第一阶段增大剂量研究copanlisib结合吉西他滨或顺铂+吉西他滨在晚期癌症患者。

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金路,老爱,佩纳C, Genvresse我Ajavon-Hartmann,夏C,凯利,Grilley-Olson我

第一阶段增大剂量研究copanlisib结合吉西他滨或顺铂+吉西他滨在晚期癌症患者。

Br J癌症。2018年2月20日,118 (4):462 - 470。doi: 10.1038 / bjc.2017.428。Epub 2018年1月18日。

PubMed ID

29348486 (在PubMed

]

文摘

背景:Copanlisib pan-class我磷脂酰肌醇3-kinase (PI3K)抑制剂主要PI3K-alpha /δ活动表明临床活动和可控的安全管理作为单一疗法在第二阶段的研究。联合治疗可能克服可能发生补偿信号抑制PI3K通路,导致增强的抑制活性,临床前研究与吉西他滨copanlisib已经证明有效的体内抗肿瘤活性。方法:第一阶段,非盲、剂量递增研究来评估安全、耐受性和推荐剂量二期(RP2D) copanlisib与吉西他滨或顺铂+吉西他滨(CisGem)在晚期恶性肿瘤患者,其中包括一个扩张组患者的胆道癌(BTC) RP2D copanlisib加CisGem。Copanlisib和吉西他滨在天1,8 - 15 28天的周期;最大耐受剂量(MTD)和RP2D copanlisib测定。Copanlisib + CisGem在天1和8的21天的周期;药物动力学和生物标志物评估。结果:50例接受治疗如下:剂量组,n = 16;copanlisib + CisGem队列,n = 14;和BTC扩张组,n = 20。 Copanlisib 0.8 mg kg(-1) plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29). CONCLUSIONS: Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

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药物转运蛋白

药物	转运体	类	生物	药理作用	行动
Copanlisib	多种药物和毒素挤压蛋白2	蛋白质	人类	未知的	抑制剂	细节