Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) allows for delivery of albumin-bound paclitaxel across the blood-brain barrier in patients with recurrent glioblastoma, according to research published in The Lancet Oncology.
Researchers found that LIPU-MB increased brain parenchymal concentrations of paclitaxel, and the treatment method was considered well tolerated.
This phase 1 trial (ClinicalTrials.gov Identifier: NCT03744026) included 17 adults with recurrent glioblastoma and a tumor diameter of 70 mm or smaller. The patients’ median age was 57 (range, 52-63) years, and 53% of patients were men. All patients had previously received radiotherapy, and 94% had received temozolomide.
After patients underwent tumor resection, a 9-emitter ultrasound device was implanted into a skull window. The patients then received LIPU-MB with intravenous albumin-bound paclitaxel infusion every 3 weeks for up to 6 cycles. Six dose levels were tested: 40 mg/m², 80 mg/m², 135 mg/m², 175 mg/m², 215 mg/m², and 260 mg/m².
One patient each was treated at the first 5 dose levels, and 12 patients were treated at 260 mg/m2. The median number of chemotherapy cycles per patient was 3.
A majority of patients (71%) had immediate yet transient grade 1-2 headache. Other grade 1-2 neurological deficits included paresthesia (12%), facial or limb weakness (24%), dysphasia (12%), dysarthria (12%), dysesthesia (18%), and blurred vision (29%).
“These acute treatment-emergent adverse events were anatomically associated with the brain region being sonicated (eg, sonication of the left temporal LIPU-MB led to transient grade 1 dysphasia),” the researchers noted.
There was 1 dose-limiting toxicity. It was grade 3 encephalopathy in a patient receiving the 260 mg/m2 dose. Another patient had grade 2 encephalopathy at the 260 mg/m2 dose. In both cases, this toxicity resolved in 1-2 days with supportive care, and both patients were able to continue on treatment with a dose reduction (to 175 mg/m2 and 215 mg/m2, respectively).
One patient developed grade 2 peripheral neuropathy on the 260 mg/m2 dose, which persisted even after a dose reduction to 215 mg/m2.
The most common grade 3-4 treatment-emergent adverse events were neutropenia (47%), leukopenia (29%), and hypertension (29%). There were no treatment-related deaths.
Pharmacokinetic analyses showed a significant increase in the mean brain parenchymal concentration of albumin-bound paclitaxel from the nonsonicated brain to the sonicated brain (from 0.037 to 0.139 μM; P <.0001). A post hoc analysis suggested restoration of the blood-brain barrier within 1 hour of LIPU-MB.
At the data cutoff, all patients had experienced disease progression, and 59% of patients had died from disease progression. The median progression-free survival was 2.9 months, and the median overall survival was 11 months.
“Along with several other reports, our findings support the feasibility of LIPU-MB to effectively bypass the blood-brain barrier and treat diseases in the brain, an organ that is beyond the reach of many pharmacological agents,” the researchers concluded.
They are now testing LIPU-MB for the delivery of albumin-bound paclitaxel and carboplatin in a phase 1/2 trial of patients with glioblastoma (ClinicalTrials.gov Identifier: NCT04528680).
Disclosures: The current study was partly supported by Carthera and Bristol Myers Squibb. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
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. Published online May 2023. doi:10.1016/S1470-2045(23)00112-2.