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 ibrutinib (PCI-32765) on traditional and new biomarkers in HCL
including:
Va. Confirmation of expression BRAFV600E in leukemia cells Vb. Pharmacodynamic effects of BTK
inhibition on phosphorylated (phospho) ERK regulation, as well as other potential protein
kinase targets of ibrutinib (exploratory) Vc. Serum soluble IL-2 receptor correlation with
response to ibrutinib therapy Vd. 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. Cycles repeat every 28
days for up to 8 cycles if lack of response to therapy, up to 12 cycles if failure to achieve
an objective response (CR/PR), or continually at per physician discretion 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 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 >= 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 > 100.5 degrees 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
- 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) =< 3.0 x ULN (unless disease related)
- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN
- Partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5
x ULN
- 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 >= 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
Exclusion Criteria:
- Chemotherapy =< 21 days prior to first administration of study treatment and/or
monoclonal antibody =< 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; 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
- 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; patients who are currently taking vitamin K antagonists
are also ineligible for this study
- Patients requiring daily corticosteroids at a prednisone equivalent of >= 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 Bruton's tyrosine kinase (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 failure as
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 =< 1, or to
the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
- Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
- Unwilling or unable to participate in all required study evaluations and procedures
- Currently active, clinically significant hepatic impairment (>= moderate hepatic
impairment according to the National Cancer Institute [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
