Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer.
Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer.
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DOI：
10.1186/s12885-021-08973-4
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发表时间：
2021-11-24
期刊：
影响因子：
3.8
通讯作者：
Iwata H
中科院分区：
文献类型：
--
作者：
Masuda N;Tamura K;Yasojima H;Shimomura A;Sawaki M;Lee MJ;Yuno A;Trepel J;Kimura R;Nishimura Y;Saji S;Iwata H
恩替司他是一种I类组蛋白脱乙酰酶的口服抑制剂，用于激素受体阳性（HR+）晚期或转移性乳腺癌（BC）的内分泌治疗抵抗患者。我们在日本患者中检查了恩替司他单药治疗和恩替司他/阿司美坦联合治疗的安全性、疗效和药代动力学。这项I期研究（3 + 3剂量递增设计）入组了既往接受过非甾体芳香酶抑制剂治疗的晚期/转移性HR + BC绝经后女性。评估恩替司他单药治疗（3 mg/qw、5 mg/qw或10 mg/q2w）和恩替司他+阿司美坦（5 mg/qw +25 mg/qd）的剂量限制性毒性（DLT）。在多个时间点测量药代动力学、赖氨酸乙酰化（Ac-K）和T细胞活化标志物。12例患者入组。未发生DLT或3 - 5级不良事件（AE）。DLT观察期间的药物相关AE（≥ 2例患者）为低磷血症、恶心和血小板计数降低。6例患者（50%）达到疾病稳定（SD）≥ 6个月，包括1例治疗> 19个月。中位无进展生存期为13.9个月（95% CI 1.9-无法计算）;未达到中位总生存期。血浆浓度-时间曲线下面积和外周血CD 19 + B细胞中的Ac-K与剂量成比例增加。恩替司他浓度的变化规律与Ac-K水平具有良好的相关性。T细胞活化标志物随时间推移而增加; SD ≥ 6个月的患者中CD69的增加幅度大于SD <6个月的患者。恩替司他单药治疗和恩替司他/维司坦联合治疗在日本患者中耐受性良好，与既往报告相比没有额外的安全性问题。药代动力学与外周血CD 19 + B细胞中Ac-K以及T细胞活化标志物之间的相关性值得进一步研究。日本临床试验信息，JapicCTI-153066。2015年11月12日注册。ClinicalTrials.gov 2015年12月8日注册。在线版本包含补充材料，可通过10.1186/s12885 - 021 - 08973 - 4获得。
Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients. This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points. Twelve patients were enrolled. No DLTs or grade 3–5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9–not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months. Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation. JAPIC Clinical Trial Information, JapicCTI-153066. Registered 12 November 2015. ClinicalTrials.gov, NCT02623751. Registered 8 December 2015. The online version contains supplementary material available at 10.1186/s12885-021-08973-4.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
28.4
作者：
Sledge, George W.;Toi, Masakazu;Llombart-Cussac, Antonio
通讯作者：
Llombart-Cussac, Antonio
组蛋白脱乙酰酶和 Bromodomain 联合抑制对非小细胞肺癌的协同免疫刺激作用和治疗效果。
影响因子：
28.2
作者：
Adeegbe DO;Liu Y;Lizotte PH;Kamihara Y;Aref AR;Almonte C;Dries R;Li Y;Liu S;Wang X;Warner-Hatten T;Castrillon J;Yuan GC;Poudel-Neupane N;Zhang H;Guerriero JL;Han S;Awad MM;Barbie DA;Ritz J;Jones SS;Hammerman PS;Bradner J;Quayle SN;Wong KK
通讯作者：
Wong KK
影响因子：
5.7
作者：
Sabnis GJ;Goloubeva OG;Kazi AA;Shah P;Brodie AH
通讯作者：
Brodie AH
影响因子：
20.3
作者：
Piekarz, Richard L.;Frye, Robin;Bates, Susan E.
通讯作者：
Bates, Susan E.