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

Cancer. 2016 Feb 15;122(4):588-597. doi: 10.1002/cncr.29783. Epub 2015 Nov 13.


Background: Inhibitors 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.

Methods: In this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients 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 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.

Results: Eleven 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 (γ-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).

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.

Keywords: birinapant; inhibitors of apoptosis proteins (IAP); ovarian cancer; pharmacodynamics; second mitochondria-derived activator of caspases (SMAC) mimetic.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma, Clear Cell / drug therapy*
  • Adenocarcinoma, Clear Cell / metabolism
  • Aged
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis Regulatory Proteins
  • B-Lymphocytes
  • Carcinoma, Endometrioid / drug therapy*
  • Carcinoma, Endometrioid / metabolism
  • Carcinoma, Ovarian Epithelial
  • Caspase 3 / metabolism
  • Dipeptides / pharmacokinetics
  • Dipeptides / therapeutic use*
  • Disease-Free Survival
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Indoles / pharmacokinetics
  • Indoles / therapeutic use*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Killer Cells, Natural
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Count
  • Lymphopenia / chemically induced
  • Middle Aged
  • Mitochondrial Proteins
  • Neoplasms, Cystic, Mucinous, and Serous / drug therapy*
  • Neoplasms, Cystic, Mucinous, and Serous / metabolism
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Platinum Compounds / therapeutic use
  • T-Lymphocytes
  • Treatment Failure
  • Treatment Outcome
  • Ubiquitin-Protein Ligases / metabolism


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Dipeptides
  • Indoles
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Platinum Compounds
  • birinapant
  • BIRC2 protein, human
  • Ubiquitin-Protein Ligases
  • Caspase 3