Background: The RTK Axl represents an independent prognostic factor and therapeutic target in AML. BGB324 is an orally available selective potent Axl inhibitor, which has antileukemic activity in preclinical models of AML. Methods: A standard 3 + 3 dose escalation study was performed to identify the maximum tolerated dose of BGB324 in patients with previously treated AML or high risk MDS. BGB324 was administered as an oral loading dose on days one and two followed by a reduced daily maintenance. Three dose levels were explored 400/100mg, 600/200mg and 900/300mg Results: To date, 13 patients with AML and 3 patients with MDS were treated in the first three dose levels. 6 patients remain on treatment and 11 are evaluable. Therapy has been well-tolerated and the MTD has not yet been reached. The majority of adverse events reported have been Grade 1 and 2. The most common related adverse events are diarrhea and fatigue. One patient with pre-existing cardiac conduction abnormalities discontinued study treatment because of prolonged QTc prolongation leading to an expansion of the first dose cohort to six patients. The use of a loading dose achieved steady state between three and six days which was maintained throughout treatment. One AML patient has an ongoing CRi > 5 months, one patient achieved clearance of circulating blasts accompanied by peripheral blood count recovery > 3 months and three AML patients experienced disease stabilisation for more than four months. The status of patients with MDS remained unchanged. Evidence of target inhibition in leukemic blasts was demonstrated by almost complete inhibition of Axl phosphorylation accompanied by reduction in phosphoErk and phosphoAkt signalling at day 21 of treatment. Conclusions: BGB324 can be safely administered for prolonged periods at doses that abrogate AXL signalling. Treatment with BGB324 exhibits anti-leukemic activity. Clinical trial information: NCT02488408.