Background: Lisavanbulin (BAL101553, prodrug of BAL27862) is a novel, oral microtubule destabilizer that leads to cell death mediated by modulating the spindle assembly checkpoint. It has promising antitumoral activity in orthotopic glioblastoma (GBM) models in combination with radiation (RT) ± temozolomide (TMZ), including in MGMT promoter unmethylated (uMGMT) tumors. Lisavanbulin is a lipophilic and small molecule (MW 387), and data in rodents showed its ability to cross the blood-brain barrier (brain-plasma ratio 1:1). Methods: This multicenter phase 1 study was to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy in 30 fractions) in patients with newly diagnosed uMGMT GBM. Dose escalation followed a modified 3+3 design. The safety evaluation period ended 4 weeks after completion of radiation, which was also the end of study. Patients were allowed to continue treatment with standard adjuvant TMZ as per treating physician’s recommendation. Results: Twenty-six patients with uMGMT GBM (median age 64y, 42.3% male, 61.5% with gross total resection, median KPS 80) were enrolled. Two GBM harbored an IDH1 mutation. Patients were treated at 5 different dose levels of Lisavanbulin administered once daily for 6 weeks concomitantly with RT: Lisavanbulin 4 mg (5 pts), 6 mg (5 pts), 8 mg (7 pts), 12 mg (5 pts), and 15 mg (4 pts). The initial starting dose was 8 mg. Due to Grade 4 aseptic meningoencephalitis in the first patient, the study was held and the dose decreased to 4 mg. Dose escalation resumed and continued to 15 mg with 1 DLT of Grade 2 confusion and memory impairment observed at 12 mg. A planned dose expansion was not conducted due to discontinuation of funding. Grade 3 AEs were hypertension (2), seizure (2), cognitive disturbance (1), cerebral edema (1), hyponatremia (1), and lymphopenia (1); no additional grade 4 AE was observed other than the 1 case of aseptic meningoencephalitis. Median OS was 12.8 months (95%CI: 9.1-18.3 months). At data cut-off, 8 subjects (30.8%) were still alive. 38.5% subjects had no information on disease progression and were censored during the estimation of PFS. The median PFS was 7.7 months (95%CI: 3.0-9.5 months). Conclusions: The maximum studied safe dose for Lisavanbulin in combination with RT in newly diagnosed uMGMT GBM was determined at 15 mg daily during radiation. Overall, the safety of this combination was acceptable. Next steps in developing Lisavanbulin in newly diagnosed GBM include safety studies in combination with TMZ and of TMZ+RT in MGMT promoter methylated GBM prior to formally studying efficacy in a prospective randomized trial. Clinical trial information: NCT03250299.