Ibrutinib: First-in Class Inhibitor of BTK
O

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
NH 2
N
N
N
N
N
O
Ibrutinib
PCI-32765
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
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
NCI 9268 Ibrutinib for Relapsed HCL: Objectives
Primary Objective
To 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: Eligibility
 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: Schema
 N = 44 patients
 6 participating centers