Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Cancer Chemother Pharmacol. 2023 Mar;91(3):281-290. doi: 10.1007/s00280-023-04511-0. Epub 2023 Mar 2.
Belinostat is an intravenous histone deacetylase inhibitor with approval for T-cell lymphomas. Adavosertib is a first in class oral Wee1 inhibitor. Preclinical studies of the combination demonstrated synergy in various human acute myeloid leukemia (AML) lines as well as AML xenograft mouse models.
This was a phase 1 dose-escalation study of belinostat and adavosertib in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS). Patients received both drugs on days 1-5 and 8-12 of a 21-day cycle. Safety and toxicity were monitored throughout the study. Plasma levels of both drugs were measured for pharmacokinetic analysis. Response was determined by standard criteria including bone marrow biopsy.
Twenty patients were enrolled and treated at 4 dose levels. A grade 4 cytokine release syndrome at dose level 4 (adavosertib 225 mg/day; belinostat 1000 mg/m) qualified as a dose-limiting toxicity event. The most common non-hematologic treatment-related adverse events were nausea, vomiting, diarrhea, dysgeusia, and fatigue. No responses were seen. The study was terminated prior to maximum tolerated dose/recommended phase 2 dose determination.
The combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the relapsed/refractory MDS/AML population.
贝林司他是一种静脉注射组蛋白去乙酰化酶抑制剂，已获批准用于治疗 T 细胞淋巴瘤。阿达沃西替布是一种首创的口服 Wee1 抑制剂。该联合的临床前研究表明，在各种人类急性髓系白血病（AML）系以及 AML 异种移植小鼠模型中具有协同作用。
这是一项评估贝林司他和阿达沃西替布在复发/难治性 AML 和骨髓增生异常综合征（MDS）患者中的 1 期剂量递增研究。患者在 21 天周期的第 1-5 天和第 8-12 天接受两种药物治疗。在整个研究过程中监测安全性和毒性。测量两种药物的血浆水平进行药代动力学分析。根据包括骨髓活检在内的标准标准确定反应。
共 20 名患者入组并接受了 4 个剂量水平的治疗。在第 4 个剂量水平（阿达沃西替布 225 毫克/天；贝林司他 1000 毫克/平方米）出现 4 级细胞因子释放综合征，被认为是剂量限制毒性事件。最常见的非血液学治疗相关不良事件包括恶心、呕吐、腹泻、味觉障碍和疲劳。未观察到反应。在达到最大耐受剂量/推荐的 2 期剂量之前，该研究提前终止。
在复发/难治性 MDS/AML 人群中，贝林司他和阿达沃西替布在测试的剂量水平联合使用是可行的，但没有疗效信号。
