一个阶段我研究的细胞周期蛋白依赖性激酶抑制剂Ribociclib 4/6 (LEE011)在晚期实体肿瘤和淋巴瘤患者。

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小亲王,凯西PA, Gerecitano摩根富林明,Witteveen阿宝,丘格R, Ribrag V, Chakraborty, Matano,小多布森,水晶,Parasuraman年代,夏皮罗GI

一个阶段我研究的细胞周期蛋白依赖性激酶抑制剂Ribociclib 4/6 (LEE011)在晚期实体肿瘤和淋巴瘤患者。

癌症研究杂志2016年12月1;22 (23):5696 - 5705。Epub 2016年8月19日。

PubMed ID

27542767 (在PubMed

]

文摘

目的:Ribociclib(口服、高度特定的细胞周期蛋白依赖性激酶抑制剂4/6)抑制肿瘤生长在临床前模型完整视网膜母细胞瘤(Rb +)的蛋白质。这个first-in-human研究调查了MTD,推荐剂量扩张(RDE),安全,初步活动,药物动力学和药效学ribociclib Rb患者+高级实体肿瘤或淋巴瘤。实验设计:患者接受剂量的升级ribociclib (3-weeks-on / 1-week-off或连续)。剂量升级是由贝叶斯Logistic回归模型与过量控制原理。结果:132例患者中,125收到ribociclib 3-weeks-on / 1-week-off和7连续服用。九dose-limiting毒性观察70名MTD / RDE可评价的患者在周期1,最常见的中性粒细胞减少(n = 3)和血小板减少症(n = 2)。MTD和建立了RDE 3-weeks-on / 1-week-off 900和600毫克/天,分别。常见的治疗相关的不良事件(各年级;年级的3/4)中性粒细胞减少(46%;27%)、白血球减少症(43%;17%),疲劳(45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses >/=600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. CONCLUSIONS: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696-705. (c)2016 AACR.

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药物

Ribociclib