Background: PON is a potent oral TKI active against native and mutated forms of BCR-ABL, including T315I. The ph 2 PACE study demonstrated that PON is highly active in heavily pretreated Ph+ leukemia pts. Methods: EPIC was an international, Ph 3 trial of PON (45 mg QD) vs IM (400 mg QD) in newly diagnosed CP-CML pts, with randomization stratified by Sokal risk score. The primary endpoint was major molecular response (MMR) rate at 1 yr. On 18 Oct 2013,EPIC was terminated due to accumulating vascular events in long-term follow-up of the PACE trial. Data as of 7 Oct 2013 are presented, median follow-up 3 (0.03-12) m. Results: At the time of analysis, 306 were randomized. Baseline characteristics were balanced for PON vs IM; median age 55 vs 52 yrs, 17% vs 16% high Sokal risk score, 62% vs 66% received prior hydroxyurea. Data on 267 treated pts were available (133 PON; 134 IM). 77% PON and 84% IM pts were ongoing; 14 PON and 6 IM pts D/C, (D/C due to AE; 9 PON pts [most common: thrombocytopenia and rash] and 1 IM pt). Response rates are in the table (evaluable pts). Most common (≥25%) all grade (G) AEs were PON: rash (36%), abdominal pain (32%), headache (31%), lipase increased (26%), myalgia (26%); IM: nausea (32%), muscle spasms (31%). 11% PON and 2% IM had G 3/4 thrombocytopenia; 3% PON and 8% IM had G 3/4 neutropenia. Serious AEs (SAEs) occurring in ≥3 PON pts were: pancreatitis (5 pts), atrial fibrillation (3), thrombocytopenia (3); no individual SAEs occurred in ≥3 IM pts. 9 (7%) PON and 5 (4%) IM pts experienced vascular occlusive events (SAEs: 6 PON, 1 IM). Updated data will be presented. Conclusions: While PON demonstrated early activity in frontline CP-CML, EPIC was terminated as its objectives could not be met with PON dose reductions implemented mid-trial due to safety observations in PACE. Further investigation of PON safety is warranted. PON remains an important treatment option for pretreated CML and Ph+ ALL pts in whom the need and benefit outweigh the risk. Clinical trial information: NCT01650805.