Background: Patients (pts) with relapsed or refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Selinexor (SEL), an oral inhibitor of the nuclear transport protein XPO1, has shown promising single-agent activity in clinical trials of AML and preclinical synergy with topoisomerase (topo) II inhibitors. Hence, we tested the combination of SEL plus chemotherapy with topo II inhibitor in pts with R/R AML. Methods: This phase 1, open-label 3+3, dose escalation study tested SEL plus mitoxantrone, etoposide, and cytarabine (MEC) in pts aged < 60 years with R/R AML (NCT02299518). The primary objectives were to evaluate the safety and preliminary efficacy of this combination. Pts received MEC IV on days 1-6, and up to 6 doses of SEL, across 3 dose levels ranging from 30-55 mg/m² on days 1, 3, 8, 10, 15, and 17. Results: We enrolled 23 pts (median age 47 years); 11 were treated on the dose escalation portion. Due to dose limiting hyponatremia in 2 pts on dose level 2 (SEL 40 mg/m²), the maximum tolerated dose was 30 mg/m². However, based on the totality of safety data from other SEL trials in R/R AML, we established the RP2D of SEL in pts with AML to be 60 mg. We treated an additional 12 pts with 60 mg of SEL in combination with MEC. Common grade ≥3 toxicities for 21 treated pts for whom all analyses are complete (2 remain on therapy) are shown in Table 1. Of 21 pts, the overall response rate was 39% with 4 pts (19%) achieving complete remission (CR), 2 (10%) with CR with incomplete count recovery, and 2 (10%) with a morphologic leukemia-free state. Five responders proceeded to allogeneic stem cell transplantation. Conclusions: SEL plus MEC is a feasible treatment for pts with R/R AML. Toxicities of the combination are similar to cytotoxic chemotherapy alone. Clinical trial information: NCT02299518