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


Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

PRIMARY OBJECTIVES: 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 ibrutinib. SECONDARY OBJECTIVES: 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 v-raf murine sarcoma viral oncogene homolog B V600E mutation (BRAFV600E) in leukemia cells; pharmacodynamic effects of Bruton agammaglobulinemia tyrosine kinase (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. OUTLINE: 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.

Who is eligible to participate?

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 > 100.5º Fahrenheit (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: - After at least 1 prior purine nucleoside analog-containing regimen (fludarabine, pentostatin, or cladribine), or - Relapsed or de novo disease if deemed medically unfit for therapy with a purine nucleoside analog - 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) - Patients will be eligible without respect to baseline peripheral blood cell counts if they otherwise meet inclusion criteria - 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 - History of allergic reactions attributed to compounds of similar chemical or biologic composition as ibrutinib - Any medications or substances that are strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/5 and/or cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) (e.g., itraconazole, ketoconazole, clarithromycin, and bupropion) should be discontinued; patients unable to change these medications must be excluded from participation - 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; 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; patients who are currently taking vitamin K antagonists are also ineligible for this study - 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 10 days or minor surgery within 5 days 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 disease - 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

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