Background: Patients (pts) with recurrent GBM have few treatment options and a poor prognosis. Selinexor is an oral inhibitor of XPO1 mediated nuclear export resulting in nuclear retention of multiple tumor suppressor proteins (TSPs) including p53, pRB, CDKN2A, p21 and FOXO. Mean IC₅₀ of selinexor in pt derived GBM neurosphere cultures was 133 nM. In a pt derived orthotopic murine xenograft model, selinexor demonstrated marked inhibition of tumor growth in vivo and prolonged survival (P= .001). Methods: This study (NCT01986348) is an open label, multicenter, two-arm phase II trial enrolling pts with recurrent GBM after radiation therapy with concurrent and adjuvant temozolomide. Pts in Arm A received 3 doses (50 mg/m²) of selinexor prior to surgery, and resumed selinexor after surgery. Pts in Arm B received selinexor alone (50 mg/m² BIW) until disease progression. Results: (Jan 22, 2015) 7 pts (6/1 M/F, median age 57, 1–2 prior treatment regimens) were treated on Arm A and 15 pts (11/4, M/F, median age 62; 1–3 prior treatment regimens) were treated on Arm B. Mean plasma PK concentration was 999 nM (311-2071 nM) and mean tumor concentration was 136 nM (40-291 nM) in 6 pts. Grade 1/2 AE’s (Arm B) included thrombocytopenia (27%/27%), anorexia (13%/33%), fatigue (7%/40%), and hyponatremia (47%/0%). One Grade 3 AE was reported in ≥ 2 pts (fatigue) and no Grade 4 AEs were reported. Investigator reported best responses for 12 evaluable pts (Arm B) were: 2 partial responses (17%), 4 stable disease (33%) and 6 progressive disease (50%). Analysis of XPO1 and TSP expression in tumor tissue is ongoing. Conclusions: Oral selinexor at 50 mg/m² BIW achieves concentrations in GBM tissue exceeding the IC₅₀ in pre-clinical models. Main toxicities are fatigue and anorexia. Partial responses and stable disease were observed. Clinical trial information: NCT01986348