Background: KPT-330 (Selinexor) is a SINE XPO1 antagonist that forces nuclear retention and activation of >10 tumor suppressor proteins (TSP) and associated with reduction in c-myc and Bcl-X_L. Anti-NHL activity was observed in murine models and in spontaneous canine aggressive lymphomas. Methods: Oral KPT-330 was given at 8-10 doses / 28-day cycle. XPO1 inhibition leads to rapid elevations in XPO1 mRNA, representing a pharmacodynamic (PDn) marker for KPT-330. Tumor biopsies were performed. Response evaluation was done in cycles 1, 2, and every 2 cycles. All pts had heavily pretreated NHL with progressive disease (PD) on study entry. Results: Thirty-two pts (18 M, 14 F; median age 68 yrs; ECOG PS 0/1: 9/23; median prior regimens: 3 range 1-11) received KPT-330 across 8 dose levels (3 to 60 mg/m²). Dosing at 60 mg/m² twice weekly (BIW) is ongoing and MTD has not been reached. Cycle 1 (DLT period) Grade 3/4 events in >1 pt included thrombocytopenia (20%) and neutropenia (20%). The most common grade 1/2 AEs in cycle 1: anorexia (53%), nausea (50%), fatigue (50%), and vomiting (43%). Supportive care with appetite stimulants and anti-emetics diminished constitutional symptoms. Increases in XPO1 mRNA levels were observed at 4-48 hours, supporting BIW dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reduction, and apoptosis. Objective responses were observed in all histologies of NHL (Table). 5/16 pts have remained on therapy for an average of 9 months (>5-17) months without clinically significant toxicities. Conclusions: KPT-330 is generally well tolerated and can be administered over prolonged periods. The recommended phase 2 dose is ≥45 mg/m²BIW. Durable single agent activity was observed in heavily pretreated NHL pts, and phase 2 studies in DLBCL and Richter’s Syndrome are planned. Clinical trial information: NCT01607892.