Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median overall survival (OS) of 15 months for patients with newly diagnosed GBM (ndGBM) and 5-7 months for patients with recurrent GBM (rGBM). To improve the prognosis of patients with GBM, novel therapies are urgently needed. Selinexor is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing death of cancer cells. Selinexor is an FDA-approved treatment for patients with heavily pretreated multiple myeloma, for patients who received at least one prior therapy, and for patients with relapsed/refractory diffuse large B-cell lymphoma. Increased XPO1 expression in gliomas was associated with higher pathological stage and poorer prognosis. In a phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. In preclinical studies, selinexor showed synergy with radiation, temozolomide, or lomustine. The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes for patient with ndGBM or rGBM. Methods: This phase 1 dose finding study is followed by a 1:1 randomized phase 2 (n= 350) efficacy exploration trial to independently evaluate 3 regimens: Arm A – radiation +/- selinexor in unmethylated O⁶-methylguanine-DNA-methyltransferase (uMGMT) ndGBM; Arm B – radiation and temozolomide +/- selinexor in mMGMT ndGBM; Arm C – lomustine +/- selinexor in first relapsed rGBM following frontline radiation and temozolomide. The phase 1 primary endpoint is maximum tolerated dose/recommended phase 2 dose, with secondary endpoints of overall response rate (ORR) per modified Response Assessment in Neuro-Oncology (mRANO), duration of response (DOR), progression free survival (PFS), and OS. The phase 2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS at 6 months, ORR, and DOR. For Arm C, the phase 2 primary endpoint is OS, while key secondary endpoints are PFS, PFS at 6 months, ORR, and DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy in Arms A and B, and 80% power to detect a hazard ratio of 0.70 for Arm C. We are currently enrolling patients nationwide. Clinical trial information: NCT04421378