Acalabrutinib, Obinutuzumab and Chlorambucil in Treatment naïve CLL
Condition: Chronic Lymphocytic Leukemia
MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Acalabrutinib; Obinutuzumab; Chlorambucil
Intervention MeSH terms: Obinutuzumab; Acalabrutinib; Chlorambucil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 535.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This Primary objective is evaluating the efficacy of obinutuzumab in combination with
      chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) for
      the treatment of previously untreated chronic lymphocytic leukemia (CLL). Secondary
      objectives: 1) To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm
      A) versus acalabrutinib monotherapy (Arm C) based on IRC assessment of PFS per IWCLL 2008
      criteria.

      2)To compare obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib plus obinutuzumab
      (Arm B) and obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C)
      in terms of: IRC-assessed objective response rate (ORR); Tine to next treatment (TTNT);
      Overall Survival (OS).
    

Eligibility criteria:

        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).

        Exclusion Criteria:

          1. Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed).

          2. Known CNS lymphoma or leukemia.

          3. Known prolymphocytic leukemia or history of, or currently suspected, Richter's
             syndrome.

          4. Missing or incomplete documentation of FISH results reflecting the presence or absence
             of 17p del and the percentage of cells with the deletion in subject records before
             randomization.

          5. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary
             to autoimmune destruction within the screening period or requirement for high doses of
             steroids (> 20 mg daily of prednisone daily or equivalent).

          6. Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as
             indicated for other medical conditions such as inhaled steroid for asthma, topical
             steroid use, or as premedication for administration of study drug or contrast. For
             example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent
             systemic exposure daily, or those who are administered steroids for leukemia control
             or WBC count lowering are excluded.

          7. Major surgery within 4 weeks before first dose of study drug.

          8. History of prior malignancy except for the following:

               1. Malignancy treated with curative intent and with no evidence of active disease
                  present for more than 3 years before Screening and felt to be at low risk for
                  recurrence by treating physician.

               2. Adequately treated lentigo maligna melanoma without current evidence of disease
                  or adequately controlled non-melanomatous skin cancer.

               3. Adequately treated cervical carcinoma in situ without current evidence of
                  disease.

          9. 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, or QTc > 480 msec at screening.

         10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
             gastrointestinal function, or resection of the stomach or small bowel or gastric
             bypass, symptomatic inflammatory bowel disease, or partial or complete bowel
             obstruction.

         11. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as
             exhibiting ongoing signs/symptoms related to the infection and without improvement,
             despite appropriate antibiotics or other treatment) or ongoing intravenous
             anti-infective treatment.

         12. Known history of infection with HIV. 13. Vaccinated with live, attenuated vaccines
             within 4 weeks of first dose of study drug.

        14. Serologic status reflecting active hepatitis B or C infection. Subjects with hepatitis
        B core antibody positive who are surface antigen negative or who are hepatitis C antibody
        positive will need to have a negative PCR result before randomization. Those who are
        hepatitis B surface antigen positive or hepatitis B PCR positive and those who are
        hepatitis C PCR positive will be excluded.

        15. History of stroke or intracranial hemorrhage within 6 months before randomization.

        16. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

        17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
        (e.g., phenprocoumon) within 7 days of first dose of study drug.

        18. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
        lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

        19. Breast feeding or pregnant. 20. Current life-threatening illness, medical condition, or
        organ system dysfunction which, in the Investigator's opinion, could compromise the
        subject's safety or put the study at risk.

        21. Concurrent participation in another therapeutic clinical trial. 22. Requires treatment
        with a strong CYP3A inhibitor/inducer. 23. Presence of a gastrointestinal ulcer diagnosed
        by endoscopy within 3 months before screening.