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

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