PRIMARY OBJECTIVES:
I. To compare the 2-year progression-free survival (PFS) rate in treated patients.
SECONDARY OBJECTIVES:
I. To determine safety and tolerability, the overall response rate (ORR), the estimated PFS,
changes in immune parameters (lymphocyte subpopulations, immunoglobulin levels) and biomarker
responses in relapsed chronic lymphocytic leukemia (CLL) patients receiving ibrutinib (i)
versus ibrutinib and rituximab (iR).
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: 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.
ARM II: Patients receive ibrutinib as in Arm I beginning on day 1 or 2. Patients also receive
rituximab intravenously (IV) over 3-8 hours on days 1, 8, 15, and 22 of course 1 and day 1 of
courses 2-6. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up at 60 days and then every 4
months for 5 years.
Inclusion Criteria:
- Patients must have a diagnosis of CLL/small lymphocytic lymphoma (SLL) or
prolymphocytic leukemia (PLL) and be previously treated; given the poor outcome of
CLL/SLL/PLL patients with 17p deletion (del) or tumor protein (TP)53 mutation to
standard frontline chemo-immunotherapy, such patients will be eligible if they are
untreated
- Patients must have an indication for treatment by 2008 International Workshop on
Chronic Lymphocytic Leukemia (IWCLL) criteria
- Patient must understand and voluntarily sign an informed consent, and be able to
comply with study procedures and follow-up examinations
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Patients of childbearing potential must be willing to practice highly effective birth
control (e.g., condoms, implants, injectables, combined oral contraceptives,
intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the
study and for 30 days after the last dose of study drug; women of childbearing
potential include any female who has experienced menarche and who has not undergone
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or is not postmenopausal
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) except for patients
with bilirubin elevation due to Gilbert's disease who will be allowed to participate
- Alanine aminotransferase (ALT) =< 2.5 x ULN
- Estimated creatinine clearance (CrCl) of > 30 mL/min, as calculated by the
Cockcroft-Gault equation unless disease related
- Free of prior malignancies for 3 years with exception of patients diagnosed with basal
cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
breast, who are eligible even if they are currently treated or have been treated
and/or diagnosed in the past 3 years prior to study enrolment; if patients have
another malignancy that was treated within the last 3 years, such patients can be
enrolled, after consultation with the principal investigator, if the likelihood of
requiring systemic therapy for this other malignancy within 2 years is less than 10%,
as determined by an expert in that particular malignancy at MD Anderson Cancer Center
- A urine pregnancy test (within 7 days of enrollment date) is required for women with
childbearing potential
Exclusion Criteria:
- Pregnant or breast-feeding females
- Prior therapy with ibrutinib or other kinase inhibitors that target Bruton's tyrosine
kinase (BTK); patients who previously received therapy with the phosphoinositide-3
kinase (PI3K) delta inhibitor idelalisib (Zydelig) are allowed to be enrolled
- Treatment including chemotherapy, chemo-immunotherapy, monoclonal antibody therapy,
radiotherapy, high-dose corticosteroid therapy (more than 60 mg prednisone daily or
equivalent), or immunotherapy within 21 days prior to enrollment or concurrent with
this trial
- Investigational agent received within 30 days prior to the first dose of study drug
- Systemic fungal, bacterial, viral, or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment)
- Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune
thrombocytopenia (ITP)
- Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil
count of less than 500/MuL, unless disease-related, and/or a platelet count of less
than 30,000/MuL at time of screening for this protocol
- Any other severe concurrent disease, or have a history of serious organ dysfunction or
disease involving the heart, kidney, liver or other organ system that may place the
patient at undue risk to undergo therapy with ibrutinib and rituximab
- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification
- History of stroke or cerebral hemorrhage within 6 months
- Evidence of bleeding diathesis or coagulopathy within 3 months
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to enrollment date, anticipation of need for major surgical procedure during the
course of the study
- Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
prior to enrollment date; bone marrow aspiration and/or biopsy are allowed
- Serious, non-healing wound, ulcer, or bone fracture
- Treatment with Coumadin; patients who recently received Coumadin must be off Coumadin
for at least 7 days prior to start of the study
