A comparative oncology study of iniparib defines its pharmacokinetic profile and biological activity in a naturally-occurring canine cancer model

Corey Saba, Melissa Paoloni, Christina Mazcko, William Kisseberth, Jenna H Burton, Annette Smith, Heather Wilson-Robles, Sara Allstadt, David Vail, Carolyn Henry, Susan Lana, E. J. Ehrhart, Brad Charles, Michael S Kent, Jessica Lawrence, Kristine Burgess, Antonella Borgatti, Steve Suter, Paul Woods, Ira GordonPatricia Vrignaud, Chand Khanna, Amy K. LeBlanc

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV). Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT) and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD) of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, inipariband metabolite plasma:tumor ratios were < 0.088 and < 1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within the comparative oncology approach are evident from this successfully executed comparative clinical trial and exemplify the value of such studies in drug development.

Original languageEnglish (US)
Article numbere0149194
JournalPLoS One
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Saba, C., Paoloni, M., Mazcko, C., Kisseberth, W., Burton, J. H., Smith, A., Wilson-Robles, H., Allstadt, S., Vail, D., Henry, C., Lana, S., Ehrhart, E. J., Charles, B., Kent, M. S., Lawrence, J., Burgess, K., Borgatti, A., Suter, S., Woods, P., ... LeBlanc, A. K. (2016). A comparative oncology study of iniparib defines its pharmacokinetic profile and biological activity in a naturally-occurring canine cancer model. PLoS One, 11(2), [e0149194]. https://doi.org/10.1371/journal.pone.0149194