Low-intensity focused ultrasound with systemic microbubble oscillators for blood-brain barrier disruption for liquid biopsy in glioblastoma (LIBERATE).

Manmeet Singh Ahluwalia Miami Cancer Institute, Baptist Health South Florida, Miami, FL info_outline Manmeet Singh Ahluwalia, Michael W McDermott, Terry C Burns, John Frederick de Groot, John Y.K. Lee, Alon Mogilner, Theodore Schwartz, Bhavya Shah, Chetan Bettegowda, Ahmad Ozair, Atulya Aman Khosla, Arjun Sahgal, Mark V. Mishra, Achal Achrol, Nir Lipsman, Graeme Woodworth

Authors Manmeet Singh Ahluwalia Miami Cancer Institute, Baptist Health South Florida, Miami, FL info_outline Manmeet Singh Ahluwalia, Michael W McDermott, Terry C Burns, John Frederick de Groot, John Y.K. Lee, Alon Mogilner, Theodore Schwartz, Bhavya Shah, Chetan Bettegowda, Ahmad Ozair, Atulya Aman Khosla, Arjun Sahgal, Mark V. Mishra, Achal Achrol, Nir Lipsman, Graeme Woodworth Organizations Miami Cancer Institute, Baptist Health South Florida, Miami, FL, Miami Neuroscience Institute, Baptist Health South Florida, Miami, FL, Mayo Clinic, Rochester, MN, University of California, San Francisco, San Francisco, CA, University of Pennsylvania, Philadelphia, PA, NYU Langone Health, `New York, NY, Cornell University, New York, NY, UTSW, Dallas, TX, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, Sunnybrook Hospital, Toronto, ON, Canada, University of Maryland School of Medicine, Bel Air, MD, InSightec Inc, Dallas, TX, Sunnybrook Research Institute, Toronto, ON, Canada, University of Maryland, Baltimore, MD Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Insightec Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with IV microbubble oscillators (DEFINITY), non-invasively causes BBB disruption (BBBD). This clinical trial aims to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. Methods: LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged >18-80 years with suspected GBM planned for tumor biopsy or resection at eleven centers in North America are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. Patient enrollment commenced in 2022 and 7 patients have been recruited by 02/13/2023. Clinical trial information: NCT05383872.

Clinical