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Protocol Details

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

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: No longer recruiting/follow-up only
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required


Population Exclusion(s)

Pregnant Women;


B-Cell Malignancies

Recruitment Keyword(s)



Hairy Cell Leukemia;
Hairy Cell Leukemia Variant

Investigational Drug(s)

Ibrutinib (PCI-32765)

Investigational Device(s)



Drug: Ibrutinib

Supporting Site

National Cancer Institute


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.

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 Preclinical work, while unpublished, has been done at OSU, NIH and MD Anderson to define the potential activity of ibrutinib in HCL.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.


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


- 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 (Fludarabine, Pentostatin, or Cladribine), 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


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 44 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.

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Histologically confirmed diagnosis of Hairy Cell Leukemia or variant according: to WHO criteria with any of the following indications for therapy:

--Hemoglobin < 11 g/dL

--Platelet count < 100,000/mL

--Absolute neutrophil count < 1,000/mL

--Progressive or symptomatic splenomegaly or hepatomegaly

--Enlarging lymphadenopathy greater than or equal to 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, CTEP active version of the CTCAE grade 2 or 3 fatigue, fevers >100.5 degrees 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 conditions:

a. After at least 1 prior purine nucleoside analog-containing regimen, (Fludarabine, Pentostatin, or Cladribine) or

b. 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.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of ibrutinib in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.

-ECOG performance status <2 (Karnofsky >60%)

-Life expectancy of greater than 12 months.

-Patients will be required to meet the following laboratory parameters:

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

Creatinine clearance (estimated GFR [Cockcroft-Gault]) greater than or equal to 30 mL/min

b. Total bilirubin less than or equal to 1.5 x ULN (unless disease related or due to Gilbert s disease)

c. AST less than or equal to 3.0 x ULN (unless disease related)

d. PT/INR <1.5 (SqrRoot) ULN and PTT (aPTT) <1.5 (SqrRoot) ULN

e. 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.

-Female patients who are of non-reproductive potential (i.e., post-menopausal by history -

no menses for greater than or equal to 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female patients of childbearing potential must have a negative serum pregnancy test upon study entry.

-Male and female patients who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete sexual abstinence, or sterilized partner) during the period of therapy

and for 90 days after the last dose of study drug.

-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.

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


-Chemotherapy less than or equal to 21 days prior to first administration of study treatment and/or monoclonal antibody less than or equal to 6 weeks prior to first administration of study treatment.

-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.

-History of allergic reactions attributed to compounds of similar chemical or biologic composition as ibrutinib.

-Ibrutinib is extensively metabolized by CYP3A4/5. Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or patients who require continuous treatment with a strong CYP3A inhibitor. Therefore, any medications or substances that are strong inhibitors of CYP3A4/5 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 product.

-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. Recent infections requiring systemic treatment need to have completed therapy >14 days before the first dose of study drug.

-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.

-HIV-positive patients will be eligible unless they have been previously diagnosed with an 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. Patients who are currently taking vitamin K antagonists are also ineligible for this study.

-Patients requiring daily corticosteroids at a prednisone equivalent of greater than or equal to 20 mg daily should not be enrolled. If corticosteroids can be discontinued (or reduced to <20 mg per day of prednisone or equivalent), the discontinuation or dose reduction should be done at least 7 days prior to first dose

-Prior exposure to a BTK inhibitor.

-Major surgery within 4 weeks of 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 disease.

-Currently active clinically significant cardiovascular disease such as: uncontrolled arrhythmia, congestive heart failure, or Class 3 or 4 congestive heart failureas defined by the New York Heart Association Functional Classification or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to first dose with study drug.

-Patient is unable to swallow capsules, or has disease significantly affecting gastrointestinal function or resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

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

-Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded).

-Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug.

-Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

-Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 5), grade less than or equal to 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia.

-Known bleeding disorders (e.g., von Willebrands disease) or hemophilia.

-Unwilling or unable to participate in all required study evaluations and procedures.

-Currently active, clinically significant hepatic impairment (greater than or equal to moderate hepatic impairment according to the NCI/Child Pugh classification )

-Incarceration at time of enrollment. Prisoners will be excluded from enrollment. Subjects who become incarcerated after starting study treatment will be allowed to continue in the study.

Inclusion of Women and Minorities:

Both men and women of all races and ethnic groups are eligible for this trial.

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Not Provided

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Principal Investigator

Referral Contact

For more information:

Robert J. Kreitman, M.D.
National Cancer Institute (NCI)
(301) 648-7375

Holly Eager (DiFebo), R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 13N240
10 Center Drive
Bethesda, Maryland 20892
(240) 858-7229

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office

Clinical Trials Number:


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