Umbralisib，一种新型PI3Kdelta和酪蛋白激酶-1epsilon抑制剂，用于复发或难治性慢性淋巴细胞白血病和淋巴瘤:一项开放标签，1期，剂量递增，首次人体研究。

文章的细节

引用 复制到剪贴板

Burris HA 3, flynn IW, Patel MR, Fenske TS, Deng C, Brander DM, Gutierrez M, Essell JH, Kuhn JG, Miskin HP, Sportelli P, Weiss MS, Vakkalanka S, Savona MR, O'Connor OA

《医学杂志》2018年4月19日(4):486-496。doi: 10.1016 / s1470 - 2045(18) 30082 - 2。Epub 2018 2月20日。

PubMed ID

29475723 (PubMed视图

］

摘要

背景:Umbralisib (tg -1202)是一种新型的下一代磷脂酰肌醇3-激酶(PI3K)异构体p110delta (PI3Kdelta)抑制剂，它在结构上与其他PI3Kdelta抑制剂不同，并表现出更好的异构体选择性。Umbralisib还能独特地抑制酪蛋白激酶-1epsilon，这是蛋白质翻译的主要调节因子。这项首次人体一期研究的目的是建立umbralisib在血液系统恶性肿瘤患者中的安全性和初步活性。方法:我们在美国7家诊所进行了一项开放标签、一期剂量递增研究。我们招募了年龄至少18岁的复发或难治性慢性淋巴细胞白血病或小淋巴细胞淋巴瘤、b细胞和t细胞非霍奇金淋巴瘤或霍奇金淋巴瘤患者，这些患者之前接受过一种或多种治疗，疾病可测量和评估，器官系统功能充足。患者自行服用伞布利西口服片剂，以28天为周期，每天一次，剂量递增采用传统的3 + 3设计，以建立安全性并确定最大耐受剂量。在初始队列中，患者在禁食状态下服用50 mg的起始剂量，然后增加到100、200、400、800、1200和1800 mg，直到达到最大耐受剂量，或者累积最大剂量队列而没有剂量限制毒性。随后的队列在喂食状态下自行服用umbralisib片剂的微细配方，初始剂量为200 mg，逐渐增加到400、800、1200和1800 mg，直到达到最大耐受剂量或最大剂量水平。2014年8月，所有仍在研究中的患者都被过渡到800毫克的微粉配方，初始配方的剂量被停止。该研究的主要终点是研究人员评估的所有治疗患者(安全人群)的安全性、最大耐受剂量和umbralisib的药代动力学。 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.

引用本文的药物库数据

药物

Umbralisib

药物靶点

药物	目标	种类	生物	药理作用	行动
Umbralisib	酪蛋白激酶I异构体	蛋白质	人类	是的	抑制剂	细节
Umbralisib	磷脂酰肌醇4,5-二磷酸3-激酶催化亚基δ亚型	蛋白质	人类	是的	抑制剂	细节