A Phase 2 Trial of Zanubrutinib and Venetoclax in Previously Treated CLL/SLL Patients

This study is being done to test the effectiveness of zanubrutinib in combination with
venetoclax in participants with previously treated chronic lymphocytic leukemia (CLL) or
small lymphocytic lymphoma (SLL).

Inclusion Criteria

- Confirmed diagnosis of CLL or SLL as per 2018 International Workshop on CLL (IWCLL)
criteria.

- Participants must have relapsed after at least one prior line of therapy and must
currently require therapy by 2019 IWCLL criteria.

- For enrollment to Cohort A: Participants must be covalent BTK and BCL-2 inhibitor
naïve. Participants who have received prior therapy with a covalent BTK or BCL-2
inhibitor are not eligible, including but not limited to prior treatment with
ibrutinib or acalabrutinib.

- For enrollment to Cohort B: Participants must have had prior treatment with a BTK
inhibitor or a BCL-2 inhibitor, but not both, and must not have experienced disease
progression as defined by iwCLL criteria while receiving therapy.

- For enrollment to Cohort C: participants must have a disease that progressed during
therapy with a covalent BTK inhibitor, not including zanubrutinib.

- Age ≥ 18 years. Because no dosing or adverse event data are currently available on the
use of zanubrutinib and venetoclax in participants < 18 years of age and CLL/SLL is
extremely rare in this population, children are excluded from this study.

- ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).

- Participants must have adequate organ function as defined below:

- Platelet count ≥ 20,000/mcL

- Total bilirubin ≤ 2 × institutional upper limit of normal (ULN) (unless due to
controlled hemolysis, Gilbert's disease, or is of non-hepatic origin)

- AST (SGOT) and ALT (SGPT) ≤ 4 × institutional ULN

- Serum Creatinine ≤ 1.5 × institutional ULN, OR

- Calculated creatinine clearance ≥ 50 mL/min (as calculated by the Cockcroft-Gault
formula)

- The effects of zanubrutinib or venetoclax on the developing human fetus are unknown.
For this reason and because anti-cancer agents are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of study agent administration.

- Ability to understand and the willingness to sign a written informed consent document.

- Ability to swallow and retain oral medication.

Exclusion Criteria:

- Known BTK C481X mutation.

- For enrollment to Cohort B: participants who have received prior treatment with both a
BTK inhibitor and BCL-2 inhibitor.

- Participants who have had previous anti-cancer therapy (e.g., chemotherapy,
radiotherapy, immunotherapy, biologic therapy, hormonal therapy, surgery,
investigational agents, and/or tumor embolization) within 2 weeks of Cycle 1 Day 1
with the following exceptions:

- Hormonal therapy given in the adjuvant setting

- Corticosteroid therapy (prednisone or equivalent ≤ 20 mg daily) is allowed as
clinically warranted as long as the dose is stabilized at least for 7 days prior to
initial dosing. Topical, inhaled, intra-articular, or ophthalmologic corticosteroids
are permitted

- Participants enrolling to Cohort C may remain on prior BTK inhibitor therapy up until
2 days prior to Cycle 1 Day 1

- History of a prior allogeneic hematologic stem cell transplant.

- Participants with known central nervous system (CNS) involvement, because of their
poor prognosis and because they often develop progressive neurologic dysfunction that
would confound the evaluation of neurologic and other adverse events. Participants
with no known history of CNS involvement are not required to undergo CT scan or lumbar
puncture (LP) for trial eligibility unless the participant is symptomatic as judged by
the treating investigator.

- Participants who are receiving any other investigational agents at the time of study
entry.

- History of other malignancies, with the following exceptions:

- Malignancy treated with curative intent and with no known active disease present
for ≥ 2 years before the first dose of study drug and felt to be at low risk for
recurrence by treating physician

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease

- Adequately treated carcinoma in situ without evidence of disease

- Low-risk prostate cancer on active surveillance

- Participants who have been vaccinated with live, attenuated vaccines < 4 weeks prior
to Cycle 1 Day 1.

- Recent infection requiring intravenous antibiotics completed ≤ 7 days before the first
dose of study drug, or any uncontrolled active systemic infection.

- Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia.

- History of stroke, intracranial hemorrhage, or recent major bleed within 6 months
prior to study entry.

- Participants who require warfarin or other vitamin K antagonists for anticoagulation
(other anticoagulants are allowed with approval from the overall principal
investigator).

- Participants who are known at the time of study entry to require concomitant treatment
with any medications or substances that are moderate or strong CYP3A inhibitors or
inducers. Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently-updated medical reference. As part of the
enrollment/informed consent procedures, the participant will be counseled on the risk
of interactions with other agents, and what to do if new medications need to be
prescribed or if the participant is considering a new over-the-counter medicine or
herbal product.

- Known history of human immunodeficiency virus (HIV), active hepatitis C virus (HCV),
or hepatitis B virus (HBV).

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to zanubrutinib or venetoclax.

- Participants with psychiatric illness/social situations that would limit compliance
with study requirements.

- Pregnant women are excluded from this study because zanubrutinib and venetoclax are
anti-cancer agents with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with zanubrutinib or venetoclax, breastfeeding
should be discontinued if the mother is treated with zanubrutinib or venetoclax.

- Participants with malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel, symptomatic
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
obstruction.

- Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
Association Functional Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome within 6 months prior to study entry.

- Any life-threatening illness, medical condition, or organ system dysfunction that, in
the treating investigator's opinion, could compromise the participant's safety or the
integrity of the trial.

- Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia.