Background: The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas, a diffuse tumor infiltrating the peri-tumoral normal brain. Low-intensity pulsed ultrasound directed at the brain with concomitant administration of intravenous microbubbles (LIPU/MB), temporarily opens the BBB. This technique was previously shown with a first generation of the device in combination with carboplatin chemotherapy (Idbaih et al. 2019). Here we investigate the pharmacokinetics and safety of this approach in the context of repeated delivery of albumin-bound paclitaxel (ABX) to the peri-tumoral brain. To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection. Methods: A Phase 1 dose-escalation trial using Bayesian adaptive design was initiated at our institution (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and normal bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, was performed every 3 weeks. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection for investigation of pharmacokinetics. Results: Seventeen patients have been enrolled and six dose levels of ABX were used (40-260 mg/m²). Severe, reversible taxane-associated encephalopathy was observed in one patient at the max. planned dose level (260 mg/m²). The patient continued treatment at a lower dose in subsequent cycles. One patient developed grade 2 cumulative peripheral neuropathy. Other mild to moderate and reversible toxicities for ABX including myelosuppression, fatigue, alopecia were observed as expected. Intraoperative sonication and pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased several-fold after LIPU/MB. On electron microscopy, sonicated tissue showed ultra-structural alterations in brain capillary endothelial cells. Molecular studies showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis, cell permeability as well as cell-cell and cell-matrix adhesion. Updated results will be presented. Conclusions: The LIPU/MB using skull-implantable ultrasound enhances the penetration of large chemotherapeutic drugs such as ABX in large regions of the brain, a procedure that can be performed repeatedly and safely. LIPU-based BBB opening leads to ultrastructural and transcriptional alterations in brain endothelial cells. A Phase 2 clinical trial is planned to investigate efficacy of this approach. Funding: NIH/NCI 1R01CA245969-01A1, Carthera (SC9 devices), Celgene/BMS, Malnati Brain Tumor Institute, Moceri Family Foundation. Clinical trial information: NCT04528680.