Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL)

Inclusion Criteria:

• Signed, informed consent

• Ability and willingness to comply with the requirements of the study protocol

• Age ≥18 years

• Diagnosis of the following histories according to the WHO criteria

1. CLL or SLL

2. MCL

• For patients with SLL, peripheral blood flow cytometry must be positive withCLL-like cells accounting for at least 1% of circulating WBC.

• No prior systemic therapy for disease under study except:

1. prior local radiation for symptomatic disease is permitted

2. Short course systemic corticosteroids is permissible for disease control,improvement of performance status or non-cancer indication (must be ≤ 14 daysand < 100 mg/day prednisone or ≤ 20 mg/day dexamethasone). Steroids must bediscontinued prior to study treatment. Inhaled steroids for asthma, topicalsteroids, and replacement/Stress corticosteroids are permitted. Low-dosesteroids for ITP are also permitted up to the equivalent prednisone 20mg/dailyat time of eligibility review.

• ECOG performance status of 0 to 2

• Adequate hematologic parameters unless due to disease under study:

1. Absolute neutrophil count (ANC) ≥1.0 x 109/L unless neutropenia is clearly dueto disease under study (per investigator discretion)

2. Platelet count ≥ 75,000/mm3 - OR - Platelet count ≥ 20,000/mm3 ifthrombocytopenia is clearly due to disease under study (per investigatordiscretion)

3. Hemoglobin ≥9.0 g/dL unless anemia is clearly due to marrow involvement due todisease under study (per investigator discretion)

• Adequate renal and hepatic function, per laboratory reference range at Screening asfollows: a. AST/SGOT, ALT/SGPT ≤2.0 x ULN b. Total bilirubin ≤ 2.0 x ULN unless: i. Considered secondary to Gilbert"s syndrome, in which case ≤3 x ULN ii. Considereddue to disease under study (Per PI or Co-PI discretion) c. Creatinine clearance of eGFR>30 mL/min according to the Cockcroft-Gault Equation

• For females of childbearing potential, a negative serum pregnancy test within 7 daysof study treatment

• For female patients of childbearing potential, agreement to use highly effectiveform(s) of contraception (i.e., one that results in a low failure rate [<1% peryear] when used consistently and correctly) or remain abstinent (refrain fromheterosexual intercourse) during the treatment period and to continue its use for 90days after the last dose of zanubrutinib AND 30 days after the last dose ofvenetoclax AND for 18 months after the last dose of obinutuzumab (whichever date islater)

A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>/= 12 continuous months of amenorrhea with no identified cause other than menopause), and it not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Mullerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method.

1. The reliability of sexual abstinence should be evaluated in relation to the durationof the clinical trial and the preferred and usual lifestyle of the patient. Periodicabstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) andwithdrawal are not acceptable methods of contraception.

• For men with a female partner of childbearing potential or a pregnant femalepartnet: agreement to remain abstinent (refrain from heterosexual intercourse)or use a condom during the treatment period and to continue its use for 90 daysafter the last dose of zanubrutinib, or venetoclax AND for 18 months after thelast dose of obinutuzumab (whichever date is later) The reliability of sexual abstinence should be evaluated in relation duration of theclinical trial and the preferred and usual lifestyle of the patient. Periodicabstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) andwithdrawal are not acceptable methods of contraception - Willingness to not donateor bank sperm or oocytes during the entire study treatment period and aftertreatment discontinuation for 90 days after the last dose of zanubrutinib AND 30days after the last dose of venetoclax AND for 18 months after the last dose ofobinutuzumab (whichever date is later) Additional Eligibility Criteria for CLL Cohort:

1. Diagnosis of untreated CLL or SLL according to WHO criteria 2. For patientswith SLL, peripheral blood flow cytometry must be positive with CLL-like cellsaccounting for at least 1% of circulating WBC 3. No prior systemic therapy forCLL: prior single site of local radiation for symptomatic disease is permitted

2. Subject requires treatment according to IWCLL guidelines (See Appendix A) Additional Eligibility Criteria for TP53 Mutant MCL cohorts:

3. Diagnosis of untreated stage II-IV mantle cell lymphoma

a. Prior radiotherapy for localized disease is permitted 2. Presence of TP53 mutation irrespective of variant allele frequency (TP53 cohort)

OR

Presence of p53 overexpression by immunohistochemistry defined as strong nuclear staining of >30% positive nuclei.

Additional Eligibility Criteria for Transplant Ineligible MCL cohort:

1. Diagnosis of untreated stage II-IV mantle cell lymphoma

2. Prior radiotherapy for localized disease is permitted

3. Patients must meet one of the following criteria (a or b): a. Age ≥65 years If age <65 years of age, then patients must be ineligible forHDT/ASCT on the basis of comorbidity or organ dysfunction. Specifically, patients must meet at least one of the following criteria below: i.. Comorbid disease, such as CAD, CHF, pulmonary dysfunction, liver or kidneydysfunction, precluding high dose therapy secondary to expected increased morbidityand mortality. ii. ECOG 2 iii. Ejection fraction ≥35% and <45% iv. Impairedpulmonary function test with DLCO <50% expected v. Medical conditions which in theopinion of the treating physician in consultation with the study PI or Co-PI and DMTpreclude HDT/ASCT.

Exclusion Criteria: Other malignancies:

• Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter"s transformation)

• Active malignancy or systemic therapy for another malignancy within 3 years;local/regional therapy with curative intent such as surgical resection orlocalized radiation within 3 years of treatment is permitted

• Other diagnosis of active cancer Co-morbidities:

• Any uncontrolled illness that in the opinion of the investigator would precludeadministration of study therapy (e.g. significant active infections,hypertension, angina, arrhythmias, pulmonary disease, or autoimmunedysfunction)

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or otherinfection (excluding fungal infections of nail beds) at study enrollment, orany major episode of infection requiring treatment with IV antibiotics orhospitalization (relating to the completion of the course of antibiotics)within 4 weeks prior to Cycle 1, Day 1

• Known bleeding diathesis

• Prior major surgical procedure within 4 weeks of study, or anticipation of needfor a major surgical procedure during the course of the study

• Known CNS hemorrhage or stroke within 6 months of the study

• History of progressive multifocal leukoencephalopathy (PML)

• History of HIV infection

1. Patients with a history of HIV infection that is well controlled onantiretroviral therapy are eligible if all of the following criteria aremet: (1) undetectable HIV viral load by standard clinical assay AND (2)CD4+ T cell count of ≥ 200 cells/microliter NOTE: Many HIV regimens are excluded based on drug interactions, and concomitantantiretroviral therapy need to cleared by the clinical pharmacist and approved bythe site PI)

• Active hepatitis B (chronic or acute) or hepatitis C infection a. Patients withoccult or prior HBV infection (defined as positive total hepatitis B coreantibody [HBcAb] and negative HBsAg) may be included if HBV DNA isundetectable. These patients must be willing to take appropriate anti-viralprophylaxis as indicated and undergo monthly DNA testing.b. Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV RNA

• Congestive heart failure, New York Heart Association classification III/IV

• Clinically significant history of liver disease, including viral or otherhepatitis, current alcohol abuse, or cirrhosis

• Receipt of live-virus vaccines within 28 days prior to the initiation of studytreatment or need for live-virus vaccines at any time during study treatment

• Known condition or other clinical situation that would affect oral absorption

• Psychiatric illness/social situations that would interfere with studycompliance

• Inability to swallow a large number of tablets Concomitant medications and drug interactions:

• Administration within 7 days prior to the first dose of study drug orconcurrent therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9and CYP2C19. The same applied for moderate inhibitors or inducers of CY_3A

• Live-virus vaccines given within 28 days prior to the initiation of studytreatment

• Immunotherapy

• Hormone therapy (other than contraceptives, hormone replacement therapy, ormegestrol acetate)

• Any therapies intended for the treatment of lymphoma/leukemia whether FDAapproved or experimental (outside of this study)

• Radiation therapy intended to treat MCL or CLL/SLL

• Warfarin or warfarin derivatives

• Consumption of one or more of the following within 3 days prior to the firstdose of study drug: Grapefruit or grapefruit products Seville oranges, including marmalade containingSeville oranges Star Fruit (carambola) Prior therapy:

• Prior anti-CD20 monoclonal antibody therapy for non-malignant indication

• Obinutuzumab is contraindicated in patients with a known hypersensitivity (IgE-mediated) reaction to obinutuzumab or to any of its excipients

• Prior systemic therapy for CLL; prior single site of local radiation forsymptomatic disease is permitted Other:

• Females who are currently pregnant or breastfeeding

• Participation in a separate investigational therapeutic study unless authorizedby the investigator