TY - JOUR
T1 - A comparative oncology study of iniparib defines its pharmacokinetic profile and biological activity in a naturally-occurring canine cancer model
AU - Saba, Corey
AU - Paoloni, Melissa
AU - Mazcko, Christina
AU - Kisseberth, William
AU - Burton, Jenna H.
AU - Smith, Annette
AU - Wilson-Robles, Heather
AU - Allstadt, Sara
AU - Vail, David
AU - Henry, Carolyn
AU - Lana, Susan
AU - Ehrhart, E. J.
AU - Charles, Brad
AU - Kent, Michael
AU - Lawrence, Jessica
AU - Burgess, Kristine
AU - Borgatti, Antonella
AU - Suter, Steve
AU - Woods, Paul
AU - Gordon, Ira
AU - Vrignaud, Patricia
AU - Khanna, Chand
AU - LeBlanc, Amy K.
N1 - Funding Information:
This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. The results and interpretations presented herein do not reflect the views of the US Government. We wish to thank the clinical staff at each participating COTC site, and the pets and their owners for participation.
PY - 2016/2
Y1 - 2016/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84959423397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84959423397&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0149194
DO - 10.1371/journal.pone.0149194
M3 - Article
C2 - 26866698
AN - SCOPUS:84959423397
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 2
M1 - e0149194
ER -
