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Targeting the B-cell receptor: lessons learned treating dogs with BTK inhibitors

Targeting the B-cell receptor: lessons learned treating dogs with BTK inhibitors

Targeting the B-cell receptor: lessons learned treating dogs with BTK inhibitors

Veterinary Cancer Society
Veterinary Cancer Society
on behalf of Missouri Veterinary Medical Association

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$ 12.50 $ 12.50 $ 12.50
Normal Price: FREE $12.50

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Launch date: 22 Dec 2016
Expiry Date:

Last updated: 10 Feb 2017

Reference: 167572

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This course is only available to trainees days after purchase. It would need to be repurchased by the trainee if not completed in the allotted time period. This course is no longer available. You will need to repurchase if you wish to take the course again.

Description

Significant advances have been made in our understanding of the molecular basis of B-cell lymphomas. In humans, this has resulted in a growing number of new therapeutic agents in development. Evaluation of these agents in dogs with spontaneous lymphoma is increasingly being incorporated into the development of these agents and represents a significant opportunity to enhance the drug development process and improve therapy for people and dogs with lymphoma. Notably, the recognition that many B-cell malignancies rely on chronic stimulation of the B-cell receptor (BCR) pathway has resulted in the development of multiple agents targeting different components of the BCR pathway. The development of inhibitors of one component of that pathway, Bruton’s tyrosine kinase (BTK), is particularly notable in that preclinical trials in dogs with lymphoma were incorporated into and enhanced the development of both FDA-approved BTK inhibitors, ibrutinib and acalabrutinib (ACP-196), currently in use. Here we briefly review spontaneous lymphoma in the dog as a model for the human disease, the BCR pathway as a target for therapy, results of a clinical trial of aclarubinitib in dogs with lymphoma, and perspectives moving forward.
A multicenter open-label, nonrandomized, sequential group, dose-escalation study of acalabrutinib in companion dogs with spontaneous B-cell lymphoma was conducted. Treatment-naïve dogs and dogs with prior therapies and a confirmed diagnosis of new or relapsed B-cell lymphoma were eligible. Twenty dogs were enrolled and administered acalabrutinib orally once or twice daily for a 7-day cycle and continued until clinical progression. Assessment of clinical toxicities and tumor response were performed at each visit. Dogs were evaluated for hematologic and biochemical toxicities every 7 days. The DLT was considered to be any grade 3 or 4 hematologic or non-hematologic toxicity based on established VCOG-CTCAE v1.1 criteria
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.
Conclusions: These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients. More broadly, BTK inhibitor trials in dogs provided additional preclinical assessment of toxicities and tolerability, biologic activity, and pharmacodynamic marker development and assessment. Furthermore, the unique ability to readily obtain serial biologic samples provides great opportunities for addressing important biologic, correlative, and mechanistic questions regarding such targeted therapies.

Objectives

Learning Objectives:
• List some of the components of the B-cell receptor pathway.
• Understand the observed toxicities and clinical responses observed in dogs with lymphoma treated with BTK inhibitors.
• Understand how spontaneous lymphoma in the dog can be used as a translational model for human anticancer drug development.
Veterinary Cancer Society

Author Information Play Video Bio

Veterinary Cancer Society
on behalf of Missouri Veterinary Medical Association

Dr. William Kisseberth - Dr. Kisseberth received his DVM degree from the University of Illinois. He completed a residency in Medical Oncology and received his MS and PhD from the University of Wisconsin-Madison. Dr. Kisseberth currently is an Associate Professor in the Department of Veterinary Clinical Sciences at The Ohio State University where he is a staff oncologist in the Veterinary Medical Center and member of the Leukemia Research Program at the Ohio State University Comprehensive Cancer Center. He is Co-Director of The Ohio State University College of Veterinary Medicine Biospecimen Repository. His clinical and research interests are in veterinary and comparative oncology, focused primarily on experimental therapeutics, drug development, and comparative genomics.

Current Accreditations

This course has been certified by or provided by the following Certified Organization/s:

  • Missouri Veterinary Medical Association
  • 0.50 Hours -
    Exam Attempts: 3
    -
    Exam Pass Rate: 50

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