Background: Binding of E-selectin (E-sel) to sialyl Le^x, the E-sel ligand (E-sel-L), on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Expression of E-sel-L is associated with increased relapse and poor survival. Uproleselan (GMI-1271), a novel E-sel antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity such as mucositis with improved survival in vivo. Preclinical data support combination with multiple agents to achieve improved chemosensitivity and toxicities. A phase I/II study of uproleselan added to chemotherapy in R/R AML showed promising remission rates (CR/CRi) and survival outcomes, and reduced rates of mucositis. High E-sel-L expression on leukemic blasts in the bone marrow, rather than connoting treatment resistance and poor survival, instead correlated with longer survival than expected with addition of uproleselan. Breakthrough Therapy Designation was granted by FDA for treatment of patients with R/R AML. A pivotal phase 3 study (NCT03616470) is underway to assess the efficacy and safety of uproleselan with standard salvage chemotherapy in R/R AML. Methods: This study is a global, randomized, double-blind, phase 3 trial in adults aged 18-75 years with R/R AML and fit for chemotherapy. Patients may have primary refractory AML (received 1 prior induction containing an anthracycline and cytarabine), or be in untreated first or second relapse; prior HSCT is allowed. Treatment is MEC (mitoxantrone, etoposide, cytarabine) or FAI (fludarabine, cytarabine, idarubicin) induction regimen with blinded study drug (Uproleselan:placebo at 1:1 ratio) administered 1 day prior (sentinel dose) and then BID through 2 days post chemotherapy. Consolidation (HIDAC/IDAC) with uproleselan/placebo (same assignment) up to 3 cycles is allowed. The primary endpoint is overall survival; key secondary endpoints include the incidence of severe oral mucositis during induction and CR/CRh rate. Measurable residual disease, E-sel-L expression on leukemic cells, event free survival, safety, and pharmacokinetics will also be evaluated. Clinical trial information: NCT03616470