title: Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.
abstract: 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).
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Bonnie K
authors.identifier: http://orcid.org/0000-0003-2658-6188
authors.initials: BK
authors.lastname: Harrington
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gardner
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Raquel
authors.initials: R
authors.lastname: Izumi
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hamdy
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Wayne
authors.initials: W
authors.lastname: Rothbaum
authors.affiliation: Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Todd
authors.initials: T
authors.lastname: Covey
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Allard
authors.initials: A
authors.lastname: Kaptein
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Gulrajani
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Van Lith
authors.affiliation: Acerta Pharma BV, Oss, Netherlands.
authors.forename: Cecile
authors.initials: C
authors.lastname: Krejsa
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Coss
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Russell
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Pittsburgh Veterinary Specialty and Emergency Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Urie
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: London
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Kisseberth
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000503:physiopathology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D045744:Cell Line, Tumor; D003967:Diarrhea / Q000139:chemically induced / Q000503:physiopathology; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004285:Dogs; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D053609:Lethargy / Q000139:chemically induced / Q000503:physiopathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000662:veterinary*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D014839:Vomiting / Q000139:chemically induced / Q000503:physiopathology; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000604908:acalabrutinib