Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, MDM2 inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity of the investigational oral, selective MDM2 inhibitor AMG 232 as monotherapy or combined with the MEK kinase inhibitor trametinib in pts with r/r AML. Methods: Pts with r/r AML received AMG 232 for 7 days every 2 weeks (7 days on/7 days off) at 60, 120, 240, 480, and 960 mg PO QD as monotherapy (Arm 1) or combined with trametinib 2 mg PO QD (Arm 2). Primary endpoints were the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), and PK. Additional endpoints included best response (revised IWG) and serum MIC-1 level (increased MIC-1 suggests p53 activation). p53 target gene (P21, BAX, and PUMA) expression in bone marrow was assessed by microarray. Results: In total, 35 pts (Arm 1, n = 26; Arm 2, n = 9; median age, 68 y; range, 26–86) were treated. Arm 1 enrolled AMG 232 at 60 mg (n = 4), 90 mg (n = 4), 180 mg (n = 5), 240 mg (n = 3), and 360 (n = 10). Twenty-two (85%) pts in Arm 1 had treatment-related AEs; the most common were nausea (n = 14), diarrhea (n = 14), and vomiting (n = 6). No DLTs occurred; one pt is still on treatment. The MTD was determined as 360 mg based on tolerance of gastrointestinal toxicity. Arm 2 enrollment is ongoing at a fixed AMG 232 dose of 60 mg plus trametinib (n = 9). AMG 232 plasma exposure increased with dose escalation; PK was unaffected by trametinib. Trametinib PK was as expected. Increases from baseline (BL) to day 10 in serum MIC-1 were dose dependent. Evidence of increased P21, BAX, and PUMA expression (BL to day 7 or 8) was seen (n = 3). One pt (Arm 2) had complete remission (CR); three pts (Arm 1) achieved CRi/MLFS. Median response duration was 66 days [range, 21–377+]). Conclusions: AMG 232 monotherapy was tolerable in pts with r/r AML at doses up to 360 mg on a 7 days on/7 days off schedule with expected PK, on-target biological effects, and early evidence of antileukemia activity. Clinical trial information: NCT02016729