Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL

Study design: This is a randomized, multicenter, open-label, Phase 3 study designed to compare the safety and efficacy of Ibrutinib versus Chlorambucil in treatment-naive patients 65 years or older who have CLL or SLL.

Eligible patients will be randomized in a 1:1 ratio to Treatment Arm A or B:

• Treatment Arm A: Oral Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle; the dose can be increased, if well tolerated, in increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg; patients receive a minimum of 3 and a maximum of 12 cycles, in the absence of progressive disease or unacceptable toxicity.
• Treatment Arm B: Oral Ibrutinib 420 mg/day Randomization will be stratified on Eastern Cooperative Oncology Group (ECOG) performance status (0,1 versus 2); presence of advanced Rai stage (yes/no), advanced being defined as Stages 3-4; and geographic region: US versus non-US.

Inclusion criteria

• Males or females of 65 years of age or greater. Patients between the ages of 65 and 70 years of age must have 1 or more of the following comorbidities that may preclude the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, or rituximab:

• creatinine clearance < 70 mL/min using the Cockcroft-Gault equation
• platelet count < 100,000/μL or hemoglobin < 10 g/dL
• clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immune thrombocytopenia)
• ECOG performance score = 1 or 2
• Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)
• Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for requiring treatment:

• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia Massive, progressive, or symptomatic splenomegaly
• Massive nodes or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis
• Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or standard therapy
• Constitutional symptoms
• Measurable nodal disease by computed tomography (CT)
• ECOG performance status of 0-2
• Life expectancy > 4 months from randomization
• Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL (independent of growth factor support for at least 7 days prior to screening) and platelet count ≥ 50,000/μL (independent of transfusion and growth factor support for at least 7 days prior to screening)
• Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) < 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x ULN
• Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
• Willingness to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study
• Willingness of male patients, if sexually active with a female of childbearing potential, to use an effective barrier method of contraception during the study and for 3 months following the last dose of study drug
• Ability to provide written informed consent and to understand and comply with the requirements of the study

Exclusion criteria

• Known involvement of the central nervous system by lymphoma or leukemia
• History or current evidence of Richter's transformation or prolymphocytic leukemia
• Documentation of deletion of the short arm of chromosome 17: del(17p13.1) in more than 20% of cells examined on any pretreatment fluorescence in situ hybridization (FISH) or cytogenetic evaluation
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
• Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL
• Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to randomization
• Corticosteroid use within 1 week prior to first dose of study drug, with the exception of inhaled, topical, or other local administrations. Patients requiring systemic steroids at daily doses > 20 mg prednisone (or corticosteroid equivalent, see Appendix N), or those who are administered steroids for leukemia control or white blood cell (WBC)-count-lowering are excluded.
• Major surgery within 4 weeks prior to randomization
• 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 treating physician
• adequately treated nonmelanomatous 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 or a history of myocardial infarction within 6 months prior to randomization
• Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function
• Uncontrolled active systemic fungal, bacterial, viral, or other infection or requirement for intravenous (IV) antibiotics
• Known history of infection with human immunodeficiency virus (HIV)
• Serologic status reflecting active hepatitis B or C infection
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Current life-threatening illness, medical condition, or organ-system dysfunction that could compromise patient safety or put the study at risk
• Requirement for anticoagulation with warfarin
• Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor