Zanubrutinib in Combination With Sonrotoclax for the Treatment of Underrepresented Ethnic and Racial Minorities With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Assent, when appropriate, will be obtained per institutional guidelines

• Age: ≥ 18 years on the day of signing the informed consent form

• Eastern Cooperative Oncology Group (ECOG) ≤ 2

• Patients are of the following self-identified racial/ethnic groups:

• Cohort 1: Patients in any of the following categories:

• Black or African American

• Hispanic or Latino

• American Indian/Native Alaskan

• Pacific Islander/Native Hawaiian

• Any other patient that does not fit the definition of Cohort 2

• Cohort 2: Patients in either of following categories:

• Non-Hispanic White

• Non-Hispanic Asian

• Confirmed diagnosis (per World Health Organization [WHO] guidelines, unlessotherwise noted) of one of the following disease subtypes. Note that for diseasesubtypes that are known to respond to BTK inhibitor (BTKi) and/or BCL2 inhibitor (BCL2i) (e.g., marginal zone lymphoma [MZL], mantle cell lymphoma [MCL], CLL/SLL),newly diagnosed or r/r patients are allowed

• Diffuse large B cell lymphoma (DLBCL)

• R/R DLBCL (including all subtypes of DLBCL) defined as disease thatrelapsed after, or was refractory to, at least 2 prior lines of therapy.Patients should be considered by the investigator to be refractory to ornot a candidate for approved therapies with proven efficacy including butnot limited to chimeric antigen receptor (CAR) T cell therapy orbispecific antibody therapy

• Active disease requiring treatment

• Follicular lymphoma (FL)

• R/R FL (grade 1, 2 or 3a based on WHO 2008 classification of tumors ofhematopoietic and lymphoid tissue) and defined as disease that relapsedafter, or was refractory to, at least 1 prior systemic therapy. Patientsshould be considered by the investigator for all approved therapies withproven efficacy including but not limited to CAR T cell therapy orbispecific antibody therapy

• Active disease requiring treatment

• Marginal zone lymphoma (MZL)

• R/R extranodal, splenic, or nodal MZL defined as disease that relapsedafter, or was refractory to, at least 1 prior therapy

• Active disease requiring treatment

• Mantle cell lymphoma (MCL)

• R/R MCL defined as disease that relapsed after, or was refractory to, atleast 1 prior systemic therapy

• Requiring treatment in the opinion of the investigator

• Chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL)

• CLL/SLL diagnosis that meets the International Workshop on CLL (International Workshop on Chronic Lymphocytic Leukemia [IWCLL]) criteria

• Patients with previously untreated and/or r/r CLL defined as disease thatrelapsed after, or was refractory to, at least 1 prior therapy will beincluded

• Patients must have an indication to start treatment

• Measurable disease, defined as:

• CLL: at least 1 lymph node > 1.5 cm in longest diameter and measurable in 2perpendicular dimensions by computed tomography (CT)/magnetic resonance imaging (MRI) or clonal lymphocytes measured by flow cytometry

• DLBCL, FL, MZL, MCL, or SLL: at least 1 lymph node > 1.5 cm in longest diameterOR 1 extranodal lesion > 1.0 cm in the longest diameter, measurable in 2perpendicular dimensions by CT/MRI. For MZL, isolated splenomegaly isconsidered measurable for this study. For MCL, clonal lymphocytes measured byflow cytometry is considered measurable

• Life expectancy of ≥ 6 months

• Without bone marrow involvement: Absolute neutrophil count (ANC) ≥ 1,000/mm^3

• NOTE: Growth factor is not permitted within 7 days of ANC assessment unlesscytopenia is secondary to disease involvement

• With bone marrow involvement: ANC ≥ 500/mm^3

• NOTE: Growth factor is not permitted within 7 days of ANC assessment unlesscytopenia is secondary to disease involvement

• Without bone marrow involvement: Platelets ≥ 75,000/mm^3

• NOTE: Platelet transfusions are not permitted within 7 days of plateletassessment unless cytopenia is secondary to disease involvement

• With bone marrow involvement: Platelets ≥ 30,000/mm^3

• NOTE: Platelet transfusions are not permitted within 7 days of plateletassessment unless cytopenia is secondary to disease involvement

• Hemoglobin ≥ 7g/dL

• NOTE: Red blood cell transfusions are not permitted within 7 days of hemoglobinassessment unless cytopenia is secondary to disease involvement

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease)

• Aspartate aminotransferase (AST) ≤ 2.5 x ULN

• Alanine aminotransferase (ALT) ≤ 2.5 x ULN

• Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the Cockcroft-Gaultformula

• Fridericia's formula-corrected QT interval (QTcF) ≤ 480 ms

• Note: Performed within 28 days prior to day 1 of protocol therapy

• Seronegative for HIV antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV),active hepatitis B virus (HBV) (surface antigen negative) OR

• If seropositive for HIV, HCV or HBV, nucleic acid quantitation must beperformed. Viral load must be undetectable

• HIV-infected patients on effective anti-retroviral therapy with undetectableviral load within 6 months are eligible for this trial

• Meets other institutional and federal requirements for infectious disease titerrequirements

• Note Infectious disease testing to be performed within 28 days prior to day 1of protocol therapy

• Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test

• If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least 90 days after the last dose of protocol therapy

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Major surgery ≤ 4 weeks of the first dose of study drug

• Prior autologous stem cell transplant unless ≥ 30 days after transplant; or priorchimeric antigen receptor T cell (CAR-T) therapy unless ≥ 30 days after cellinfusion

• Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD),or requiring immunosuppressive drugs for treatment of GVHD, or have takencalcineurin inhibitors within 4 weeks prior to consent

• Prior therapy ≥ 2 months with or progression on a Bcl2 inhibitor (eg, venetoclax)

• Vaccination or requirement for vaccination with a live vaccine within 35 days priorto the first dose of study drug or at any time during planned study treatment

• Requires ongoing treatment with a strong CYP3A inducer

• Requires ongoing treatment with warfarin or warfarin derivatives

• Concurrent participation in another therapeutic clinical trial

• Use of the following substances prior to the first dose of study drug:

• ≤ 28 days before first dose of study drug: Any biologic and/orimmunologic-based therapy(ies) including experimental therapy(ies) forleukemia, lymphoma, or myeloma (including, but not limited to, monoclonalantibody therapy, eg, rituximab, and/or cancer vaccine therapy)

• ≤ 14 days before the first dose of study drug: systemic chemotherapy orradiation therapy

• ≤ 7 days before the first dose of study drug: corticosteroid given withantineoplastic intent other than control of BTK inhibitor withdrawal flare

• ≤ 5 half-lives before the first dose of study drug: BTK inhibitor, tyrosinekinase inhibitor, or other targeted small molecule given with antineoplasticintent

• Known current central nervous system involvement by lymphoma/leukemia

• Known plasma cell neoplasm, prolymphocytic leukemia, history of or currentlysuspected Richter's syndrome

• Any uncontrolled or clinically significant cardiovascular disease including thefollowing:

• Myocardial infarction (MI) within 6 months before screening

• NYHA (New York Heart Association) heart failure class III-IV

• Unstable angina within 3 months before screening

• History of clinically significant arrhythmias (e.g., sustained ventriculartachycardia, ventricular fibrillation, torsades de pointes)

• History of Mobitz II second-degree or third-degree heart block without apermanent pacemaker in place

• Prior malignancy within the past 3 years, except for curatively treated basal orsquamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ ofthe cervix or breast, or localized Gleason score 6 prostate cancer

• History of severe bleeding disorder such as hemophilia A, hemophilia B, vonWillebrand disease, or history of spontaneous bleeding requiring blood transfusionor other medical intervention

• History of stroke or intracranial hemorrhage within 6 months before first dose ofstudy drug

• Severe or debilitating pulmonary disease

• Unable to swallow capsules or disease significantly affecting gastrointestinalfunction such as malabsorption syndrome, resection of the stomach or small bowel,bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial orcomplete bowel obstruction

• Active fungal, bacterial and/or viral infection requiring systemic therapy

• Underlying medical conditions that, in the investigator's opinion, will render theadministration of study drugs hazardous or obscure the interpretation of toxicity oradverse events (AEs)

• Known active infection with HIV, or serologic status reflecting active hepatitis Bor C infection as follows:

• Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible ifhepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable (< 20 IU),and if they are willing to undergo monitoring every 4 weeks for HBVreactivation

• Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCVantibody are eligible if HCV ribonucleic acid (RNA) is undetectable

• Any condition which in the discretion of the investigator would compromise theability to comply with study procedures

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to the study agents

• Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (e.g.,idiopathic thrombocytopenia purpura)

• Females only: Pregnant or breastfeeding

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)