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Introduction/Purpose Recurrent glioblastoma (rGBM) is highly aggressive with poor prognosis. Upon recurrence, treatment options are limited with no standard of care. Neurovascular radiotherapy (NVRT) represents a novel intra-arterial approach, utilizing glass yttrium-90 (Y-90) microspheres (TheraSphere™, Boston Scientific) to super-selectively deliver high-dose radiation to the tumor. The FRONTIER trial evaluates the safety and technical feasibility of this endovascular microsphere-based approach to treat rGBM.Materials and Methods The FRONTIER trial is a prospective, single-arm, multi-center phase-1 study in rGBM patients with 1-5cm diameter T1-contrast-enhancing disease who received ≤two prior lines of systemic therapy. The primary endpoint is 30-day incidence of treatment-related Limiting Toxicities (primarily ≥grade 3 non-hematologic toxicities, with some additional exclusions). Secondary endpoints include adverse event (AE) rate, neurological changes, technical success (PET absorbed dose within ±20% of target dose), and efficacy. Intra-arterial procedure planning involved diagnostic cerebral mapping angiography and cone-beam CT (CBCT) to evaluate angiographic eligibility and determine optimal microcatheter position(s) in a distal arterial segment completely perfusing the tumor. The region of anticipated microsphere deposition (perfused volume [PV]) was defined as the CBCT-contrast-enhancing region from up to two vessel administration locations, with a maximum total PV of 150cc. Tumor coverage was assessed using MR-CBCT fusion. Patient groups were defined by eloquence involvement in the PV and by hemisphere. Those meeting eligibility criteria returned for NVRT treatment within 14 days, targeting 40Gy absorbed dose to the PV. Post-treatment evaluations included MRI, Y90-PET (via internal pair production enabling PET imaging), and neurological assessments.Results Eighteen patients are included in this interim analysis of the ongoing trial. Median total PV volume was 84.6cc (range 40.9-149.5cc). All patients tolerated the procedure well with no treatment-related Limiting Toxicities. Ten patients (56%) experienced 20 procedure-related AEs; fourteen Grade 1, four Grade 2, and two Grade 3 events. Three procedure-related AEs were serious; one Grade 1 and one Grade 2 seizure in the same patient, and a grade 3 procedure-related thromboembolic event in another. Four patients (22%) experienced seven device-related AEs; three Grade 1 and four Grade 2. Transient increases in neurological assessments were observed in 6/18 patients, which resolved to within one NIHSS-point of baseline within 1-month in 5/6[AE1] . Technical success was achieved in 94% of cases, and post-treatment Y90-PET revealed a median absorbed dose of 41.3Gy (range 29.8-46.5Gy) to the PV. Due to preferential tumor perfusion within the PV, the median tumor absorbed dose was notably higher at 124.2Gy (range 54.1-508.5Gy).Conclusion Results from the FRONTIER trial demonstrate that intra-arterial Y-90 microsphere administration is technically feasible and well-tolerated in rGBM. This novel therapeutic approach has been successfully reproduced across four independent sites. Future studies will refine dose planning and response modeling to optimize therapeutic efficacy. Enrollment in the FRONTIER trial is ongoing.Disclosures S. Ansari: 2; C; Boston Scientific. R. Stupp: None. M. Tate: None. R. Lukas: None. K. Dixit: None. N. Butowski: None. J. Boockvar: None. J. Boockvar: None. J. Weinstein: None. Y. Serulle: None. B. Toskich: None. F. Basabarescu: None. P. Kennedy: None. A. Eldridge: None. S. Ryan: None. S. Ryan: None. M. Dreher: None. R. Salem: None.Abstract O-023 Table 1CharacteristicsN (%)PV LocationNon-dominant hemisphere, non-eloquent region13 (72%)Non-dominant hemisphere, eloquent region4 (22%)Dominant hemisphere, non-eloquent region1 (6%)Dominant hemisphere, eloquent region0 (0%)Number of vessels treated to achieve complete tumor coverage112 (66%)26 (33%)Arterial Territory and Segment LevelMCA20 (83%)M23 (13%)M310 (42%)M47 (29%)PCA4 (17%)P33 (13%)P41 (4%)