A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.
A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.
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ONC201 治疗复发/难治性转移性乳腺癌和晚期子宫内膜癌的单臂、开放标签 II 期研究。
DOI：
10.1093/oncolo/oyad164
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lipko
中科院分区：
文献类型：
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作者：
Atkins,SarahLP;Greer,YoshimiEndo;Jenkins,Sarah;Gatti-Mays,MargaretE;Houston,Nicole;Lee,Sunmin;Lee,Min-Jung;Rastogi,Shraddha;Sato,Nahoko;Burks,Christina;Annunziata,ChristinaM;Lee,Jung-Min;Nagashima,Kunio;Trepel,JaneB;Lipko
背景ONC 201是一种小分子，可通过线粒体功能丧失引起非凋亡性细胞死亡。ONC 201在难治性实体瘤患者中的I/II期试验结果显示，肿瘤反应和长期稳定的疾病在一些patients.MethodsThis单臂，开放标签，II期临床试验评价ONC 201在推荐的II期剂量（RP 2D）复发或难治性转移性乳腺癌或子宫内膜癌患者的疗效。新鲜的组织活检和血液收集在基线和周期2天2correlative studies.ResultsTwenty-two患者入组; 10例子宫内膜癌，7例激素受体阳性乳腺癌，和5例三阴性乳腺癌。总缓解率为0%，临床获益率（完全缓解（CR）+部分缓解（PR）+疾病稳定（SD））为27%（n= 3/11）。所有患者均发生了不良事件（AE），主要为低级别。4例患者发生3级AE;未发生4级AE。肿瘤活检没有显示ONC 201持续诱导线粒体损伤或肿瘤坏死因子相关凋亡诱导配体（TRAIL）或TRAIL死亡受体的改变。ONC 201治疗引起外周免疫细胞亚群的改变。结论ONC 201单药治疗在RP 2D每周625 mg剂量下未诱导复发性或难治性转移性乳腺癌或子宫内膜癌的客观缓解，但具有可接受的安全性（ClinicalTrials.gov Identifier：NCT 03394027）。
BackgroundONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients.MethodsThis single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies.ResultsTwenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor–positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n= 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets.ConclusionONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).