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 CLL or SLL according to WHO criteria.

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

- No prior systemic therapy for CLL; prior single site of local radiation for
symptomatic disease is permitted

- Subject requires treatment according to IWCLL guidelines

- 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 due to
disease under study (per investigator discretion)

2. Platelet count ≥ 75,000/mm3 - OR - Platelet count ≥ 20,000/mm3 if
thrombocytopenia is clearly due to disease under study (per investigator
discretion)

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

- Adequate renal and hepatic function, per laboratory reference range at Screening as
follows:

1. AST/SGOT, ALT/SGPT ≤2.0 x ULN

2. Total bilirubin ≤ 2.0 x ULN unless considered secondary to Gilbert‟s syndrome, in
which case ≤3 x ULN

3. Creatinine clearance of eGFR>50 mL/min according to the Cockcroft-Gault Equation

- QT-interval corrected according to Fridericia‟s formula (QTcF) ≤450 milliseconds (ms)

- For females of childbearing potential, a negative serum pregnancy test within 7 days
of study treatment

- For female patients of childbearing potential and male patients with partners of
childbearing potential, agreement (by patient and/or partner) to use highly effective
form(s) of contraception (i.e., one that results in a low failure rate [<1% per year]
when used consistently and correctly) and to continue its use for 90 days after the
last dose of zanubrutinib or venetoclax AND for 18 months after the last dose of
obinutuzumab (whichever date is later)

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

- Willingness to not donate sperm or oocytes during the entire study treatment period
and after treatment discontinuation

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 or localized
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 preclude
administration of study therapy (e.g. significant active infections, hypertension,
angina, arrhythmias, pulmonary disease, or autoimmune dysfunction)

- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at study enrollment, or any major episode
of infection requiring treatment with IV antibiotics or hospitalization (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 need for 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 or active hepatitis B (chronic or acute) or hepatitis C
infection

1. Patients with occult or prior HBV infection (defined as positive total hepatitis
B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is
undetectable. These patients must be willing to take appropriate anti-viral
prophylaxis as indicated and undergo monthly DNA testing.

2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase 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 other hepatitis,
current alcohol abuse, or cirrhosis

- Receipt of live-virus vaccines within 28 days prior to the initiation of study
treatment 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 study compliance

Concomitant medications and drug interactions:

- Concurrent therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and
CYP2C19

- Requires dual antiplatelet therapy or anticoagulation (such as low molecular weight
heparin or warfarin)

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 for symptomatic
disease is permitted

Other:

- Females who are currently pregnant or breastfeeding

- Participation in a separate investigational therapeutic study unless authorized by the
investigator