First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors.
First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors.
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DOI：
10.1158/2159-8290.cd-20-0868
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发表时间：
2021-01
期刊：
影响因子：
28.2
通讯作者：
de Bono, Johann S.
中科院分区：
文献类型：
--
作者：
Yap, Timothy A.;Tan, David S. P.;Terbuch, Angelika;Caldwell, Reece;Guo, Christina;Goh, Boon Cher;Heong, Valerie;Haris, Noor R. Md;Bashir, Saira;Drew, Yvette;Hong, David S.;Meric-Bernstam, Funda;Wilkinson, Gary;Hreiki, Joseph;Wengner, Antje M.;Bladt, Friedhelm;Schlicker, Andreas;Ludwig, Matthias;Zhou, Yinghui;Liu, Li;Bordia, Sonal;Plummer, Ruth;Lagkadinou, Eleni;de Bono, Johann S.
靶向共济失调毛细血管扩张和RAD3相关(ATR)酶是一种很有前途的抗癌策略，可用于DNA损伤反应(DDR)缺陷和复制应激的肿瘤，包括失活共济失调毛细血管扩张突变(ATM)信号。我们报告了口服ATR抑制剂BAY 1895344在21名晚期实体肿瘤患者中间歇性服用5-80毫克，每天两次(BID)的I期首次人体试验的剂量递增部分。最大耐受量为40 mg，每日2次，共3天，停药4天。最常见的不良事件是可控和可逆的血液毒性。4例部分缓解，8例病情稳定。中位有效时间为315.5天。应答者有自动柜员机蛋白丢失和/或有害的自动柜员机突变，并接受剂量≥40 mg，2次。总体而言，BAY 1895344对某些DDR缺陷的癌症具有良好的耐受性，包括自动取款机丢失。DDR缺乏症患者的扩张期仍在继续。
Targeting the ataxia telangiectasia and Rad3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5–80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. Commonest adverse events were manageable and reversible hematological toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses ≥40 mg BID. Overall, BAY 1895344 is well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency.