Abstract 3809: Evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in spontaneous canine cancer: Results of phase I and phase II clinical trials
Authors: London Cheryl A. , Bernabe Luis Feo , Barnard Sandra , Kisseberth William , Borgatti Antonella , Henson Michael , Wilson-Robles Heather , Jensen Kiersten , Ito Daisuke , Modiano Jaime , Bear Misty , Pennell Michael , Saint-Martin Jean-Richard , McCauley Dilara , Kauffman Michael , Shacham Sharon 
Published: May 2015

Abstract
SINE (Selective Inhibitors of Nuclear Export) block the activity of XPO1/CRM1, 1 of 7 nuclear export proteins in cells, forcing the nuclear retention of key tumor suppressor proteins, leading to selective apoptosis of tumor cells. The purpose of these studies was to evaluate the in vitro activity of SINE against canine tumor cell lines and investigate the biological activity of verdinexor (KPT-335) in dogs with spontaneous cancers as proof of principle for human clinical studies. Several different canine tumor cell lines including those derived from non-Hodgkin Lymphoma (NHL) exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE; NHL cells were particularly sensitive with IC50 2-42 nM. A Phase I clinical trial of verdinexor was performed in dogs with cancer with an emphasis on NHL given in vitro activity demonstrated against the tumor cell lines. The MTD was 1.75 mg/kg twice per week although biological activity was observed at 1 mg/kg. Clinical benefit including Partial Response (PR) and Stable Disease (SD) for at least 4 weeks was observed in 9/14 dogs with NHL with a median time to progression of 66 days (range 35-256). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg verdinexor on a Monday/Wednesday/Friday (MWF) regimen; clinical benefit (PR+SD) was observed in 4/6 dogs with a median time to progression of 83 days (range 35-354). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care and dose modulation. A validated health related Quality of Life (QOL) form used to assess dogs during treatment demonstrated that the overall quality of life did not decrease in dogs in this study supporting the notion that clinical toxicities associated with verdinexor are generally well tolerated. Based on these findings, a Phase IIb study was performed in 58 dogs with either newly diagnosed or relapsed NHL. Drug was administered initially at 1.5 mg/kg MWF, but this dosing regimen was changed to 1.25 mg/kg M/Th due to the high rate of anorexia and weight loss on the MWF regimen; dose escalation was permitted to 1.5 mg/kg on the M/Th regimen.. The objective response rate was 29% (1 CR, 16 PR) with an additional 25 dogs experiencing SD for a minimum of 4 weeks, resulting in a of 72% disease control rate. While the median time to progression was approximately 6 weeks, 19 dogs (32%) remained on study drug for more than 8 weeks. Laboratory abnormalities were minimal. Together, these data provide robust evidence that the novel orally bioavailable XPO1 inhibitor vrdinexor exhibits single agent biological activity in a spontaneous large animal model of human NHL. Furthermore, verdinexor was well tolerated even in the absence of supportive care, suggesting that SINE compounds could exhibit good long-term tolerability in people.
Citation Format: Cheryl A. London, Luis Feo Bernabe, Sandra Barnard, William Kisseberth, Antonella Borgatti, Michael Henson, Heather Wilson-Robles, Kiersten Jensen, Daisuke Ito, Jaime Modiano, Misty Bear, Michael Pennell, Jean-Richard Saint-Martin, Dilara McCauley, Michael Kauffman, Sharon Shacham. Evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in spontaneous canine cancer: Results of phase I and phase II clinical trials. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3809. doi:10.1158/1538-7445.AM2014-3809