A Phase 2 Trial Of The Combination Of Zanubrutinib, Sonrotoclax, And Obinutuzumab For Patients With Treatment-Naïve Chronic Lymphocytic Leukemia

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 mAb for cytoreduction in those patients presenting with significantly elevated WBC count or significant adenopathy/organomegaly and those who previously received steroids/CD20 mAb for immune cytopenias are eligible to enroll; Washout of 3 months applies for CD20 mAb and dose of prednisone (or equivalent) should be less than 20 mg/day by day 1 of study initiation) 2. Age greater than or equal to 18 years of age 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 a. Adequate renal function defined by a value ≥30 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 and must agree to use an effective contraception method (combined hormonal contraception, progestogenonly hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, or vasectomized partners) during the study and for at least 18 months following the last dose of study drug. Women of non-childbearing potential are those who are postmenopausal greater than 2 year or who have had a bilateral tubal ligation or hysterectomy. Men who have partners of childbearing potential must agree to use an effective contraceptive method (condom or vasectomy) during the study and for at least 18 months following the last dose of study drug. Egg and sperm donation should be refrained for at least 18 months from the last dose of study drug, respectively. 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 antiviral 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 arrhythmias), or myocardial infarction within 6 months, or stroke within 6 months, or intracranial bleeding 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. Patients 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 half-lives, whichever is longer, before the first dose of study treatment(s) OR requiring long-term use of strong CYP3A inhibitors or inducers. 15\. Patients consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment 16. Known central nervous system involvement by CLL/SLL 17. 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. 18. Known hypersensitivity to any component or excipient of study drugs 19. Malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drugs 20. Receipt of live-virus vaccines within 4 weeks prior to starting study drugs 21. 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 22. Known prolymphocytic leukemia or history of, or currently suspected, Richter transformation (biopsy based on clinical suspicion may be needed to rule our transformation)