11 research outputs found
Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma
<div><p>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).</p></div
Adverse events listed by grade and frequency.
<p>Adverse events listed by grade and frequency.</p
Median PFS and OR of Treatment Naïve and relapsed Patients.
<p>Median PFS and OR of Treatment Naïve and relapsed Patients.</p
Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma - Fig 4
<p><b>PFS.</b> Kaplan-Meier curves showing overall PFS (A) and PFS of dogs achieving SD compared with PR (B). Dogs achieving PR survived significantly longer than those achieving SD (p = 0.010).</p
Median PFS and OR of Patients Achieving PR and SD.
<p>Median PFS and OR of Patients Achieving PR and SD.</p
Pharmacokinetic data.
<p>Plasma levels of acalabrutinib were measured at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after oral dose administration from 7 patients on day 14. 1000 ng/mL = 2.1 μM.</p
Percentage BTK target occupancy in peripheral blood B-cells and lymphoma aspirates of dogs following treatment with acalabrutinib.
<p>All values are presented as the average percentage BTK occupancy relative to control levels of BTK in matched pre-study samples. Due to poor sample quality the 5 mg/kg cohort was not included in the analysis. ND–not determined.</p
Reduced target lesion size in acalabrutinib treated dogs.
<p>Waterfall plot showing percentage decrease in mean sum of longest diameter of index lymph nodes as compared to baseline measurements.</p