Background: GMI-1271 is a novel antagonist of E-selectin (E-sel) that down-regulates cell survival pathways and enhances chemotherapy response. We assessed GMI-1271 plus salvage chemotherapy with mitoxantrone, etoposide, and cytarabine (MEC) for the treatment of patients (pts) with relapsed/refractory (R/R) AML. Methods: A phase (Ph) 1trial in pts with R/R AML escalated GMI-1271 across pharmacologically active doses from 5-20 mg/kg combined with MEC. Safety, tolerability and anti-leukemia activity were assessed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. Eligible pts had an ECOG score 0-2, received ≤2 prior inductions, WBC < 20K ( < 40K after 2 dose levels), no active CNS disease, and adequate renal/hepatic function. E-sel expression was assessed. After confirming safety and tolerability, a Ph 2 study of GMI-1271 at 10 mg/kg plus MEC was initiated. Results: To date, 47 pts have enrolled (Ph 1 = 19; Ph 2 = 28 of planned 47). The recommended Ph 2 dose is 10 mg/kg based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and clinical outcomes. Ph1/Ph2 combined median age was 55yrs (range 26-84) with 70% male pts. Prior AML history included 26% primary refractory, 36% CR1 < 6 mos; 17% prior SCT; 55% unfavorable cytogenetics (by SWOG). Common Gr 3/4 AEs were febrile neutropenia (36%), sepsis (26%), bacteremia (13%), hypoxia (13%). 30 and 60 d mortality were 0 and 7%, respectively. ORR (CR/CRi/MLFS/PR) was 21/42 evaluable (50%). Remission rate (CR/CRi) was 45%. Observed/expected remission (CR/CRi) ratio was > 2.75 (Estey, Blood 1996). With a median follow-up of 11 mos, the Ph 1 median Leukemia Free Survival was not reached and Overall Survival was 7.6 mos. The median E-sel ligand binding at baseline was 35% of blasts (range, 1-75%) and was higher in those achieving remission. Conclusions: The addition of GMI-1271, a novel E-sel antagonist, to MEC chemotherapy is well tolerated with a high ORR, low induction mortality, and promising initial survival outcomes in pts with R/R AML. Furthermore, the baseline expression of E-sel ligand is predictive of response. Clinical trial information: NCT02306291