、小说PI3Kdelta Umbralisib酪蛋白kinase-1epsilon抑制剂,在复发或难治性慢性淋巴细胞白血病和淋巴瘤:一个非盲、第一阶段,剂量递增,first-in-human学习。

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伯哈三,Flinn IW, Patel先生,Fenske TS,邓C,打烙印DM,古铁雷斯M, Essell JH,库恩詹,米惠普,Sportelli P,维斯女士,Vakkalanka年代,萨沃纳先生,奥康纳OA

、小说PI3Kdelta Umbralisib酪蛋白kinase-1epsilon抑制剂,在复发或难治性慢性淋巴细胞白血病和淋巴瘤:一个非盲、第一阶段,剂量递增,first-in-human学习。

柳叶刀杂志。2018年4月,19 (4):486 - 496。doi: 10.1016 / s1470 - 2045 (18) 30082 - 2。Epub 2018 2月20。

PubMed ID

29475723 (在PubMed

]

文摘

背景:Umbralisib (tgr - 1202)是一种新型的下一代抑制剂的磷脂酰肌醇3-kinase (PI3K)同种型p110delta (PI3Kdelta),在结构上不同于其他PI3Kdelta抑制剂并显示同种型选择性提高。Umbralisib也抑制酪蛋白kinase-1epsilon独有,蛋白质翻译的主要监管机构。这first-in-human第一阶段研究的目的是建立的安全性和初步活动概要umbralisib血液学的恶性血液病患者。方法:我们做了一个非盲、第一阶段,剂量递增在七个诊所在美国学习。我们招募病人至少18岁与复发或难治性慢性淋巴细胞白血病或小淋巴细胞性淋巴瘤,b细胞和t细胞非霍奇金淋巴瘤,或霍奇金淋巴瘤,之前曾收到一个或多个行治疗,可测量和可评价的疾病,和足够的器官系统功能。病人自行umbralisib口服片剂每天一次的28天周期,与传统剂量升级完成3 + 3设计建立安全和确定最大耐受剂量。初始群体,病人把umbralisib在禁食状态开始50毫克的剂量,增加到100,200,400,800,1200,和1800毫克,直到达到最大耐受剂量,或最大剂量队列是应计没有dose-limiting毒性。后续组自行micronised制定umbralisib平板电脑在一个联邦国家的初始剂量200毫克,在增量增加到400,800,1200,1800毫克,直到最大耐受剂量或最大剂量水平应计。2014年8月,所有患者仍在研究转换到800毫克的粉化配方和剂量的初始配方是停止。研究的主要终点是investigator-assessed安全在所有治疗患者(安全人口),最大耐受剂量,umbralisib的药物动力学。 Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766. FINDINGS: Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4.7 cycles (IQR 2.0-14.0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib. INTERPRETATION: Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kdelta inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting. FUNDING: TG Therapeutics.

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药物

Umbralisib

药物靶点

药物	目标	类	生物	药理作用	行动
Umbralisib	酪蛋白激酶我同种型ε	蛋白质	人类	是的	抑制剂	细节
Umbralisib	磷脂酰肌醇4,5-bisphosphate 3-kinase催化亚基δ同种型	蛋白质	人类	是的	抑制剂	细节