National University Corporation, Gunma University, Maebashi, Japan.
Severence Hospital, Yonsei University Health System, Seoul, South Korea.
J Hematol Oncol. 2022 May 11;15(1):56. doi: 10.1186/s13045-022-01264-w.
Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10-44 mg/m, with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m for co-administration with azacitidine 75 mg/m in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients.Trial registration: clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468.
培维酮司他，首个 NEDD8 激活酶小分子抑制剂，在西方急性髓系白血病（AML）和骨髓增生异常综合征（MDS）患者中展现出了临床活性。我们报告了一项在东亚 AML 或 MDS 患者中进行的 1/1b 期研究结果，旨在评估培维酮司他单药或联合阿扎胞苷在该人群中的安全性/耐受性和药代动力学特征，并确定培维酮司他联合阿扎胞苷的 2/3 期推荐剂量。来自日本、韩国和中国台湾的 23 名极高/高/中危 AML 或 MDS 成年患者入组了该项研究。所有 23 名患者均经历了至少一次≥3 级治疗相关不良事件。联合治疗组的 1 名患者报告了剂量限制性毒性。18 名患者停药；9 名患者因疾病进展而停药。3 名患者在研究期间因认为与研究药物无关的原因死亡。培维酮司他在 10-44mg/m 的剂量范围内表现出线性药代动力学特征，多次给药后蓄积最小。联合治疗组的 11 例（45%）可评估反应的患者中有 5 例（5/11）达到客观缓解（所有患者均患有 AML），而单药治疗组无缓解。本研究表明，与既往报道的西方患者研究结果一致，东亚患者中培维酮司他联合阿扎胞苷的药代动力学和安全性特征与西方患者相似。在 2/3 期研究中，培维酮司他联合阿扎胞苷的 2/3 期推荐剂量（RP2/3D）确定为 20mg/m，与西方患者确定的 RP2/3D 相同。试验注册：clinicaltrials.gov：NCT02782468，2016 年 5 月 25 日。https://clinicaltrials.gov/ct2/show/NCT02782468。
