Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL
Condition: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Ibrutinib; Chlorambucil
Intervention description: Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.; Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle. The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.
Intervention MeSH terms: Chlorambucil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 269.0
Sex: All
Minimum age: 65 Years
Healthy volunteers: No
Keywords: CLL, SLL

Summary:

      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.
    

Eligibility criteria:

        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