A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.

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:

1. 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

2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)

3. 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

4. Measurable nodal disease by computed tomography (CT)

5. ECOG performance status of 0-2

6. Life expectancy > 4 months from randomization

7. 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)

8. 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

9. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation

10. Willingness to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study

11. 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

12. Ability to provide written informed consent and to understand and comply with the requirements of the study

Exclusion Criteria:

1. Known involvement of the central nervous system by lymphoma or leukemia

2. History or current evidence of Richter's transformation or prolymphocytic leukemia

3. 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

4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura

5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL

6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to randomization

7. 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.

8. Major surgery within 4 weeks prior to randomization

9. 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

10. Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 6 months prior to randomization

11. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function

12. Uncontrolled active systemic fungal, bacterial, viral, or other infection or requirement for intravenous (IV) antibiotics

13. Known history of infection with human immunodeficiency virus (HIV)

14. Serologic status reflecting active hepatitis B or C infection

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

16. Current life-threatening illness, medical condition, or organ-system dysfunction that could compromise patient safety or put the study at risk

17. Requirement for anticoagulation with warfarin

18. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor

We share this information with FDA and other authorities for the purposes of analyzing the study but not with other researchers