Study of Ibrutinib for Treatment of Relapsed Hairy Cell Leukemia

Pr(SqrRoot)(Copyright)cis

Background:

Hairy Cell Leukemia (HCL) is an uncommon chronic B-cell lymphoproliferative disorder first
described by Bouroncle et al. in 1958 (1), with only approximately 2,000 new cases diagnosed
in North America and Western Europe annually. The WHO now recognizes two distinct forms of
HCL, classic HCL and variant HCL (2). The majority of patients have classic HCL, with only
10% of patients having variant HCL. Classic HCL has a characteristic immunophenotype of
positivity for CD20, CD11c, CD25, CD103, and CD123, while variant HCL lacks CD25. In
addition, variant HCL is characterized by an aggressive clinical course, poor response to
therapy, frequent deletion of chromosome 17p13.1, and leukocytosis. Recently, somatic
mutations of BRAF V600E have been described in patients with classic hairy cell but not
variant (3, 4).

For patients relapsing beyond the second therapy or for patients who are unfit to receive a
purine nucleoside analog, there is currently no consensus on optimal treatment. In addition,
it is not known what proportion of patients will develop long- term complications of
repeated courses of purine nucleoside analogs, such as myelodysplasia or therapy-associated
acute myeloid leukemia.

PCI-32765 (ibrutinib) is a selective, small molecule irreversible inhibitor of Bruton s
tyrosine kinase (BTK) with antitumor activity in patients with hematologic malignancies,
particularly chronic lymphocytic leukemia and mantle cell lymphoma (5). Preclinical and
clinical data indicate that B-cell receptor (BCR) signaling is effectively inhibited by
ibrutinib, leading to highly selective cytotoxicity in malignant B cells. Preclinical work,
while unpublished, has been done at OSU, NIH and MD Anderson to define the potential
activity of ibrutinib in HCL. Both phosphorylated and non-phosphorylated forms of BTK are
expressed in HCL patient samples, and BTK phosphorylation can be inhibited in vitro using
ibrutinib. As presented at the 2012 American society of hematology meeting, HCL cell
survival, which is partly dependent on B-cell receptor signaling is decreased with
increasing concentrations of ibrutinib (6). In HCL cells, ibrutinib also inhibits CXCL12
signaling, a key pathway for bone marrow homing. Incubation of fresh patient HCL cells has
been done for > 20 samples and dose-dependent cytotoxicity has been demonstrated. These data
increase the importance of the testing of ibrutinib in HCL.

Objectives:

Primary Objective:

-To determine the overall response rate (CR and PR) of hairy cell leukemia (HCL) at 32 weeks
after beginning therapy with single-agent ibrutinib

Eligibility:

- Histologically confirmed hairy cell leukemia (HCL) or variant hairy cell leukemia
(vHCL)

- For HCL:

- Greater than or equal to 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

- Laboratory parameters:

- Creatinine less than or equal to 2.0 mg/dL, and/or

- Creatinine Clearance greater than or equal to 30 mL/min

- Total Bilirubin less than or equal to 1.5 ULN (unless due to Gilbert s)

- AST less than or equal to 2 x ULN (unless disease related)

- ECOG performance status less than or equal to 2

- Non-pregnant and non-nursing

- No uncontrolled infection and/or other intercurrent illness

- No concomitant strong inhibitors or inducers of CYP3A4/5

- No concomitant warfarin anticoagulation

- Estimated life expectancy > 12 months

Design:

This is a phase II, multi-institution open-label, non-randomized monotherapy study to
evaluate the clinical efficacy and toxicity of ibrutinib (PCI-32765, PCI) when administered
to patients with hairy cell leukemia or variant hairy cell leukemia. The study will enroll
up to 31 patients from 8 centers. 12- 18 patients will be enrolled at NCI.

All patients meeting eligibility criteria will undergo baseline assessments to include CT
scans and/or ultrasound of spleen and involved nodal areas and bone marrow biopsy. Patients
will then be treated with ibrutinib capsules administered once daily at a dose of 420 mg for
28 day cycles. Weekly clinical and laboratory monitoring during the first 28-day cycle will
be followed by monthly evaluations during the first 12 cycles of therapy; clinical
monitoring with labs on a frequent basis will be adequate to detect HCL progression. Formal
response assessment, including physical examination, laboratory studies, CT scans and/or
ultrasound and bone marrow biopsy for pathology and MRD assessment will occur after 8 and 12
cycles. Responding patients will continue ibrutinib indefinitely absent unacceptable
toxicity or confirmation of progressive disease.

- Eligibility:

- Histologically confirmed hairy cell leukemia (HCL) or variant hairy cell leukemia
(vHCL)

- For HCL:

- Greater than or equal to 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

- Laboratory parameters:

- Creatinine less than or equal to 2.0 mg/dL, and/or

- Creatinine Clearance greater than or equal to 30 mL/min

- Total Bilirubin less than or equal to 1.5 ULN (unless due to Gilbert s)

- AST less than or equal to 2 x ULN (unless disease related)

- ECOG performance status less than or equal to 2

- Non-pregnant and non-nursing

- No uncontrolled infection and/or other intercurrent illness

- No concomitant strong inhibitors or inducers of CYP3A4/5

- No concomitant warfarin anticoagulation

- Estimated life expectancy > 12 months