Purpose: Data suggest that activity of p38 MAPK and Tie2 kinase are dysregulated in MDS and may be targets for novel therapies. A Phase 1 study of ARRY 614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by IWG 2006 criteria. Experimental Design: Forty-five patients received ARRY-614 either QD or BID in dose escalation (400, 600, 900 or 1200 mg QD; 200 or 300 mg BID) or expansion cohorts. Results: The 300 mg BID schedule was not tolerated, and a maximum tolerated dose was not reached for QD dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Inter-patient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 RBC transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI. Conclusions: ARRY-614 was well tolerated with sufficient activity to warrant further evaluation in this patient population. We recommend 1200 mg QD as the optimal dose for further study. This study was registered at http://www.clinicaltrials.gov as NCT00916227.