Preclinical Evaluation of the Novel, Orally Bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Spontaneous Canine Cancer: Results of a Phase I Study

Abstract

BackgroundThe purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability.Methods and FindingsCanine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2–42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35–256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35–354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities.ConclusionsThis study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

“…Those novel mutations, and mutations reported in other cancers but not lymphoma, may indicate novel treatment possibilities in lymphoma. Generally, the same chemotherapeutic agents are effective in both dogs and humans (Honigberg et al 2010;London et al 2014). Hence, it is highly likely that the significantly mutated genes identified in dogs are suggestive of genes and pathways involved in human lymphoma, possibly allowing new treatment options.…”

“…The treatment outcome of canine lymphoma is predictive of the human response to the same treatment (Honigberg et al 2010;Marconato et al 2013;London et al 2014), and canine clinical trials, although highly regulated, are easier to complete compared with human trials. Hence, a better understanding of canine lymphoma offers great potential to accelerate development of new treatments for human patients.…”

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

“…PMBL cell lines are sensitive to the SINE compound [20] . Verdinexor (KPT-335) has been approved by Food and Drug Administration for the treatment of non-Hodgkin lymphoma (NHL), osteosarcoma, mast cell tumor and melanoma in canines [48] . This study used oral doses of verdinexor (1.75 mg/kg two times a week) and showed significant response with the manageable toxicity [48] .…”

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

“…The SINE XPO1 inhibitors have also been investigated in a comparative oncology setting, using dogs with newly diagnosed and chemotherapy-refractory cancers ( 80 ). In one study, the SINE compound verdinexor was administered in 17 dogs with NHL, mast cell tumor, or osteosarcoma.…”

“…Dose-limiting toxicities were anorexia and vomiting, which occurred at 2 mg/kg twice weekly. Among 16 evaluable dogs, 2 achieved partial responses (both with NHL) and 12 others achieved stable disease, indicating activity of XPO1 inhibitors in large-animal models ( 80 ). Verdinexor is currently in phase II studies in dogs with newly diagnosed or recurring lymphoma.…”