Rituximab and Zanubrutinib in Patients With Indolent B-cell Lymphomas

Inclusion Criteria:

• Cohort A: Previously untreated MZL. Prior therapy with H. Pylori antibiotic therapyor hepatitis C antiviral therapy are allowed on Cohort A.

• Cohort B: Previously untreated FL

• Pathological confirmation of lymphoma: availability of archival tissue confirmingdiagnosis of MZL (cohort A) or FL (cohort B). Availability of formalin-fixed,paraffin-embedded (FFPE) archival tumor specimens from within past 18 months fromscreening and pathological diagnosis confirmed by a pathologist at the participatingsite or willingness of the participant to undergo a fresh tumor biopsy if adequatearchival tissue not available is required. This includes:

• MZL (Cohort A):

1. Nodal MZL requiring systemic therapy

2. Splenic MZL requiring systemic therapy

3. Extra-nodal marginal zone lymphoma:

4. Non-gastric/non-cutaneous MZL requiring systemic therapy.

5. Cutaneous MZL will be eligible only if they have pathologically confirmedextra-cutaneous disease.

6. Gastric MZL only if advanced stage disease requiring systemic therapy (e.g., stage IIE, II2, IV- supradiaphragmatic nodal or disseminatedextranodal disease such as bone marrow or additional extra nodal sites.

• FL (Cohort B): a. Pathological grade 1, 2, or 3a based on the World Health Organization (WHO 2008)classification of tumors of hematopoietic and lymphoid tissue.

1. Please note, grade 3B are excluded.

• All participants must have disease requiring systemic therapy rather than localradiation (ie, stage II only if not eligible for radiation therapy or with stageIII/IV).

• All participants should have measurable disease. Measurable disease is defined as alymph node or tumor mass that is ≥ 1.5 cm in at least one dimension by CT or the CTportion of the PET/CT.

• Documentation of CD20+ status.

• All participants must have an indication for therapy such as: symptoms attributableto lymphoma, threatened end-organ function, or cytopenia secondary to lymphoma.

• All participants must be 18 years of age or older.

• All participants must have an Eastern Cooperative Oncology Group (ECOG) PerformanceStatus of 0-2.

• All participants must be able to swallow whole pills.

• All participants must have the ability and willingness to comply with therequirements of the study protocol.

• All female participants who are of non-reproductive potential (i.e., post-menopausalby history - no menses for ≥1 year; OR history of hysterectomy; OR history ofbilateral tubal ligation; OR history of bilateral oophorectomy).

• All female participants of childbearing potential must have a negative serumpregnancy test upon study entry.

• All male and female participants of reproductive potential who agree to use both ahighly effective method of birth control (e.g., implants, injectables, combined oralcontraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilizedpartner) and a barrier method (e.g., condoms, vaginal ring, sponge, etc) during theperiod of therapy. Female participants of reproductive potential who are notsurgically sterile must practice adequate birth control for a minimum of 30 daysafter last dose of zanubrutinib or 12 months after last dose of rituximab, whicheveris longer. Male participants are eligible if abstinent, vasectomized, or if theyagree to the use of barrier contraception in combination with other methodsdescribed above during the study treatment period and for ≥ 30 days after the lastdose of zanubrutinib, or 12 months after the last dose of rituximab, whichever islonger.

• All participants must have adequate organ function.

Exclusion Criteria:

• Prior therapy for lymphoma including chemotherapy or immunotherapy. Participant mayhave received corticosteroids but should be off them 5 days prior to study entry.

• Prior exposure to a BTK inhibitor.

• Known prior significant hypersensitivity to rituximab (not including infusionreactions).

• Prior history of malignancies unless the patient has been disease free for ≥ 2years. Exceptions include basal cell carcinoma or squamous cell carcinoma of theskin; carcinoma in situ of cervix; carcinoma in situ of breast, localized prostatecancer, or superficial bladder cancer that has undergone curative therapy.

• Participants with evidence of large B cell transformation or other aggressivehistology (such as large cells seen on biopsy or high PET avidity in a single nodeseen on PET scan) are not eligible.

• Known central nervous system (CNS) involvement by lymphoma.

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

• Concomitant use of warfarin or other Vitamin K antagonists.

• Requires ongoing treatment with a moderate or strongCYP3A inhibitor or inducer.

• Known active bacterial, viral, fungal, mycobacterial, or other infection (excludingfungal infections of nail beds) or any major episode of infection requiringtreatment with IV antibiotics or hospitalization (related to the completion of thecourse of antibiotics) within 4 weeks before the start of Cycle 1.

• Known infection with human immunodeficiency virus (HIV).

• Viral Hepatitis:

1. Participants with active hepatitis B defined by hepatitis B surface antigenpositivity or core antibody positivity in the presence of detectable serumhepatitis B DNA viremia are not eligible for this study.

2. Participants with a positive hepatitis B core antibody but with negativehepatitis B DNA may be considered for participation, but must agree to receiveappropriate hepatitis B antiviral therapy while on rituximab and have hepatitisB DNA monitored with real-time PCR by the treating physician. These patientsshould be referred to a hepatologist or gastroenterologist for appropriatemonitoring and management.

3. Hepatitis C: Patients with positive hepatitis C serology unless HCV RNA isconfirmed negative by PCR.

• Vaccination with a live vaccine ≤ 28 days prior to the start of treatment.

• Participants should not have a history of uncontrolled seizures.

• Currently active, clinically significant cardiovascular disease, such asuncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by theNew York Heart Association Functional Classification; or a history of myocardialinfarction, unstable angina, or acute coronary syndrome within 6 months prior toenrollment on the study.

• Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressuremeasurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening.

• Participants should not have a stroke or intracranial hemorrhage within last 6months.

• Participants may not have had major surgery within 28 days of enrollment, or minorsurgery within 7 days of enrollment. Examples of minor surgery include dentalsurgery, insertion of a venous access device, skin biopsy, or aspiration of a joint.The decision about whether a surgery is major or minor can be made at the discretionof the treating physician.

• Any life-threatening illness, medical condition, or organ system dysfunction that,in the investigator's opinion, could compromise the subject's safety or put thestudy outcomes at undue risk.