Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in @entity1 with relapsed XXXX -resistant or -refractory epithelial @entity43 .

@entity43 @entity1 @entity522 @entity2905 @entity5 @entity902 @entity6714
BACKGROUND: Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in @entity43 . It was hypothesized that blocking IAPs with birinapant would increase @entity5 cell death and result in objective responses for @entity1 with @entity902 -refractory and -resistant @entity43 . METHODS: In this phase 2, @entity5 Therapy Evaluation Program-sponsored study, @entity1 received birinapant at 47   mg/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 @entity5 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. RESULTS: Eleven @entity1 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 @entity2905 . Pretreatment biopsy samples and PBMCs were collected; paired posttreatment biopsy samples and PBMCs were collected from 7 and 10 @entity1 , respectively. There was consistent downregulation of cellular inhibitor of apoptosis protein 1 in @entity5 (P   =   .016) and PBMCs (P   <   .01). @entity522 also decreased in @entity5 (P   =   .031) and PBMCs (P   <   .01); cleaved caspase 3 colocalized with @entity6714 (y-H2AX) in @entity5 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). CONCLUSIONS: Birinapant 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. @entity5 2016;122:588-597.    2015 American @entity5 Society.
