Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and the B cell lymphoma 2 inhibitor (BCL-2i) venetoclax are drug classes used to treat patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). Anti-CD20 therapy may not be required for all patients. The investigators hypothesis is that it may be better to give anti-CD20 therapy (obinutuzumab) only to patients that still have detectable cancer in their blood (minimal residual disease [MRD]) after being treated with a combination of two oral medications, zanubrutinib (a BTKi ) and venetoclax (a BCL-2i), instead of giving a combination of three drugs to all patients from the start of treatment. This strategy, if effective, will prevent overtreatment with anti-CD20 antibodies; reduce side effects of treatment while potentially increasing MRD negativity rates; and will possibly make the anti-CD20 antibody therapy more effective given the low tumor burden present when utilized. This study will test this hypothesis by treating subjects with 3 cycles of a zanubrutinib monotherapy lead-in, in order to debulk and mitigate tumor lysis risk, followed by 13 cycles of zanubrutinib and venetoclax combination therapy. Subjects who are both peripheral blood and bone marrow MRD negative at the completion of the 13 cycles of combination therapy will stop treatment and enter an observation phase every 3 months. Subjects that are MRD positive will continue combination therapy with zanubrutinib and venetoclax for an additional 6 cycles but also receive 6 cycles of obinutuzumab in order to augment response and increase MRD negative rates for the overall treated cohort.

This is an open label, phase II, investigator-initiated clinical trial of 50 subjects. Subjects with CLL/SLL who have treatment indications per the 2018 International Workshop for CLL (iwCLL) will be eligible to enroll. The investigators hypothesize that anti-CD20 therapy may not be required for all patients and a response-adapted strategy will prevent over treatment of a significant number of patients and reduce toxicity of treatment while still achieving a high rate of MRD negativity. The investigators also hypothesize that late addition of anti-CD20 therapy can eliminate low burden residual disease in subjects and maximize undetectable MRD negativity in subjects who remain MRD positive.

All subjects will initiate induction therapy with 3 cycles of zanubrutinib monotherapy in order to debulk subjects and mitigate tumor lysis risk. This lead-in period will then be followed by 12 cycles of zanubrutinib and venetoclax combination. Standard ramp-up protocols for venetoclax based on TLS risk assessed prior to C4D1 will be utilized. All subjects will complete 12 cycles of zanubrutinib and venetoclax combination therapy or 15 cycles of total treatment. Peripheral blood and bone marrow MRD assessments will occur at C16D1. Subjects will continue on combination treatment for an additional 1 month while results of MRD testing are obtained. In total, all subjects will be on treatment for at least 16 full cycles. Subjects that meet definition of MRD negativity will stop therapy at C17D1 and enter an observation phase with study visits every 3 months. Subjects that meet definition of MRD positivity will continue combination therapy with zanubrutinib and venetoclax, but will also receive 6 cycles of obinutuzumab starting at C17D1. In this subgroup, peripheral blood and bone marrow MRD assessments will occur after an additional 6 cycles of the triplet combination therapy (C23D1) at which point all subjects will stop study treatment regardless of MRD status.

Inclusion Criteria

1. Subject must be able to voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.

2. Subject must be ≥ 18 years of age.

3. Subject must have confirmed diagnosis of CLL/SLL based upon 2018 iwCLL Guidelines.

   a. Please note, participants with SLL must have identifiable B-cells in peripheral blood or bone marrow consistent with CLL/SLL immuno-phenotype, based on flow-cytometry, in order to be enrolled

4. Subject must have indications for treatment per the 2018 iwCLL Guidelines.

5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

6. Subject must have adequate organ function defined as:

   1. Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or the Modification of Diet in Renal Disease equation, or as measured by nuclear medicine scan or 24-hour urine collection).
   2. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 2.5 × upper limit of normal (ULN) unless due to CLL/SLL.
   3. Serum total bilirubin < 3.0 × ULN (unless documented Gilbert's syndrome)

7. Subject must have adequate bone marrow function and meet the below thresholds unless approved by sponsor if cytopenias are felt to be due to significant marrow involvement of CLL:

   1. Absolute neutrophil count ≥ 1.0 x103/μL
   2. Hemoglobin ≥ 7 g/dL (can be transfused up to 1 week prior to study enrollment)
   3. Platelets ≥ 75,000 cells/μL OR platelets ≥ 30,000 cells/μL if clearly due to disease under study (per investigator discretion)

8. Subjects of childbearing potential must be willing to comply with pregnancy prevention interventions (as defined in Section 4.4)

Exclusion Criteria

A subject will be ineligible for the study if he/she meets the following criteria:

1. Previous exposure to any systemic anti-cancer therapy as a treatment for CLL/SLL, including but not limited to chemotherapy, immunotherapy, radiotherapy, hormone therapy (other than contraceptives, hormone-replacement therapy or megestrol acetate) or investigational therapy.

2. Subject with a history of malignancy except for non-melanoma skin cancers. Subjects treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 35 years from treatment end will be allowed to enroll. Adjuvant hormonal therapy will be allowed at time of enrollment if the subject otherwise is not excluded by the 3-year waiting period.

3. Subject requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry.

4. Subjects with active autoimmune hemolytic anemia or immune thrombocytopenia purpura.

5. Subject with prolymphocytic leukemia or Richter's Transformation.

6. Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).

7. Subject requires warfarin or equivalent vitamin K antagonist.

8. Uncontrolled or active significant infection requiring systemic treatment, subjects are eligible if they have completed antibiotic therapy 2 weeks prior to study enrollment.

9. History of suspected or confirmed PML

10. Clinically significant cardiovascular disease including the following:

    1. Myocardial infarction within 6 months before screening.
    2. Unstable angina within 3 months before screening.
    3. New York Heart Association class III or IV congestive heart failure
    4. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes).
    5. QT interval corrected with Fridericia's formula (QTcF) > 480 milliseconds based on Fridericia's formula.
    6. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.
    7. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening.

11. Patients with stroke or CNS hemorrhage within 6 months.

12. Pregnant or breastfeeding.

14. Major surgical procedure within 28 days of first dose of study drug. If a subject had surgery, they must have recovered adequately from any toxicity or complications before the first dose of study drug.

15. Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication.

16. Subject is known to be positive for human immunodeficiency virus (HIV). 17. Active hepatitis C, as confirmed by being positive for Hep C RNA by PCR. 18. Active hepatitis B infection documented by a positive PCR for Hep B DNA. If hepatitis B serology is positive for hepatitis B core antibody, but Hep B DNA PCR is negative, patient is eligible to enroll.

19. Subject requires:

1. Strong and moderate CYP3A inhibitors within 7 days prior to the initiation of study treatment.

2. Strong and moderate CYP3A inducers within 7 days prior to the initiation of study treatment.

3. Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids for asthma, topical steroids, or replacement/stress corticosteroids within 7 days prior to the first dose of study drug administration.

4. Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study drug and throughout venetoclax administration.

   20. Known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use.

   21. Vaccination with live vaccine ≤28 days prior to start of treatment.