title: 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: BACKGROUND
  The 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.
  
  
  RESULTS
  Canine 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.
  
  
  CONCLUSIONS
  This 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.
authors: Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: Cheryl A
authors: CA
authors: London
authors: Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: Luis Feo
authors: LF
authors: Bernabe
authors: Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: Sandra
authors: S
authors: Barnard
authors: Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: William C
authors: WC
authors: Kisseberth
authors: Department of Veterinary Clinical Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis/St. Paul, Minnesota, United States of America.
authors: Antonella
authors: A
authors: Borgatti
authors: Department of Veterinary Clinical Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis/St. Paul, Minnesota, United States of America.
authors: Mike
authors: M
authors: Henson
authors: Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors: Heather
authors: H
authors: Wilson
authors: Department of Veterinary Clinical Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis/St. Paul, Minnesota, United States of America.
authors: Kiersten
authors: K
authors: Jensen
authors: Department of Veterinary Clinical Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis/St. Paul, Minnesota, United States of America.
authors: Daisuke
authors: D
authors: Ito
authors: Department of Veterinary Clinical Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis/St. Paul, Minnesota, United States of America.
authors: Jaime F
authors: JF
authors: Modiano
authors: Departments of Veterinary Biosciences and Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: Misty D
authors: MD
authors: Bear
authors: Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, Ohio, United States of America.
authors: Michael L
authors: ML
authors: Pennell
authors: Karyopharm Therapeutics, Natick, Massachusetts, United States of America.
authors: Jean-Richard
authors: JR
authors: Saint-Martin
authors: Karyopharm Therapeutics, Natick, Massachusetts, United States of America.
authors: Dilara
authors: D
authors: McCauley
authors: Karyopharm Therapeutics, Natick, Massachusetts, United States of America.
authors: Michael
authors: M
authors: Kauffman
authors: Karyopharm Therapeutics, Natick, Massachusetts, United States of America.
authors: Sharon
authors: S
authors: Shacham
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000662:veterinary*; D011788:Quality of Life; D014230:Triazoles
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D006834:Hydrazines; C000593855:verdinexor; D014230:Triazoles