Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer.
Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer.
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DOI：
10.1002/cncr.29783
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发表时间：
2016-02-15
期刊：
影响因子：
6.2
通讯作者：
Annunziata CM
中科院分区：
文献类型：
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作者：
Noonan AM;Bunch KP;Chen JQ;Herrmann MA;Lee JM;Kohn EC;O'Sullivan CC;Jordan E;Houston N;Takebe N;Kinders RJ;Cao L;Peer CJ;Figg WD;Annunziata CM
凋亡蛋白抑制剂（IAPs）是细胞凋亡的关键调控因子，在卵巢癌中经常出现失调。我们假设用birinapant阻断IAPs会增加肿瘤细胞死亡，从而导致铂难治和耐药卵巢癌女性患者的客观反应。在这项ctep赞助的II期研究中，患者在28天周期的第1、8、15天接受47mg/m2的birinapant治疗。第1周期获得药代动力学。在第1周期前和第6周后分别收集血浆、外周血单核细胞（PBMC）和经皮肿瘤活检。在mini-max设计中，主要终点是客观缓解或持续大于6个月的无进展生存期。11例患者接受了birinapant治疗，但由于缺乏临床益处，治疗终止。Birinapant耐受性良好，主要发生2级不良事件（AE）和1例3级淋巴细胞减少。收集治疗前活检和pbmc；分别收集7例和10例患者的配对治疗后活检和PBMC。cIAP1在肿瘤组织（P=0.016）和PBMC组织（P<0.01）中均有下调。肿瘤组织中Pro-caspase3和PBMC组织中Pro-caspase3均减少（P=0.031）， PBMC组织中Pro-caspase3也减少（P<0.01）；cleaved caspase3与γ - h2ax在双抗暴露后肿瘤中共定位。治疗后外周血T细胞和b细胞明显减少，nk细胞无显著差异（P=0.04， P=0.05， P=0.43）。Birinapant在体内表现出一致的靶标抑制，在这个小群体中没有单一的抗肿瘤活性。单药药效学是了解药物作用机制和合理联合用药的基础。临床前研究正在进行中，以确定未来临床试验的最佳协同组合。
Inhibitors of Apoptosis Proteins (IAPs) are key regulators of apoptosis, and are frequently dysregulated in ovarian cancer. We hypothesized that blocking IAPs with birinapant would increase tumor cell death resulting in objective response for women with platinum-refractory and resistant ovarian cancer. In this phase II CTEP-sponsored study, patients received birinapant 47mg/m2 on days 1, 8, 15 of 28-day cycles. Pharmacokinetics were obtained in cycle 1. Plasma, peripheral blood mononuclear cells (PBMC) and percutaneous tumor biopsies were collected prior to cycle 1, and after 6 weeks. The primary endpoint was objective response or progression-free survival lasting greater than 6 months in a mini-max design. Eleven patients received birinapant, after which accrual was terminated for lack of clinical benefit. Birinapant was well-tolerated, with predominantly grade 2 adverse events (AE) and one grade 3 lymphopenia. Pre-treatment biopsies and PBMCs were collected; paired post-treatment biopsies and PBMC were collected from 7 and 10 patients, respectively. There was consistent downregulation of cIAP1 in tumor (P=0.016) and PBMC (P<0.01). Pro-caspase3 also decreased in tumors (P=0.031) and PBMC (P<0.01); cleaved caspase3 co-localized with gamma-H2AX in tumors after birinapant exposure. Peripheral T- and B-cells decreased significantly post-treatment, but NK-cells did not (P=0.04, P=0.05, P=0.43 respectively). Birinapant shows consistent target suppression in vivo, without single agent anti-tumor activity in this small population. Single agent pharmacodynamics were necessary to understand drug mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials.