Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma

Abbey R Sadowski,Heather Wilson,Joshua Lachowicz,Alexandra Sahora,Avenelle Turner,Antonella Borgatti,David M Vail,Heather L Gardner,Mary K Klein,Cheryl A London,Angharad Waite,Christina Manley

doi:10.1186/s12917-018-1587-9

Abstract

BackgroundChemotherapeutic options for the treatment of canine lymphoma have not changed in several decades necessitating the identification of new therapeutics to improve patient outcome. KPT-335 (verdinexor) is a novel orally bioavailable selective inhibitor of nuclear export (SINE) that exhibited anti-tumor activity against non-Hodgkin lymphoma in a prior phase I study. The objective of this phase II study was to expand upon the initial findings and assess the activity and safety in a larger population of dogs with lymphoma.ResultsFifty-eight dogs with naïve or progressive B-cell and T-cell lymphoma were enrolled in this clinical trial. KPT-335 was administered orally in one of three dosing groups, based on the previously established biologically active dose of 1.5 mg/kg three times weekly. Treatment with single-agent, orally administered KPT-335 resulted in an objective response rate (ORR) of 37%, of which dogs with T-cell lymphoma had an ORR of 71%. KPT-335 was well tolerated in all dose groups with grade 1–2 anorexia being the most common adverse event. Anorexia was responsive to symptomatic and supportive medications, including prednisone.ConclusionsThese data demonstrate that KPT-335 has biologic activity in canine lymphoma, and support continued evaluation of SINE compounds such as KPT-335 in combination with standard chemotherapeutics in canine lymphoma.

Highlights

Chemotherapeutic options for the treatment of canine lymphoma have not changed in several decades necessitating the identification of new therapeutics to improve patient outcome
The primary objective of this phase II study was to build upon the phase I study findings, and describe the safety and anti-tumor activity of oral KPT-335 in dogs with naïve lymphoma, or after a single relapse. These data will provide information on the best use of selective inhibitor of nuclear export (SINE) compounds in future clinical studies. Clinical trial eligibility This clinical trial was approved by the Animal Clinical Investigation (ACI) Animal Care and Use Committee (ACUC); IACUC or equivalent approval was obtained at all participating study sites
Thirty-five dogs with naïve lymphoma and 23 dogs at the time of their first relapse were enrolled in this clinical trial

Summary

Introduction

Chemotherapeutic options for the treatment of canine lymphoma have not changed in several decades necessitating the identification of new therapeutics to improve patient outcome. KPT-335 (verdinexor) is a novel orally bioavailable selective inhibitor of nuclear export (SINE) that exhibited anti-tumor activity against non-Hodgkin lymphoma in a prior phase I study. The objective of this phase II study was to expand upon the initial findings and assess the activity and safety in a larger population of dogs with lymphoma. Neoplastic cells utilize the process of nucleo-cytoplasmic transport to export known TSP and GRP outside of the nucleus, inactivating these pathways and overcoming the normal cell cycle and genomic instability checkpoints [1, 2]. A phase I study of orally administered KPT-330 showed safety and feasibility of long-term treatment in a variety of patients with advanced solid tumors. Given the safety profile and cytotoxic effects of KPT-330 on rapidly proliferating leukemia cells in animal models and patient samples, several studies have investigated the efficacy and safety of KPT-330

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