Rituximab and Zanubrutinib for the Treatment of Patients with Marginal Zone Lymphoma or Follicular Lymphoma

Inclusion Criteria

• Participants are eligible to be included in the study only if all of the following criteria apply: * Cohort specific inclusion criteria: ** Cohort A: Previously untreated MZL. Prior therapy with H. Pylori antibiotic therapy or hepatitis C (Hep C) antiviral therapy are allowed on cohort A. ** Cohort B: Previously untreated FL *Note: H.Pylori and Hep C are only relevant to patients with MZL (Cohort A) and NOT patients with follicular lymphoma (cohort B)
• Pathological confirmation of lymphoma: availability of archival tissue confirming diagnosis of MZL (cohort A) or FL (cohort B). Availability of formalin-fixed, paraffin embedded (FFPE) archival tumor specimens from within past 18 months from screening and pathological diagnosis confirmed by a pathologist at the participating site or willingness of the participant to undergo a fresh tumor biopsy if adequate archival tissue not available is required. This includes: * MZL (Cohort A): ** Nodal MZL requiring systemic therapy. ** Splenic MZL requiring systemic therapy. Patients who are hepatitis C positive should have failed to achieve a response to hepatitis C antiviral therapy. ** Extra-nodal marginal zone lymphoma: *** Non-gastric/non-cutaneous MZL requiring systemic therapy. *** Cutaneous MZL will be eligible only if they have pathologically confirmed extra-cutaneous disease. *** Gastric MZL only if advanced stage disease requiring systemic therapy (e.g., stage IIE, II2, IV- supradiaphragmatic nodal or disseminated extranodal disease such as bone marrow or additional extra nodal sites). * FL (Cohort B): Pathological grade 1, 2, or 3a based on the World Health Organization's (WHO) 2008 classification of tumors of hematopoietic and lymphoid tissue. Please note, grade 3B are excluded
• Patients must have disease requiring systemic therapy rather than local radiation (ie, stage II only if not eligible for radiation therapy or with stage III/IV)
• All patients should have measurable disease. Measurable disease is defined as a lymph node or tumor mass that is ≥ 1.5 cm in at least one dimension by CT or the CT portion of the PET/CT
• Documentation of CD20+ status
• All patients must have an indication for therapy such as: symptoms attributable to lymphoma, threatened end-organ function, cytopenia secondary to lymphoma, bulky disease (defined as: single mass > 7 cm in diameter, or 3 or more masses > 3 cm in diameter), symptomatic splenomegaly, or B-symptoms
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patients must be able to swallow whole pills
• Ability and willingness to comply with the requirements of the study protocol
• Female subjects who are of non-reproductive potential (i.e., post-menopausal by history- no menses for ≥ 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
• Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condoms, vaginal ring, sponge, etc) during the period of therapy. Female patients of reproductive potential who are not surgically sterile must practice adequate birth control for a minimum of 30 days after last dose of zanubrutinib or 12 months after last dose of rituximab, whichever is longer. Male patients are eligible if abstinent, vasectomized, or if they agree to the use of barrier contraception in combination with other methods described above during the study treatment period and for ≥ 30 days after the last dose of zanubrutinib, or 12 months after the last dose of rituximab, whichever is longer
• Absolute neutrophil count (ANC) ≥ 1000/mm^3, except when neutropenia is assessed by the investigator to be directly due to active lymphoma, in which case ANC must be ≥ 750/mm^3
• Platelet ≥ 50,000/mm^3 (without growth factor support or transfusion within 7 days)
• Hemoglobin > 8.0 g/dL (without growth factor support or transfusion within 7 days)
• Serum aspartate transaminase or alanine transaminase ≤ 3.0 x upper limit of normal (ULN)
• Prothrombin time (PT)/international normalized ratio (INR) <1.5 x upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder)
• Estimated creatinine clearance ≥ 30 ml/min (calculated according using Cockcroft–Gault formula)
• Bilirubin ≤ 2 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non hepatic origin)
• Patients with Child Pugh B or C liver failure will be excluded

Exclusion Criteria

• Prior therapy for lymphoma including chemotherapy or immunotherapy. Patient may have 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 infusion reactions)
• Prior history of malignancies unless the patient has been disease free for ≥ 2 years. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin; carcinoma in situ of cervix; carcinoma in situ of breast, localized prostate cancer, or superficial bladder cancer that has undergone curative therapy
• Patients with evidence of large B cell transformation or other aggressive histology (such as large cells seen on biopsy or high PET avidity in a single node seen 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. * Patients can be considered eligible if they stop the moderate or strong CYP3A inhibitor or inducer after a washout period of 4 half-lives
• Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 weeks before the start of cycle 1
• Known infection with human immunodeficiency virus (HIV)
• Viral Hepatitis: * Patients with active hepatitis B defined by hepatitis B surface antigen positivity or core antibody positivity in the presence of detectable serum hepatitis B deoxyribonucleic acid (DNA) viremia are not eligible for this study. * Patients with a positive hepatitis B core antibody but with negative hepatitis B DNA may be considered for participation, but must agree to receive appropriate hepatitis B antiviral therapy while on rituximab and have hepatitis B DNA monitored with real-time polymerase chain reaction (PCR) by the treating physician. These patients should be referred to a hepatologist or gastroenterologist for appropriate monitoring and management. * Hepatitis C: Patients with positive hepatitis C serology unless hepatitis C virus (HCV) ribonucleic acid (RNA) is confirmed negative by PCR
• Vaccination with a live vaccine ≤ 28 days prior to the start of treatment
• Patients should not have a history of uncontrolled seizures
• 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 enrollment on the study
• 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
• Patients should not have a stroke or intracranial hemorrhage within last 6 months
• Prior Surgery: Patients may not have had major surgery within 28 days of enrollment, or minor surgery within 7 days of enrollment. Examples of minor surgery include dental surgery, 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 discretion of 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 the study outcomes at undue risk