Acalabrutinib, Obinutuzumab and Chlorambucil in Treatment naïve CLL

Inclusion Criteria

• •1. Men and women:
• •a. ≥ 65 years of age OR b. \> 18 and \< 65 years of age, provided that they meet at least one of the following criteria: i. Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation ii. A score higher than 6 on the CIRS-G (Appendix L).
• •2. ECOG performance status of 0, 1, or 2.
• •3. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008):
• •1. Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5.
• •2. Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
• •3. Presence of ≥ 5 x 109 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis)
• •4. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:
• •1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin \< 10 g/dL) and/or thrombocytopenia (platelets \< 100,000/μL).
• •2. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
• •3. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
• •4. Progressive lymphocytosis with an increase of \> 50% over a 2-month period or a LDT of \< 6 months. LDT may be obtained by linear regression extrapolation of ALC obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of \< 30 x 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
• •5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
• •6. Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs:
• •i. Unintentional weight loss ≥ 10% within the previous 6 months before Screening.
• •ii. Significant fatigue (i.e., ECOG performance status 2; inability to work or perform usual activities).
• •iii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.
• •iv. Night sweats for \> 1 month before Screening without evidence of infection.
• •5. This criterion was deleted as of Protocol Amendment 3.
• •6. Meet the following laboratory parameters:
• •1. ANC ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment.
• •2. Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL (30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded.
• •3. Serum AST and ALT/SGPT ≤ 3.0 x ULN.
• •4. Total bilirubin ≤ 1.5 x ULN.
• •5. Estimated creatinine clearance (i.e., eGFR using Cockcroft-Gault) ≥ 30 mL/min
• •7. Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations.
• •8. Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. Highly effective forms of contraception are defined in Section 6.4.4.
• •9. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. Highly effective forms of contraception are defined in Section 6.4.4.
• •10. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later.
• •11. Must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations). Note vulnerable subjects, as defined in International Conference on Harmonisation (ICH) GCP, are not allowed on this protocol (e.g., prisoners or institutionalized subjects).