Introduction: Exportin-1 (XPO1), a nuclear transport protein critical for the export of tumor suppressor proteins (TSPs) and select mRNAs to the cytoplasm, is highly expressed in acute myeloid leukemia (AML) and correlates with poor survival. Selinexor, an oral, first-in-class, selective inhibitor of nuclear export, blocks XPO1 function. We previously reported that sequential treatment of AML blasts using the hypomethylating agent decitabine followed by selinexor exhibited strong anti-leukemic effects in vivo by inducing the expression of silenced TSPs that are kept in the nucleus by XPO1 inhibition (Ranganathan, Blood 2015). Methods: Based on these findings, a phase I dose-escalation study was initiated to evaluate the safety, feasibility, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and preliminary clinical activity of selinexor in combination with decitabine in poor-risk AML pts (NCT02093403). Adults with relapsed or refractory (R/R) AML and older (age ≥60) unfit pts with untreated AML were eligible. Pts received 10-day decitabine induction(s) at 20mg/m2 on days 1-10 for up to four 28-day cycles in combination with selinexor once daily, twice weekly beginning on day 11. Pts with Results: Twenty-four pts were enrolled (see Table 1 for baseline pt characteristics). Nineteen pts had R/R AML (median of 3 prior chemotherapy regimens, range 1-4); five pts had previously untreated AML. Seventeen pts were treated on the dose escalation phase receiving selinexor doses ranging from 23mg/m2 to 55mg/m2. After two patients in DL 1 declined continuation of study therapy beyond cycle 1 due to grade Conclusions: The combination of selinexor plus decitabine is an active regimen in poor-risk AML pts, with CR/CRi/mCR rate of 80% in older untreated and 21% in R/R AML pts. Modification of selinexor exposure (flat dose of 60mg given twice weekly for 2 weeks after decitabine) improved tolerability of the regimen. Correlative studies, including targeted mutation analysis to assess whether specific mutations are associated with response, are ongoing and will be presented. Disclosures Bhatnagar: Karyopharm: Research Funding.