卡铂
医学
耐受性
溴尿嘧啶
子宫内膜癌
ARID1A型
联合疗法
内科学
肿瘤科
卵巢癌
临床研究阶段
BET抑制剂
癌症
临床试验
癌症研究
化疗
表观遗传学
不利影响
顺铂
突变
生物
遗传学
基因
作者
Linda Duska,Dmitriy Zamarin,Erika Hamilton,Amit M. Oza,Gini F. Fleming,Alexander I. Spira,Oladapo O. Yeku,Debra L. Richardson,Jackie Walling,Kerry Inokuchi,Bernice Matusow,Gideon Bollag,Elizabeth M. Swisher
出处
期刊:JCO precision oncology
[American Society of Clinical Oncology]
日期:2023-09-01
卷期号: (7)
被引量:3
摘要
The Bromodomain and Extra-Terminal (BET) domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small-molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all four BET family members.We conducted a multicenter and open-label study with two parallel arms: a phase IIa study of PLX2853 monotherapy in patients with advanced gynecologic malignancies with an ARID1A mutation and a phase Ib/IIa combination study of PLX2853 plus carboplatin in women with platinum-resistant OC. The primary objectives were safety and tolerability for phase Ib and efficacy for both phase IIa portions. Thirty-four of 37 enrolled patients completed at least one post-baseline response assessment.Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a best overall response of partial response (PR), 5 (35.7%) had stable disease (SD), and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable patients on the combination arm, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD.This study confirmed the safety profile of PLX2853 and demonstrated the feasibility of combination with carboplatin. Although these results did not meet the prespecified response criteria, evidence of clinical activity highlights the rationale for further exploration of BET inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway.
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