期刊
CANCER
卷 122, 期 4, 页码 588-597出版社
WILEY
DOI: 10.1002/cncr.29783
关键词
birinapant; inhibitors of apoptosis proteins (IAP); ovarian cancer; pharmacodynamics; second mitochondria-derived activator of caspases (SMAC) mimetic
类别
资金
- Intramural Research Program of National Cancer Institute
- Division of Cancer Treatment and Diagnosis of National Cancer Institute
- Cancer Therapy Evaluation Program of National Cancer Institute
BACKGROUNDInhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum-refractory and -resistant ovarian cancer. METHODSIn this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients received birinapant at 47mg/m(2) on days 1, 8, and 15 of 28-day cycles. Pharmacokinetics were obtained during cycle 1. Plasma, peripheral blood mononuclear cells (PBMCs), and percutaneous tumor biopsy samples were collected before cycle 1 and after 6 weeks. The primary endpoint was an objective response or progression-free survival lasting greater than 6 months in a mini-max design. RESULTSEleven patients received birinapant; after this, accrual was terminated for lack of a clinical benefit. Birinapant was well tolerated, with predominantly grade 2 adverse events and 1 case of grade 3 lymphopenia. Pretreatment biopsy samples and PBMCs were collected; paired posttreatment biopsy samples and PBMCs were collected from 7 and 10 patients, respectively. There was consistent downregulation of cellular inhibitor of apoptosis protein 1 in tumors (P=.016) and PBMCs (P<.01). Procaspase 3 also decreased in tumors (P=.031) and PBMCs (P<.01); cleaved caspase 3 colocalized with H2A histone family member X (-H2AX) in tumors after birinapant exposure. Peripheral T and B cells decreased significantly after treatment, but natural killer cells did not (P=.04, P=.05, and P=.43, respectively). CONCLUSIONSBirinapant shows consistent target suppression in vivo without single-agent antitumor activity in this small population. Single-agent pharmacodynamics are necessary to understand the drug's mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials. (c) 2015 American Cancer Society.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据