Purpose: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML. Patients and Methods: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3þ3 design between 200 and 400 mg twice daily) þ 7þ3 (cytarabine þ daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) þ 7þ3 in phase II. Results: Fifty-three patients (n ¼ 12, phase Ib and n ¼ 41, phase II) with previously untreated de novo (n ¼ 39) or secondary (n ¼ 14) AML were enrolled (58% male; median age, 60