Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

中文翻译：

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Pevonedistat，一种一流的 NEDD8 激活酶 (NAE) 抑制剂，联合阿扎胞苷治疗 AML 患者

Pevonedistat (TAK-924/MLN4924) 是一种新型的 NEDD8 激活酶 (NAE) 抑制剂，在复发/难治性急性髓系白血病 (AML) 中具有单药活性。我们基于临床前观察到的协同活性，对 pevonedistat (PEV) 与阿扎胞苷 (AZA) 进行了 1b 期研究。主要目标包括安全性和耐受性，次要目标包括药代动力学 (PK) 和疾病反应。≥60 岁的初治 AML（不适合标准诱导治疗）患者在第 1、3 和 5 天接受 PEV 20 或 30 mg/m2 IV 联合固定剂量 AZA（75 mg/m2 IV/皮下）治疗1 到 5、8 和 9，每 28 天。最常见的治疗中出现的不良事件是便秘 (48%)、恶心 (42%)、疲劳 (42%) 和贫血 (39%)。总共，研究人员观察到 11 例死亡并认为与研究治疗无关。天冬氨酸转氨酶 (AST) 和丙氨酸转氨酶 (ALT) 的瞬时升高是剂量限制性的。该组合中 PEV 的推荐 2 期剂量 (RP2D) 为 20 mg/m2 PEV PK 未因添加 AZA 而改变。基于意向治疗分析的总体缓解率 (ORR) 为 50%（20 次完全缓解 [CR]，5 次完全缓解伴外周计数不完全恢复，7 次部分缓解 [PR]），中位持续时间为 8.3 个月的缓解。在接受≥6 个治疗周期的患者中（n = 23, 44%），ORR 为 83%。在 TP53 突变患者中，复合 CR/PR 率为 80% (4/5)。其中两名患者继续研究超过 10 个周期。基线骨髓原始细胞百分比或细胞遗传学/分子风险不影响 ORR。