Background: KPT-330 (Selinexor) is a slowly reversible XPO1 inhibitor that forces the nuclear retention and activation of >10 tumor suppressor proteins (TSP) including NPM1c, reduces cMYC and BCLx, and induces AML cell death while sparing normal hematopoietic cells. Methods: Oral KPT-330 was given at 8-10 doses per 28-day cycle. Elevation in leukocyte XPO1 mRNA following XPO1 inhibition was a pharmacodynamic (PDn) marker for KPT-330 activity. Pharmacokinetic (PK) analyses were performed. Appetite stimulants and anti-emetics were given as part of supportive care. Results: 48 pts (24 M / 24 F; median age 68 yrs; ECOG PS 0/1: 11/37; pts were heavily pretreated with median 3 prior regimens (range of 1-7). Pts received KPT-330 across 5 dose levels (16.8 - 55 mg/m²). There have been no DLTs. Cycle 1 grade 3/4 non-DLT adverse events (AEs) in >1 pt included: fatigue (8%), thrombocytopenia (8%), neutropenia (8%), and nausea (4%). The most common Cycle 1 grade 1/2 AEs were diarrhea (35%), anorexia (33%), nausea (29%), and fatigue (25%). Prolonged administration (>4 months) of KPT-330 was feasible and there were no drug-associated deaths. PK and PDn analyses showed dose-dependent increases in C_max / AUC_0-inf (T_1/2 ~6 hrs) and increases in XPO1 mRNA. Higher doses of KPT-330 were associated with greater reductions in blast counts, which were also observed across different AML subtypes. 16 pts did not complete cycle 1 and were therefore not evaluable for response. Responses in 32 evaluable pts were: complete response (CR) with full hematological recovery: 4 pts (12%), marrow CR (CRm): 1 pt (3%), CR without hematological recovery: 1 pt (3%), duration of CR/CRi/CRm 6-13 weeks; Morphological leukemia free state: 1 pt (3%), Partial Response (PR) 2 pts (6%). Twelve (37%) of the remaining pts have experienced stable disease for > 30 days, and 11 (34%) have had progressive disease. Conclusions: KPT-330 treatment can be given over months and induce remissions in pts with heavily pretreated AML. A randomized study of KPT-330 vs available agents in chemotherapy-ineligible relapsed AML is being initiated. Clinical trial information: NCT01607892.