Dose escalation results of a phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML).

• DOI: 10.1200/jco.2017.35.15_suppl.7027
• Publication Date: 2018-09-06T15:50:36Z
• Authors: Harry Paul Erba; Pamela S. Becker; Paul J. Shami; Michael Richard G...; Donna L. Flesher; Yilong Zhang; Erik Rasmussen; Haby A. Henary; Eunice S. Wang
• Keywords: Trametinib; Mucositis; Refractory (planetary science)

7027 Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary of investigational oral, selective inhibitor AMG 232 or kinase trametinib in pts r/r AML. Methods: Pts received for 7 days every 2 weeks (7 on/7 off) at 60, 120, 240, 480, 960 mg PO QD (Arm 1) 2). Primary endpoints were incidence adverse events (AEs), dose-limiting toxicities (DLTs), PK. Additional included best response (revised IWG) serum MIC-1 level (increased suggests p53 activation). target gene ( P21, BAX, PUMA) expression bone marrow was by microarray. Results: total, 35 1, n = 26; Arm 2, 9; median age, 68 y; range, 26–86) treated. 1 enrolled 60 (n 4), 90 180 5), 240 3), 360 10). Twenty-two (85%) had treatment-related AEs; most common nausea 14), diarrhea vomiting 6). No DLTs occurred; one pt still on treatment. MTD determined based tolerance gastrointestinal toxicity. enrollment ongoing a fixed plus 9). plasma exposure increased escalation; PK unaffected trametinib. Trametinib expected. Increases from baseline (BL) to day 10 dependent. Evidence PUMA (BL 8) seen 3). One 2) complete remission (CR); three achieved CRi/MLFS. Median duration 66 [range, 21–377+]). Conclusions: tolerable doses up off schedule expected PK, on-target biological effects, early evidence antileukemia activity. Clinical trial information: NCT02016729.