Background: Sarcomas are heterogeneous diseases with multiple genetic abnormalities. XPO1 inhibition can restore the activity of multiple tumor suppressor proteins (TSP) including p53, Rb, and p27; and reduce cyclins and Akt. Selinexor is an oral XPO1 inhibitor that showed potent anti-sarcoma activity in preclinical ASPS, lipo- and bone sarcomas, and preliminary clinical activity in a phase 1 study. Methods: Oral selinexor was given at 30 mg/m² twice weekly in capsule or tablet form based on an ongoing Phase 1. Appetite stimulants and anti-nausea agents were given. Pharmacokinetic (PK) analyses were performed under fasting and fed states (low vs high fat content). Paired tumor biopsies were obtained. Response evaluation was every 8 weeks (RECIST 1.1). All pts had documented progressive disease (PD) on study entry. Results: 16 evaluable pts (7 M/9 F; median age 55 yrs; median prior regimens: 3; ECOG PS 0/1: 11/6) including 5 leiomyo- (LMS), 4 lipo- (LPS), 3 synovial (SS), and 4 other sarcomas. Grade 3-4 toxicities in cycle 1 included thrombocytopenia without bleeding (12%) and hyponatremia (6%). The most common grade 1/2 AEs in cycle 1 were: nausea (59% G1/6% G2), fatigue (29%/29%), diarrhea (41%/6%), anorexia (18%/6%). PK in 11 patients showed similar exposures (AUC_0-inf 3675 vs 3574 ng·hr/mL) of the drug in capsules or tablets; however, food (regardless of fat content) was associated with ~15% increased exposure versus fasted state. Analyses of tumor biopsies during treatment showed that selinexor resulted in nuclear localization of p53 and FOXO1, reduction in XPO1, reduced Ki67 index, increased apoptosis. Response was evaluable in 16 pts: (a) LMS: 3 stable disease (SD, 1 pt with 12% shrinkage), 2 PD; (b) LPS: 4 SD (1 pt with 10% shrinkage); (c) SS 3 PD; (d) chondrosarcoma: 1 SD, 1 PD; (e) chordoma: 1 SD; (f) spindle cell: 1 PD. 9 of the 16 pts remain on study (75-121 days). Conclusions: Selinexor should be taken with food and is generally well tolerated in pts with supportive care. Tumor shrinkage and disease stabilization was observed in a variety of soft tissue sarcomas leading to expansion of the study. Additional studies of selinexor in soft tissue sarcomas are planned. Clinical trial information: NCT01896505.