Tazemetostat EZH2抑制剂,在复发或难治性b细胞非霍奇金淋巴瘤和先进的固体肿瘤:first-in-human,非盲、第一阶段研究。
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意大利语,索里亚时JC, Toulmonde M, Michot JM, Lucchesi C,巴尔加,Coindre JM,布莱克莫尔SJ,克劳森,净重B,麦当劳AA,半圆,Ribich年代,亨德里克E, Keilhack H,汤姆森B, Owa T,科普兰RA, Ho PTC, Ribrag V
Tazemetostat EZH2抑制剂,在复发或难治性b细胞非霍奇金淋巴瘤和先进的固体肿瘤:first-in-human,非盲、第一阶段研究。
柳叶刀杂志。2018;19 (5):649 - 659。doi: 10.1016 / s1470 - 2045 (18) 30145 - 1。Epub 2018年4月9日。
- PubMed ID
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29650362 (在PubMed]
- 文摘
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背景:激活剂的zeste同族体2 (EZH2)突变或畸变的开关/蔗糖non-fermentable(瑞士/ SNF)复杂(如突变或缺失的子单元INI1或SMARCA4)会导致异常的组蛋白甲基化、致癌性转化、增殖依赖EZH2的活动。在这first-in-human研究中,我们旨在探讨安全、临床活动,药物动力学,和药效学tazemetostat first-in-class EZH2的选择性抑制剂。方法:我们做了一个开放、多中心、剂量递增,第一阶段研究计划用3 + 3的设计群体扩张的两个最高剂量低于最大耐受剂量。这项研究是在法国的两个中心:古斯塔夫Roussy研究所(瑟瓦尔德马恩)和Bergonie研究所(波尔多,吉伦特派)。符合条件的患者复发或难治性b细胞非霍奇金淋巴瘤或一个先进的固体肿瘤,年龄超过18岁,与东部合作肿瘤组0或1的性能状态,和足够的终末器官功能。Tazemetostat从100毫克,每日两次口服1600毫克每天两次在28天周期。主要终点是建立的最大耐受剂量或推荐阶段2剂量tazemetostat,由dose-limiting毒性,实验室的价值观,和其他安全或药代动力学措施周期根据当地研究者评估。安全评估病人至少一剂tazemetostat;抗肿瘤活性的评估意向处理人口。这项研究是在ClinicalTrials.gov注册,NCT01897571数量。 The phase 1 part of the study is complete, and phase 2 is ongoing. FINDINGS: Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 [33%] of 64 treatment-related events), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and vomiting (six [9%]), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. INTERPRETATION: Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours. FUNDING: Epizyme and Eisai.
DrugBank数据引用了这篇文章
- 药物
- 药物酶
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药物 酶 类 生物 药理作用 行动 Tazemetostat 细胞色素P450 3 a4 蛋白质 人类 未知的底物细节 - 药物反应
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反应 细节
