Ibrutinib : First-in Class Inhibitor of BTK

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Ibrutinib: First-in Class Inhibitor of BTK Forms a specific and irreversible bond with cysteine-481 in BTK Highly potent BTK inhibition at IC 50 = 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, 2010 Herman SEM et al: Blood 117: 6287-6296, 2011 Ponader, et al., ASH Meeting Abstracts 116:45, 2010 N N N N NH 2 O N O Ibrutinib PCI-32765

description

O. N. H. 2. N. N. N. N. N. O. Ibrutinib : First-in Class Inhibitor of BTK. Forms a specific and irreversible bond with cysteine-481 in BTK Highly potent BTK inhibition at IC 50 = 0.5 nM Orally administered with once daily dosing resulting in 24-hr target inhibition - PowerPoint PPT Presentation

Transcript of Ibrutinib : First-in Class Inhibitor of BTK

Page 1: Ibrutinib :  First-in  Class Inhibitor of BTK

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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IbrutinibPCI-32765

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Burger J A et al. ASH Education Book 2011:96-103

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Potential Role for BCR Signalling in HCL

Sivina M et al. ASH Annual Meeting 2012 Abstract #1802

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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

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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

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N = 44 patients 6 participating centers

NCI 9268 Ibrutinib for Relapsed HCL: Schema