A Phase 2 Trial Of The Bruton Tyrosine Kinase Degrader BGB-16673 In Combination With BCL-2 Inhibitor Sonrotoclax For Patients With Treatment-Naive Chronic Lymphocytic Leukemia (CLL)

Inclusion Criteria: 1. Patients with a diagnosis of previously untreated CLL/SLL meeting iwCLL 2018 indication for treatment (Note: patients who receive steroids and/or CD20 monoclonal antibody for cytoreduction in those patients presenting with significantly elevated WBC count or significant adenopathy/organomegaly and those who previously received steroids/CD20 monoclonal antibody for immune cytopenias are eligible to enroll; Washout of 4 weeks applies for CD20 monoclonal antibody and dose of prednisone (or equivalent) should be less than 20mg/day by day 1 of study initiation) 2. Age ≥ 18 years 3. Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2 4. Adequate hepatic function a. Total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with Gilbert's disease or documented disease involvement of liver (In pts with elevated total bilirubin due to increased indirect bilirubin, pts with direct bilirubin ≤1.5 x ULN are eligible) b. ALT and AST ≤3.0 x ULN, or ≤5.0 x ULN if documented disease involvement of liver 5. Adequate renal function 1. Adequate renal function defined by a value ≥50 mL/min determined via estimated GFR calculated according to the CKD-EPI equation 6. Adequate hematologic function a. Platelet count ≥50 x109/L and hemoglobin ≥8 g/dL (≥80 g/L). Platelet and hemoglobin requirements are independent of transfusions within 7 days of screening assessment and first dose of study drugs. b. Absolute neutrophil count ≥0.75 x 109/L. Absolute neutrophil count is independent of growth factor support within 7 days of screening assessment and first dose of study drugs. 7. Adequate coagulation function a. INR ≤1.5 x ULN and aPTT ≤1.5 x ULN 8. Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visit for the duration of study participation 9. Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 24 hours prior to the first dose of study drugs. 10. The effects of sorotoclax and BGB-16673 on the developing human fetus are unknown. For this reason these agents used in this trial 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. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: o Postmenopausal (no menses in greater than or equal to 12 consecutive months). o History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). * History of bilateral tubal ligation or another surgical sterilization procedure. * Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. 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. Contraception should used for the duration of the study and up to 30 days after completion of BGB-16673 and/or sonrotoclax administration. * 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 up to 30 days after completion of BGB-16673 and/or sonnrotoclax administration. 11. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: 1. Major surgery within 4 weeks prior to the first dose of study drugs 2. Uncontrolled active systemic infection 3. Known positive serology for human immunodeficiency virus (HIV) 4. Active hepatitis B infection (defined as the presence of detectable HBV DNA, HBe antigen or HBs antigen). Patients with serologic evidence of prior vaccination (HBsAg negative, anti-HBs antibody positive, anti-HBc antibody negative) are eligible. Patients who are HBsAg negative/HBsAb positive but HBcAb positive are eligible, provided HBV DNA is negative and they are willing to take appropriate anti-viral prophylaxis 5. Active hepatitis C infection (defined as detectable hepatitis C RNA in plasma by PCR) 6. Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible 7. Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy with \>20 mg daily of prednisone or equivalent 8. Clinically significant, uncontrolled cardiovascular disease (≥3 NYHA heart failure, uncontrolled or symptomatic arrythmias), or myocardial infarction within 6 months prior to start of study drugs 9. Uncontrolled hypertension defined as 2 consecutive systolic blood pressure ≥160 mmHg and /or diastolic blood pressure ≥100 mmHg within 3 months 10. History of Mobitz II second degree or third-degree heart block without a permanent pacemaker in place 11. Prolongation of the QT interval corrected for heart rate (QTcF) \>480 msec. Note: Patients with QTcF \>480 msec should have EKG repeated. If QTcF again is \>480 msec, then the patient should be referred to cardiology for evaluation. Patient can be enrolled later if cleared by cardiology and repeat QTcF less than 480 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33) 1. Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation. 2. Correction for underlying bundle branch block (BBB) allowed. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker 12. Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment 13. Concurrent use of warfarin or another vitamin K antagonist 14. Receiving treatment with a strong CYP3A inhibitor or strong CYP3A inducer ≤14 days or 5 halflives, whichever is longer, before the first dose of study treatment(s) OR requiring long-term use of strong CYP3A inhibitors or inducers. 15. Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment 16. Active second malignancy unless in remission and with life expectancy \> 2 years with exception of patients diagnosed with basal cell or squamous cell carcinoma of the skin or carcinoma "in situ" of the cervix or breast who are eligible even if diagnosed within 2 years. If patients have another malignancy that was treated within the last 2 years, such patients may be enrolled, if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at MD Anderson Cancer Center, and after consultation with the Principal Investigator. 17\. History of allergic reactions attributed to compounds of similar chemical or biological composition to sonrotoclax or BGB-16673 or other agents used in this study. 18\. Malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drugs 19. Receipt of live-virus vaccines within 4 weeks prior to starting study drugs 20. History of bleeding diathesis and/or history of known bleeding disorder including hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention 21. History of ischemic stroke or intracranial hemorrhage within 6 months of the first dose of study drug 22. Known prolymphocytic leukemia or history of, or currently suspected, Richter transformation (biopsy based on clinical suspicion may be needed to rule our transformation) 23. Known history of central nervous system involvement by CLL 24. Patients with psychiatric illness/social situations that would limit compliance with study requirements 25. Patients who are receiving any other investigational agents.