institute Press Release
See Media Coverage from CTV News, The Globe and Mail, the Baltimore Sun, the Baltimore Banner, and MedicalXpress.
Related Stories
Method Established for Measuring and Predicting Blood-Brain Barrier Opening with Focused Ultrasound August 2025
One-Year Outcome Data Published for Glioblastoma Trial October 2020
New Trial of Focused Ultrasound in Glioblastoma: Opening the Blood-Brain Barrier for Chemotherapy October 2019
First Patient Completes Treatment in Korean Glioblastoma Pilot Trial January 2019
*OS is defined as the duration of patient survival from the time of treatment initiation and is considered a direct measure of clinical benefit. PFS is defined as the time from treatment initiation until disease progression or worsening.