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 =

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

N

N

N

N

NH 2

O

N

O

IbrutinibPCI-32765

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

Potential Role for BCR Signalling in HCL

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

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

N = 44 patients 6 participating centers

NCI 9268 Ibrutinib for Relapsed HCL: Schema