Background: Sarcomas are a heterogeneous group of malignancies with diverse genetic abnormalities. Selinexor is a first-in-class, oral, inhibitor of XPO1, (nuclear exportin protein 1) with potent anti-tumor activity in multiple sarcoma cell lines and in murine liposarcoma xenografts. Here we report results from a Phase 1b dose expansion trial of selinexor in sarcoma patients (NCT01896505). Methods: Patients (pts) with advanced, refractory sarcomas with radiographic progression received oral selinexor at 50 mg/m² twice weekly per 28 day cycle. Pharmacokinetics (PK, n = 12) was assessed in the fasted and fed state. Pharmacodynamic studies were performed on fresh tumor biopsies. Response was evaluated every 2 cycles (RECIST 1.1). Results: 36 pts (14 M / 22 F, ECOG 0/1: 19/17, median age 57.5 years [range 18–86], median lines of previous treatments: 3 [range 1–9]). Disease subtypes include liposarcoma (LPS; N = 12), leiomyosarcoma (LMS; N = 8) and other sarcomas (N = 16). Grade 3 drug related adverse events (AEs) occurring in ≥ 2pts included: fatigue (17%), leucopenia (17%), anemia (11%), hyponatremia (8%) and vomiting (6%). One pt had reversible, grade 3 sensory and autonomic neuropathy and two pts had grade 4 thrombocytopenia (6%). Of the 33 evaluable patients, stable disease was seen in 21/33 (64%) of pts along with decrease of tumor burden (ranging from 5 – 23%) in 7 patients. There were 12 pts (36%) that progressed. In pts with progressive LPS and LMS, the median progression free survival (mPFS) on selinexor was 4.2 months (mo) and 3.7 mo, respectively. PK was similar to previously published results and there was better absorption in the fed state compared to fasting and fat content did not affect bioavailability. Matched pre- and post-tumor biopsies (N = 6) showed target inhibition of XPO1 by nuclear localization of p53, apoptosis by increased cleaved caspase, marked reduction in cellularity and Ki-67 and increase in stroma. Conclusions: Oral selinexor administered twice weekly was well tolerated with manageable toxicities. Selinexor demonstrated durable stable disease in various soft tissue and bone sarcomas. Based on promising results a larger study is planned. Clinical trial information: NCT01896505