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

Cheryl A. London, Luis Feo Bernabe, Sandra Barnard, William C. Kisseberth, Antonella Borgatti, Mike Henson, Heather Wilson, Kiersten Jensen, Daisuke Ito, Jaime F. Modiano, Misty D. Bear, Michael L. Pennell, Jean Richard Saint-Martin, Dilara McCauley, Michael Kauffman, Sharon Shacham

Research output: Contribution to journalArticle

49 Citations (Scopus)

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. Methods and Findings: 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.

Original languageEnglish (US)
Article numbere87585
JournalPloS one
Volume9
Issue number2
DOIs
StatePublished - Feb 4 2014

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Cell Nucleus Active Transport
non-Hodgkin lymphoma
Non-Hodgkin's Lymphoma
Canidae
Tumors
Dogs
neoplasms
dogs
Clinical Trials, Phase I
Toxicity
Anorexia
Osteosarcoma
Neoplasms
Tumor Cell Line
Mast Cells
Cells
dosage
Weight Loss
osteosarcoma
mast cells

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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. / London, Cheryl A.; Bernabe, Luis Feo; Barnard, Sandra; Kisseberth, William C.; Borgatti, Antonella; Henson, Mike; Wilson, Heather; Jensen, Kiersten; Ito, Daisuke; Modiano, Jaime F.; Bear, Misty D.; Pennell, Michael L.; Saint-Martin, Jean Richard; McCauley, Dilara; Kauffman, Michael; Shacham, Sharon.

In: PloS one, Vol. 9, No. 2, e87585, 04.02.2014.

Research output: Contribution to journalArticle

London, CA, Bernabe, LF, Barnard, S, Kisseberth, WC, Borgatti, A, Henson, M, Wilson, H, Jensen, K, Ito, D, Modiano, JF, Bear, MD, Pennell, ML, Saint-Martin, JR, McCauley, D, Kauffman, M & Shacham, S 2014, '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', PloS one, vol. 9, no. 2, e87585. https://doi.org/10.1371/journal.pone.0087585
London, Cheryl A. ; Bernabe, Luis Feo ; Barnard, Sandra ; Kisseberth, William C. ; Borgatti, Antonella ; Henson, Mike ; Wilson, Heather ; Jensen, Kiersten ; Ito, Daisuke ; Modiano, Jaime F. ; Bear, Misty D. ; Pennell, Michael L. ; Saint-Martin, Jean Richard ; McCauley, Dilara ; Kauffman, Michael ; Shacham, Sharon. / 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. In: PloS one. 2014 ; Vol. 9, No. 2.
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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. Methods and Findings: 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.",
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