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

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

Nucleo-cytoplasmic transport as a therapeutic target of cancer

“…A structurally-related SINE compound, verdinexor (KPT-335; Figure 2 o), is currently being developed for canine lymphoma [ 109 ]-[ 112 ]. Verdinexor has shown potent cytotoxic activity in canine NHL and melanoma cells when administered 2-3 times a week to companion dogs with spontaneously-occurring B- and T-cell lymphomas.…”

“…Lymphomas are some of the most common malignancies in companion dogs and the diseases are characterized by rapid progression; dogs may live up to only a few weeks if left untreated [ 109 ]. In Phase I/II canine clinical trial in companion dogs with NHL (naïve or relapsed), verdinexor was orally administered at doses of 1.0 – 1.75 mg/kg and was generally very well-tolerated, with anorexia as the most common toxicity indicator [ 112 ]. In the Phase II study, verdinexor displayed single-agent activity with an overall objective response rate of 34% (20/58 dogs).…”

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT‐330): A report from the pediatric preclinical testing program

“…As an example, verdinexor (KPT‐335) potently inhibits human and canine lymphoma cell lines with low nanomolar potency, and in a phase 1 study with dose expansion in dogs with lymphoma, partial responses were noted in 4 of 20 treated animals . In a subsequent phase 2 trial of verdinexor for canine lymphoma, objective responses (PR or CR) were noted in 20 of 58 (34%) treated animals …”