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A Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 for Treatment of Relapsed Hairy Cell Leukemia

Phase 2
18 Years
Open (Enrolling)
Progressive Hairy Cell Leukemia, Initial Treatment, Refractory Hairy Cell Leukemia, Untreated Hairy Cell Leukemia

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Trial Information

A Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 for Treatment of Relapsed Hairy Cell Leukemia


I. To determine the overall response rate (complete response [CR] and partial response [PR])
of hairy cell leukemia (HCL) at 32 weeks after beginning therapy with single-agent


I. To characterize the toxicity and tolerability of single-agent ibrutinib when administered
to patients with HCL.

II. To characterize the progression-free (PFS) and overall survival (OS) of single- agent
ibrutinib when administered to patients with HCL.

III. To determine the rate of molecular remission (minimal residual disease [MRD]-negative
CR) among all patients, defined as resolution of all detectable disease below the limits of
detection by immunohistochemistry and/or 4-color flow cytometry assay at 32 weeks after
beginning ibrutinib therapy.

IV. To characterize immunologic outcomes during single agent ibrutinib administration.

V. To explore the effect of PCI-32765 (ibrutinib) on traditional and new biomarkers in HCL
including: confirmation of expression BRAFV600E in leukemia cell; pharmacodynamic effects of
BTK inhibition on phospho extracellular signal-regulated kinase (ERK) regulation, as well as
other potential protein kinase targets of ibrutinib (exploratory); serum soluble interleukin
(IL)-2 receptor correlation with response to ibrutinib therapy; documentation of and
quantification of minimal residual disease following maximal response, with flow cytometric
analysis and immunohistochemical stains of the bone marrow, as predictors of remission
duration after ibrutinib therapy.


Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Histologically confirmed diagnosis of hairy cell leukemia or variant according to
World Health Organization (WHO) criteria

- Hemoglobin < 11 g/dL

- Platelet count < 100,000/mL

- Absolute neutrophil count < 1,000/mL

- Progressive or symptomatic splenomegaly or hepatomegaly

- Enlarging lymphadenopathy >= 2 cm

- Absolute lymphocyte count > 5,000/mL

- Disease related constitutional symptoms consisting of unexplained weight loss
exceeding 10% of body weight over the preceding 6 months, Cancer Therapy Evaluation
Program (CTEP) active version of the Common Terminology Criteria for Adverse Events
(CTCAE) grade 2 or 3 fatigue, fevers > 100.5ยบ F or night sweats for greater than 2
weeks without evidence of infection

- Patients with classic hairy cell leukemia may receive therapy under the following

- After at least 1 prior purine nucleoside analog-containing regimen, or

- Relapsed or de novo disease if deemed medically unfit for therapy with a purine
nucleoside analog

- Because there is no recognized standard of care for patients with variant
hairy cell leukemia, both previously treated and previously untreated
patients with this diagnosis will be eligible

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 12 months

- Creatinine =< 2.0 mg/dL, and/or creatinine clearance (estimated glomerular filtration
rate [GFR] [Cockcroft-Gault]) >= 30 mL/min

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless disease related or due
to Gilbert's disease)

- Aspartate aminotransferase (AST) =< 2 x ULN (unless disease related)

- Because patients with HCL are typically pancytopenic at presentation for treatment,
patients will be eligible without respect to baseline peripheral blood cell counts if
they otherwise meet inclusion criteria

- The effects of ibrutinib on the developing human fetus are unknown; for this reason,
and because tyrosine kinase inhibitors may be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry, for the duration of study
participation, and 4 months after completion of ibrutinib treatment; should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately; men treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and 4 months after completion of
ibrutinib administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- Ibrutinib is extensively metabolized by cytochrome P450 (CYP)2D6 and CYP3A4/5;
therefore, any medications or substances that are strong inhibitors of CYP3A4/5
and/or CYP2D6 (e.g itraconazole, ketoconazole, clarithromycin, and bupropion) should
be discontinued; patients unable to change these medications must be excluded from
participation; because the lists of these agents are constantly changing, it is
important to regularly consult a frequently-updated list such as; medical reference texts such as
the Physicians' Desk Reference may also provide this information; as part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because ibrutinib is a tyrosine kinase
inhibitor with the potential for teratogenic or abortifacient effects; because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with ibrutinib, breastfeeding should be discontinued if the
mother is treated with ibrutinib

- Human immunodeficiency virus (HIV)-positive patients will be eligible unless they
have been previously diagnosed with an acquired immune deficiency syndrome
(AIDS)-defining illness

- Patients who require anticoagulation with warfarin (Coumadin) or who have taken
warfarin within 28 days prior to enrollment are not eligible due to a potential
increased risk of hemorrhage

- Concurrent corticosteroid treatment (equivalent to prednisone > 20 mg daily) is
prohibited from 7 days prior to first dose and during treatment with ibrutinib

- Prior exposure to ibrutinib

- Major surgery within 4 weeks prior to the first dose of study drug

- A history of prior malignancy, with the exception of the following:

- Malignancy treated with curative intent and with no evidence of active disease
present for more than 3 years prior to screening, and felt to be at low risk for
recurrence by the treating physician

- Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma
without current evidence of disease

- Adequately treated cervical carcinoma in situ without current evidence of

- Currently active clinically significant cardiovascular disease such as: uncontrolled
arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease as defined by
the New York Heart Association functional classification or history of myocardial
infarction within 6 months prior to first dose with study drug

- Patient is unable to swallow capsules or has disease significantly affecting
gastrointestinal function and/or inhibiting small intestine absorption, such as
malabsorption syndrome, resection of the small bowel, or poorly controlled
inflammatory bowel disease affecting the small intestine

- History of stroke or intracranial hemorrhage within 6 months prior to enrollment

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall response rate (CR and PR)

Outcome Time Frame:

32 weeks

Safety Issue:


Principal Investigator

Jeffrey Jones

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

April 2013

Completion Date:

Related Keywords:

  • Progressive Hairy Cell Leukemia, Initial Treatment
  • Refractory Hairy Cell Leukemia
  • Untreated Hairy Cell Leukemia
  • Leukemia
  • Leukemia, Hairy Cell



Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201
Ohio State University Medical CenterColumbus, Ohio  43210