There is a critical unmet need for novel treatment options that can improve outcomes in patients with acute myeloid leukemia (AML) or higher-risk myelodysplastic syndromes (MDS). Pevonedistat (MLN4924; TAK-924) is an investigational small-molecule inhibitor of neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE) [1,2,3]. Upregulation of the NEDD8 cascade is associated with cancer pathogenesis, making it a compelling target for drug development [4, 5]. Pevonedistat forms an adduct with NAE, preventing activation of the cascade and ultimately leading to substrate accumulation and cell death. A phase 1b study of pevonedistat and azacitidine combination treatment conducted in Western patients aged ≥ 60 years with untreated AML showed that the combination was well tolerated and exhibited clinical activity, with an objective response rate (ORR) of 50% [6]. The recommended phase 2/3 dose (RP2/3D) of pevonedistat for co-administration with azacitidine was determined to be 20 mg/m2.

Pharmacokinetics (PK) can differ between Asian and Western patients. We conducted an open-label phase 1/1b dose escalation/expansion study (NCT02782468) to assess the safety/tolerability and PK of pevonedistat as a single agent or in combination with azacitidine in East Asian patients with AML or higher-risk MDS, and to determine the RP2/3D for combination treatment in this population. Full study design and methods are provided in Additional file 1.

A total of 23 patients were enrolled in Japan, South Korea and Taiwan (n = 12/4/7). Ten patients received single-agent pevonedistat 25 mg/m2 or 44 mg/m2 (n = 3/7), and 13 patients received pevonedistat 10 mg/m2 or 20 mg/m2 (n = 3/10) plus azacitidine 75 mg/m2. Patient demographics and disease characteristics are shown in Additional file 1: Table S1. At data cut-off, 5 patients remained on combination treatment, while 18 had discontinued study treatment, primarily due to progressive disease (PD; n = 9) or adverse events (AEs; n = 6).

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