Overview

This is a single-arm, prospective study to assess the efficacy and safety of acalabrutinib combined with obinutuzumab in subjects with previously untreated chronic lymphocytic leukemia.

Eligibility

Inclusion Criteria:

1. Men and women ≥18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing
3. Diagnosis of CD20+ CLL that meets published diagnostic criteria(Hallek 2018):
   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 2018 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 (lymphocyte doubling time) 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) may require a longer observation period to determine the LDT. 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 corticosteroids.
   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. 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 ≤3 x upper limit of normal (ULN).
               4. Total bilirubin ≤1.5 x ULN, unless directly attributable to Gilbert's syndrome
               5. Estimated creatinine clearance of ≥30 mL/min, calculated by Cockcroft-Gault
                  (using actual body weight), or serum creatinine ≤2×ULN, (if male, [140-Age] x
                  Mass [kg] / [72 x creatinine mg/dL]; multiply by 0.85 if female)
          6. Female subjects 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, whichever is
             longer.
          7. Male subjects who are sexually active must agree to use highly effective forms of
             contraception with the addition of a barrier method (condom) during the study and for
             90 days after the last dose of Obinutuzumab, whichever is later.
          8. Men must agree to refrain from sperm donation during the study and for 90 days after
             the last dose of Obinutuzumab, whichever is later.
          9. Willing and able to participate in all required evaluations and procedures in this
             study protocol, including swallowing capsules and tablets without difficulty.
         10. Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent and authorization to use protected health information (in accordance
             with national and local patient privacy regulations).
        Exclusion Criteria:
          1. Evidence of disease (such as severe or uncontrolled systemic diseases, including
             uncontrolled hypertension and renal transplant) that, in the investigator's opinion,
             make it undesirable for the patient to participate in the study or that would
             jeopardize compliance with the protocol.
          2. Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed).
          3. Known CNS lymphoma or leukemia.
          4. Known prolymphocytic leukemia or history of, or currently suspected, Richter's
             syndrome.
          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 30 days before first dose of study drug. Note: If a subject had
             major surgery, they must have recovered adequately from any toxicity and/or
             complications from the intervention before the first dose of study drug.
          8. History of prior malignancy that could affect compliance with the protocol or
             interpretation of results, except for the following:
               1. a. Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin
                  or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any
                  time prior to study.
               2. b. Other cancers not specified above that have been curatively treated by surgery
                  and/or radiation therapy from which subject is disease-free for ≥3 years without
                  further treatment.
          9. Significant cardiovascular disease such as 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
             at Screening. Note: Subjects with controlled, asymptomatic atrial fibrillation are
             allowed to enroll on study.
         10. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
         11. Received any investigational drug within 30 days or 5 half-lives (whichever is
             shorter) before first dose of study drug.
         12. Refractory nausea and vomiting, inability to swallow the formulated product, or
             malabsorption syndrome; chronic gastrointestinal disease, gastric restrictions, or
             bariatric surgery such as gastric bypass; partial or complete bowel obstruction, or
             previous significant bowel resection that would preclude adequate absorption,
             distribution, metabolism, or excretion of study treatment.
         13. Received a live virus vaccination within 28 days of first dose of study drug.
         14. Known history of infection with HIV.
         15. Any active significant infection (e.g., bacterial, viral or fungal, including subjects
             with positive cytomegalovirus [CMV] DNA polymerase chain reaction [PCR]).
         16. Serologic status reflecting active hepatitis B or C infection.
               1. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are
                  hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR
                  result before randomization and must be willing to undergo DNA PCR testing during
                  the study. Those who are HbsAg-positive or hepatitis B PCR positive will be
                  excluded.
               2. Subjects who are hepatitis C antibody positive will need to have a negative PCR
                  result before randomization. Those who are hepatitis C PCR positive will be
                  excluded.
         17. History of stroke or intracranial hemorrhage within 6 months before first dose of
             study drug.
         18. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
         19. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
             antagonists.
         20. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. The
             use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks
             of the first dose of study drug is prohibited.
         21. Breastfeeding or pregnant.
         22. Concurrent participation in another therapeutic clinical trial.
         23. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
         24. 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.