Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors
Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors
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DOI：
10.1200/jco.2018.78.2292
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发表时间：
2018-10-20
影响因子：
45.3
通讯作者：
Massard, Christophe
中科院分区：
文献类型：
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作者：
Lewin, Jeremy;Soria, Jean-Charles;Massard, Christophe
目的Birabresib（MK-8628/OTX 015）是一种新型的溴结构域抑制剂，对血液系统肿瘤有一定的抑制作用。在去势抵抗性前列腺癌、睾丸中线癌（NMC）核蛋白、患者和方法47例患者入组接受birabresib，每日一次，起始剂量为80 mg，连续给药，（队列A）或100 mg连续7天（队列B），21天为1周期，采用平行剂量递增3 + 3设计。主要目的是发生剂量限制性毒性（DLT）和确定推荐的II期dose.ResultsOf 46治疗的患者，26去势抵抗性前列腺癌，10个NMC，和10个非小细胞肺癌。对于队列A，19例可评估患者中有4例（21%）在80 mg每日一次时发生DLT（3级血小板减少[n = 3]，ALT/高胆红素血症[n = 1]），3例患者中有2例在100 mg每日一次时发生DLT（2级厌食和恶心，治疗延迟> 7天[n = 1]，4级血小板减少[n = 1]）。队列B中未发生DLT。在46例患者中，38例（83%）发生了治疗相关不良事件（腹泻，17例[37%];恶心，17例[37%];厌食，14例[30%];呕吐，12例[26%];血小板减少症，10例[22%]）。3例NMC患者（80 mg每日一次）出现部分缓解（实体瘤疗效评价标准[RECIST]第1.1版），持续时间为1.4 - 8.4个月。药代动力学分析表明，剂量成比例增加birabresib暴露和快速absorption.ConclusionThe推荐的第二阶段剂量的birabresib在选择实体瘤患者是80毫克，每天一次，连续给药。比拉瑞昔布具有剂量比例性暴露和有利的安全性特征，在NMC中观察到临床活性。birabresib的未来研究必须考虑间歇性给药，以减轻慢性给药的毒性。
PurposeBirabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study.Patients and MethodsForty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose.ResultsOf 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption.ConclusionThe recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.