Ibrutinib: First-in Class Inhibitor of BTK Forms a specific and irreversible bond with cysteine-481...
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Transcript of Ibrutinib: First-in Class Inhibitor of BTK Forms a specific and irreversible bond with cysteine-481...
Ibrutinib: First-in Class Inhibitor of BTK Forms a specific and irreversible bond
with cysteine-481 in BTK
Highly potent BTK inhibition at IC50 = 0.5 nM
Orally administered with once daily dosing resulting in 24-hr target inhibition
In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG mediated proliferation
Inhibits CLL cell migration and adhesion
No cytotoxic effect on T-cells or NK-cells
Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010Herman SEM et al: Blood 117: 6287-6296, 2011Ponader, et al., ASH Meeting Abstracts 116:45, 2010
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NH 2
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IbrutinibPCI-32765
Primary ObjectiveTo determine the overall response rate after 32 wks of ibrutinib therapy
Secondary Objectives To characterize the toxicity and tolerability of single-agent ibrutinib To characterize the progression-free (PFS) and overall survival (OS) To determine the rate of MRD-negative CR at 32 weeks To characterize immunologic outcomes during ibrutinib treatment To explore the effect of ibrutinib on traditional and new biomarkers
in HCL including: BRAFV600E in expression pERK regulation, as well as other potential protein kinase targets Serum soluble IL-2 receptor levels MRD
NCI 9268 Ibrutinib for Relapsed HCL: Objectives
Histologically confirmed hairy cell leukemia (HCL) or variant hairy cell leukemia (vHCL)
For HCL: ≥1 prior purine nucleoside analog-containing regimen, or Relapsed or de novo disease if medically unfit for purine nucleoside
analog treatment
For vHCL: Both previously untreated and relapsed patients are eligible
Preserved end-organ function, ECOG ≤ 2 Requires therapy
Hgb <11g/dL, plts <100K/mL, ANC <1,000/mL, enlarging nodes ≥2cm Progressive organomegaly Progressive disease-related constitutional symptoms
NCI 9268 Ibrutinib for Relapsed HCL: Eligibility