TY - JOUR
T1 - Preclinical evaluation of the novel BTK inhibitor acalabrutinib in canine models of B-cell non-hodgkin lymphoma
AU - Harrington, Bonnie K.
AU - Gardner, Heather L.
AU - Izumi, Raquel
AU - Hamdy, Ahmed
AU - Rothbaum, Wayne
AU - Coombes, Kevin R.
AU - Covey, Todd
AU - Kaptein, Allard
AU - Gulrajani, Michael
AU - Van Lith, Bart
AU - Krejsa, Cecile
AU - Coss, Christopher C.
AU - Russell, Duncan S.
AU - Zhang, Xiaoli
AU - Urie, Bridget K.
AU - London, Cheryl A.
AU - Byrd, John C.
AU - Johnson, Amy J.
AU - Kisseberth, William C.
N1 - Funding Information:
This work is supported by NIH R35 CA197734, R01 CA177292, NIH T32CA009338, the D. Warren Brown Foundation, CLL Research Consortium (CRC) P01 CA081534, OSU Comprehensive Cancer Center Support Grant P30 CA016058, and UL1TR001070 from the National Center for Advancing Translational Sciences. We would also like to acknowledge the staff of the Veterinary Clinical Research Support Shared Resource and the Comparative Pathology and Mouse Phenotyping Shared Resource at The Ohio State University College of Veterinary Medicine for their efforts in this publication. Funding for the clinical trial associated with this manuscript was provided by Acerta Pharma.
Publisher Copyright:
© 2016 Harrington et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/7
Y1 - 2016/7
N2 - Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL).
AB - Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL).
UR - http://www.scopus.com/inward/record.url?scp=84979239943&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979239943&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0159607
DO - 10.1371/journal.pone.0159607
M3 - Article
C2 - 27434128
AN - SCOPUS:84979239943
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 7
M1 - e0159607
ER -