Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.
Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.
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DOI：
10.1158/1078-0432.ccr-18-4071
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发表时间：
2020-03-15
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影响因子：
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通讯作者：
Mehta A
中科院分区：
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作者：
Falchook G;Rosen S;LoRusso P;Watts J;Gupta S;Coombs CC;Talpaz M;Kurzrock R;Mita M;Cassaday R;Harb W;Peguero J;Smith DC;Piha-Paul SA;Szmulewitz R;Noel MS;Yeleswaram S;Liu P;Switzky J;Zhou G;Zheng F;Mehta A
溴结构域和末端外（BET）蛋白是关键的表观遗传转录调节因子，抑制其可抑制癌基因表达。我们报告了BET抑制剂INCB 054329（研究INCB 54329-101; NCT 02431260）和INCB 057643（研究INCB 57643-101; NCT 02711137）的2项独立的首次人体I/II期剂量递增和扩展、安全性和耐受性研究的结果。患有晚期恶性肿瘤、既往接受过≥1次治疗且器官功能良好的患者（≥18岁）以21天为1周期（或28天为1周期，取决于标准治疗组合）接受口服INCB 054329（单药治疗）或INCB 057643（单药治疗或与标准治疗组合）。主要终点是安全性和耐受性。分别有69例和134例患者接受了INCB 054329和INCB 057643。研究INCB 54329-101已完成; INCB 57643-101目前正在进行中，但未招募（截至2019年1月8日，无患者接受治疗）。INCB 054329的终末消除半衰期短于INCB 057643（平均值[SD]，2.24 [2.03] vs. 11.1 [8.27]小时）。INCB 054329显示口服清除率的患者间变异性高于INCB 057643（CV%，142% vs. 45.5%）。两种药物最常见（>20%）的任何级别治疗相关不良事件相似（INCB 054329; INCB 057643）：恶心（35%; 30%）、血小板减少（33%; 32%）、疲劳（29%; 30%）、食欲下降（26%; 22%）。INCB 057643的2例确认的完全缓解和4例确认的部分缓解报告为最佳缓解。与INCB 054329相比，INCB 057643表现出更有利的PK特征;两种药物均观察到血小板减少症，这限制了可以安全维持的靶向抑制。需要进一步努力确定可以获益最多的患者人群，以及最佳给药方案以最大化治疗指数。
Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose–escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329–101; NCT02431260) and INCB057643 (study INCB 57643–101; NCT02711137). Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329–101 has been completed; INCB 57643–101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.