Assessing the Ability of Combination Treatment With Venetoclax to Permit Time Limited Therapy in Chronic Lymphocytic Leukemia

Inclusion Criteria:

   - Diagnosis of CLL according to the National Cancer Institute (NCI)/International
   Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic
   lymphoma (SLL) according to the World Health Organization (WHO) criteria. This
   includes previous documentation of:

      - Biopsy-proven small lymphocytic lymphoma OR

      - Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the
      following:

         - Peripheral blood lymphocyte count of greater than 5 x10^9/L

         - Immunophenotype consistent with CLL defined as:

            - The predominant population of lymphocytes share both B-cell antigens
            (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the
            absence of other pan-T-cell markers (CD3, CD2, etc).

            - Clonality as evidenced by kappa or lambda light chain restriction
            (typically dim immunoglobulin expression)

      - Negative fluorescent in situ hybridization (FISH) analysis for
      t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g. marrow aspirate)
      or negative immunohistochemical stains for cyclin D1 staining on involved tissue
      biopsy (e.g. marrow aspirate or lymph node biopsy)

   - No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling
   inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL

   - Has met at least one of the following indications for treatment:

      - Evidence of progressive marrow failure as manifested by the development of
      worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets <
      100 x 10^9/L)

      - Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly

      - One or more of the following disease-related symptoms:

         - Weight loss >= 10% within the previous 6 months

         - Grade 2 or 3 fatigue attributed to CLL

         - Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of
         infection

         - Clinically significant night sweats without evidence of infection

      - Progressive lymphocytosis (not due to the effects of corticosteroids) with an
      increase of > 50% over a two-month period or an anticipated doubling time of less
      than six months

   - Age >= 18 years and < 70

   - Eastern Cooperative Oncology Group (ECOG) performance status between 0-2

   - Life expectancy of >= 12 months

   - No deletion of 17p13 on cytogenetic analysis by FISH

   - Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault
   Formula (obtained =< 14 days prior to registration)

   - Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease.
   For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed
   and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to
   registration)

   - Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase
   [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT])
   =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration)

      - NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible

   - Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial
   thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN
   (obtained =< 14 days prior to registration)

   - No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
   treatment. Patients who have a positive Coombs test but no evidence of hemolysis are
   NOT excluded from participation

   - No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of
   prednisone or equivalent dose of other steroid; inhaled steroids) used for treatment
   of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted

   - No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune
   thrombocytopenia) that have developed since the initial diagnosis of CLL and have
   required treatment with high dose corticosteroids (e.g. equivalent of > 20 mg/day of
   prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of
   corticosteroids for reasons other than treatment of autoimmune complications is
   allowed

   - No other active primary malignancy (other than non-melanomatous skin cancer or
   carcinoma in situ of the cervix) requiring treatment or limiting expected survival to
   =< 2 years

      - NOTE: If there is a history of prior malignancy, the patient must not currently
      be receiving other specific treatment (other than hormonal therapy for their
      cancer)

   - Able to adhere to the study visit schedule and other protocol requirements

   - No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery
   within 3 days of first dose of study drug

   - No radiation therapy =< 4 weeks prior to registration to Step 1

   - Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV
   viral load are eligible provided they meet all other protocol criteria for
   participation and are not being treated with protease inhibitors or any non-nucleoside
   reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated
   for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that
   is not a CYP3A inhibitor

   - Women of childbearing potential and sexually active males must be strongly advised to
   use accepted and highly effective method(s) of contraception or to abstain from sexual
   intercourse for the duration of their participation in the study and for:

      - 18 months after the last dose of obinutuzumab

      - 90 days after the last dose of ibrutinib, and

      - 30 days after the last dose of venetoclax Male subjects must also agree to
      refrain from sperm donation until 90 days after the last dose of protocol
      treatment

   - Patient must be able to swallow capsules and not have the following conditions:

      - Disease significantly affecting gastrointestinal function

      - Resection of the stomach or small bowel

      - Symptomatic inflammatory bowel disease

      - Ulcerative colitis

      - Partial or complete bowel obstruction

   - Patient must undergo assessment with Timed Up and Go (TUG) test and comorbidity index

   - Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor
   lysis syndrome (TLS) prophylaxis

Exclusion Criteria:

   - Patients must not have any of the following conditions:

      - Congestive heart failure or New York Heart Association Functional Classification
      III or IV congestive heart failure

      - History of myocardial infarction, unstable angina, or acute coronary syndrome
      within 6 months prior to registration

      - Recent infections requiring systemic treatment; need to have completed
      anti-biotic therapy > 14 days before the first dose of study drug

      - Cerebral vascular accident or intracranial bleed within the last 6 months

      - Infection with known chronic, active hepatitis C

      - Positive serology for hepatitis B defined as a positive test for hepatitis B
      surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core
      antibody (HBcAb) positive (regardless of hepatitis B surface antibody [HBsAb]
      status), a hepatitis B deoxyribonucleic acid (DNA) test will be performed and, if
      positive the subject will be ineligible; if the hepatitis (Hep) B DNA test is
      negative (i.e. viral load undetectable) then the individual is eligible; if a
      patient who is HBsAg negative, HBsAb negative, HBcAb positive, and Hep B DNA
      negative is enrolled, they should be considered for either prophylactic
      anti-viral therapy (J Clin Oncol. 2013 Aug 1;31(22):2765-72) or careful
      monitoring for Hep B reactivation (J Clin Oncol. 2014 Nov 20;32(33):3736-43)

   - Patients are not eligible if they require treatment with a strong cytochrome P450
   (CYP) 3A inhibitor

   - Patients may not have received the following within 7 days prior to the first dose of
   study drug:

      - Steroid therapy for anti-neoplastic intent

      - Strong and moderate CYP3A inhibitors

      - Strong and moderate CYP3A inducers

   - Patients may not be on any other investigational agents

   - Patients may not have received warfarin or another vitamin K antagonist in the
   preceding 30 days

   - Women must not be pregnant or breast-feeding since this study involves investigational
   agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and
   newborn are unknown; all females of childbearing potential must have a blood test
   within 2 weeks prior to registration to Step 1 to rule out pregnancy; a female of
   childbearing potential is defined as any woman, regardless of sexual orientation or
   whether they have undergone tubal ligation, who meets the following criteria: 1) has
   achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
   oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
   therapy does not rule out childbearing potential) for at least 24 consecutive months
   (i.e., has had menses at any time in the preceding 24 consecutive months)

   - Patient must not be on any other systemic immunosuppressant therapy other than
   corticosteroids within 28 days of the first dose of study drug

   - Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first
   dose of study drug

   - Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or
   hemophilia

   - Patient must not have currently active, clinically significant hepatic impairment (>=
   moderate hepatic impairment according to the NCI/Child Pugh classification)