Sonrotoclax, Rituximab, and Zanubrutinib in Treating Participants With Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, and Mantle Cell Lymphoma

Inclusion Criteria:

• Provision of signed and dated written informed consent prior to any study-specificprocedures, sampling, or analyses

• Age 18 years or older

• Confirmed diagnosis (per World Health Organization [WHO] guidelines, unlessotherwise noted) of one of the following:

• CLL/SLL COHORT: CLL/SLL diagnosis that meets the International Workshop onChronic Lymphocytic Leukemia criteria:

• Meeting the following sets of prior treatment criteria:

• For the R/R cohort, disease that relapsed after, or was refractoryto, at least 1 prior therapy

• For the treatment-naïve cohort, patients should have no priortreatment for CLL/SLL (other than 1 aborted regimen < 2 weeks induration and > 4 weeks before enrollment)

• Requiring treatment per International Workshop on CLL (iwCLL) criteria

• MCL COHORT: WHO-defined MCL

• R/R MCL is defined as a disease that relapsed after, or was refractory to,at least 1 prior systemic therapy

• Measurable disease, defined as:

• CLL/SLL: 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 >= 5 x 109/L present on peripheral blood flowcytometry

• MCL, or SLL: at least 1 lymph node > 1.5 cm in the longest diameter OR 1extranodal lesion > 1.0 cm in the longest diameter, measurable in 2perpendicular dimensions by CT/MRI

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L =< 7 days before the first dose ofthe study drug with or without growth factor support. There is an exception forpatients with bone marrow involvement, in which case ANC must be >= 0.75 x 10^9/Lbefore the first dose of the study drug

• Platelets > 75,000 x 10^9/L (> 75,000 cells/mm^3) =< 7 days before the first dose ofthe study drug without the use of growth factor support or platelet transfusions.Patients with bone marrow involvement will be allowed to have a platelet count > 50,000 x 10^9/L (> 50,000 cells/mm^3) =< 7 days before the first dose of the studydrug without the use of growth factor support or platelet transfusions

• Hemoglobin > 75 g/L =< 7 days before the first dose of the study drug (with orwithout transfusion)

• Creatinine clearance or glomerular filtration rate (GFR) >= 50 mL/min as estimatedby one of the following:

• Cockcroft-Gault equation

• Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

• 24-hour urine collection

• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase =< 2 xupper limit of normal (ULN)

• Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase =< 2 x ULN

• Total bilirubin level =< 1.5 x ULN (unless documented Gilbert's syndrome). Forpatients with documented Gilbert's syndrome, total bilirubin may exceed this value,but direct bilirubin must be =< 1.0 x ULN

• Serum amylase =< 1.5 x ULN

• Serum lipase =< 1.5 x ULN

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test =< 7 days before the first dose of the study drug. In addition, they must use a highlyeffective method of birth control initiated before the first dose of the study drug,for the duration of the study treatment period, and for >= 180 days after the lastdose of the study drug

• NOTE: WOCBP is a woman who: 1) has achieved menarche at some point, 2) has notundergone a hysterectomy or bilateral oophorectomy or 3) has not been naturallypostmenopausal (amenorrhea following cancer therapy does not rule outchildbearing potential) for at least 24 consecutive months (ie, has had mensesat any time in the preceding 24 consecutive months)

• NOTE: Highly effective contraceptive methods include the following:

• Combined (estrogen and progestogen-containing) hormonal contraceptionassociated with the inhibition of ovulation. Combined hormonalcontraception may be oral, intravaginal, or transdermal

• Progestogen-only hormonal contraception associated with theinhibition of ovulation. Progesterone-only hormonal contraception maybe oral, injectable, or implantable

• An intrauterine device

• Intrauterine hormone-releasing system

• Bilateral tubal

• Vasectomized partner

• Sexual abstinence (defined as refraining from heterosexualintercourse during the entire period of risk associated with thestudy treatment, starting the day before the first dose of studytreatment, for the duration of the study, and for >= 180 days afterthe last dose of study drug. Total sexual abstinence should only beused as a contraceptive method if it is in line with the patients'usual and preferred lifestyle. Periodic abstinence (e.g., calendar,ovulation, symptothermal, post-ovulation methods), declaration ofabstinence for the duration of exposure to investigational medicinalproduct, and withdrawal are not acceptable methods of contraception

• Of note, barrier contraception (including male and female condoms with orwithout spermicide) is not considered a highly effective method ofcontraception, and, if used, this method must be used in combination withanother acceptable method listed above

• For patients using hormonal contraceptives such as birth control pills ordevices, a second barrier method of contraception (e.g., condoms) must be used

• Nonsterile men must use a highly effective method of birth control along withbarrier contraception for the duration of the study treatment period and for ≥ 180days after the last dose of the study drug. During this same period, they must notdonate sperm. Sterile men must use barrier contraception

• Life expectancy of > 6 months

• Able to comply with the requirements of the study

Exclusion Criteria:

• Exposure to a Bcl-2 inhibitor within the last 12 months or a history of diseaseprogression while taking a Bcl-2 inhibitor

• Prior malignancy (other than the disease under study) within the past 2 years,except for curatively treated basal or squamous skin cancer, melanoma, superficialbladder cancer, carcinoma in situ of the cervix or breast, or localized Gleasonscore =< 6 prostate cancer

• Underlying medical conditions that may render the administration of study drughazardous or obscure the interpretation of safety or efficacy results

• Known current central nervous system involvement by lymphoma/leukemia

• Known plasma cell neoplasm other than a monoclonal gammopathy of undeterminedsignificance (MGUS), prolymphocytic leukemia, or history of or currently suspectedRichter's syndrome

• Prior autologous stem cell transplant unless >= 3 months after transplant; or priorchimeric antigen receptor T-cell (CAR-T) therapy unless >= 3 months after cellinfusion

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

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

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

• =< 28 days before the first dose of the study drug:

• Any biologic and/or immunologic-based therapy(ies) including experimentaltherapy(ies) for leukemia, lymphoma, or myeloma (including, but notlimited to, monoclonal antibody therapy, e.g., rituximab, and/or cancervaccine therapy)

• =< 14 days before the first dose of the study drug:

• Systemic chemotherapy or radiation therapy

• =< 7 days before the first dose of the study drug:

• Corticosteroid given with antineoplastic intent

• =< 3 days (or 5 half-lives; whichever is shorter) before the first dose of thestudy drug:

• Bruton's tyrosine kinase inhibitor (BTKi) or other small moleculeinhibitor is given with antineoplastic intent

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

• Note: oral antibiotics for minor bacterial infections are allowed

• Major surgery =< 4 weeks before the first dose of study treatment

• Toxicity from prior anticancer therapy that has not recovered to grade =< 1 (exceptfor alopecia, ANC, and platelet count; for ANC and platelet count)

• Clinically significant cardiovascular disease including the following:

• Myocardial infarction =< 6 months before screening

• Unstable angina =< 3 months before screening

• New York Heart Association class III or IV congestive heart failure

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

• Heart rate-corrected QT interval > 480 milliseconds based on Fridericia'sformula

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

• Uncontrolled hypertension as indicated by a minimum of 2 consecutive bloodpressure measurements, at screening, showing systolic blood pressure > 170 mmHgand diastolic blood pressure > 105 mmHg

• Known infection with human immunodeficiency virus (HIV) or serologic statusreflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection asfollows:

• Presence of viral hepatitis B surface antigen (HBsAg) or viral hepatitis B coreantibody (HBcAb)

• Note: Patients with the presence of HBcAb, but absence of HBsAg, areeligible if HBV deoxyribonucleic acid (DNA) is undetectable and if theyare willing to undergo monitoring for HBV reactivation

• Presence of HCV antibody

• Note: Patients with the presence of HCV antibody are eligible if HCVribonucleic acid (RNA) is undetectable and if they are willing to undergomonitoring for HCV reactivation

• Pregnant or lactating women

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

• Inability to comply with study procedures

• Receiving any treatment with a strong or moderate CYP3A4 inhibitor =< 14 days (or 5half-lives, whichever is longer) before the first dose of sonrotoclax

• Unwillingness to stop consumption of grapefruit, grapefruit products, Sevilleoranges, or starfruit within 3 days before the first dose of sonrotoclax or duringthe study

• Receiving any treatment with a strong CYP3A4 inducer =< 14 days (or 5 half-lives,whichever is longer) before first dose of sonrotoclax

• History of interstitial lung disease, noninfectious pneumonitis, or uncontrolledlung diseases, including but not limited to pulmonary fibrosis and acute lungdiseases

• Autoimmune anemia and/or thrombocytopenia that is poorly controlled bycorticosteroids or other standard therapy

• Ongoing, drug-induced liver injury, alcoholic liver disease, nonalcoholicsteatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction causedby cholelithiasis, cirrhosis of the liver, or portal hypertension

• Receiving drugs known to prolong the QT/corrected QT (QTc) interval

• Vaccination with a live vaccine =< 35 days before the first dose of the study drug

• Note: Seasonal vaccines for influenza are generally inactivated vaccines andare allowed. Intranasal vaccines are live vaccines and are not allowed