Phase II Study of Combined Pirtobrutinib, Venetoclax and Obinutuzumab (PVO) Time-limited Treatment for Patients With Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).

Eligibility Criteria:

1. Age 18 years or older.

2. Diagnosis of CLL/SLL per 2018 iwCLL criteria (See Appendix 1).

3. Participants with previously treated CLL requiring therapy based on 2018 iwCLLcriteria.

4. The participant is able to take oral medications.

5. Willing and capable of giving signed informed consent which includes compliance withthe requirements and restrictions listed in the informed consent form (ICF) and inthe protocol.

6. Prior or ongoing therapy with covalent BTKi is allowed, but not required.

7. Prior or ongoing therapy (at least for six months) with BCL2i is allowed, but notrequired. Prior therapy with combined BTKi and BCL2i or triplet BTKi, BCL2 andanti-CD20 mAb is allowed, but Participants need to be at least six months aftercompletion of combination therapy. Participants with history of prior venetoclaxtherapy should have achieved at least a partial response or better while receivingvenetoclax therapy.

8. Participants are required to have the following washout periods prior to plannedCycle 1 Day1 (C1D1).

• Targeted agents, investigational agents, therapeutic monoclonal antibodies orcytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter

• immunoconjugated antibody treatment within 10 weeks

• broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy)must be completed 14 days prior to enrollment

• palliative limited field radiation must be completed 7 days prior to enrollment

9. Prior treatment-related AEs must have recovered to Grade ≤ 1 with the exception ofalopecia and Grade 2 peripheral neuropathy.

10. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.

11. Participants must have adequate renal and hepatic function:

• Serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for Participantswith Gilbert's disease or disease involvement by CLL/SLL.

• Serum creatinine clearance of ≥30ml/min (calculated or measured).

• ALT and AST ≤3.0 x ULN, unless clearly due to documented disease involvement,in which case ALT and AST ≤5.0 x ULN

12. Adequate bone marrow function:

• Platelet count of ≥50,000/μl, with no platelet transfusion in prior 2 weeks.

• ANC ≥750/μl in the absence of growth factor support within 7 days of screeningassessment.

• Hemoglobin ≥8g/dL, independent of transfusions within 7 days of screeningassessment. Please refer to Appendix 4 for details of adjustments of toxicitiesin participants with abnormal baseline values)

13. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) orpartial thromboplastin time and prothrombin time (PT) or international normalizedratio (INR) not greater than 1.5 x ULN.

14. Women of childbearing potential must have a negative serum beta human chorionicgonadotropin (β-hCG) pregnancy test result at the time of screening and serum orurine β-hCG pregnancy test within 7 days prior to the first dose of study drugs andmust agree to use both a highly effective method of birth control (eg, implants,injectables, combined oral contraceptives, some intrauterine devices [IUDs],complete abstinence, or sterilized partner) and a barrier method (eg., condoms,vaginal ring, sponge, etc) during the period of therapy and for 6 months after thelast dose of study drug (pirtobrutinib and Obinutuzumab) and 12 months after thelast dose of obinutuzumab. Women of nonchildbearing potential are those who arepostmenopausal (defined as absence of menses for ≥1 year) or who have had abilateral tubal ligation or hysterectomy. Men who have partners of childbearingpotential must agree to use effective contraception, defined above, during the studyand for 30 days following the last dose of study drug

Exclusion Criteria:

1. Participants who experienced progression of disease according to 2018 iwCLL criteriawhile on venetoclax will be excluded.

2. Patient with prior history of Richter's syndrome or current Richter's Syndrome.

3. Participants with known hypersensitivity to any of the excipients of pirtobrutinib,venetoclax,obinutuzumab or to any intended study medications.

4. Known or suspected history of central nervous system (CNS) involvement by CLL/SLL.

5. History of bleeding diathesis.

6. Participants who experienced a major bleeding event on a prior BTK inhibitor.• NOTE:Major bleeding is defined as bleeding having one or more of the following features:life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleedingassociated with a decrease in the hemoglobin level of at least 2 g/dL; or bleedingin a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial,epidural, or intracranial bleeding or intramuscular bleeding with compartmentsyndrome).

7. History of stroke or intracranial hemorrhage within 6 months of enrollment.

8. Participants requiring therapeutic anticoagulation with warfarin or another vitaminK antagonists.

9. Major surgery within 4 weeks of planned start of study therapy.

10. A significant history of renal, neurologic, psychiatric, endocrine, metabolic orimmunologic disorder, that, in the opinion of the Investigator, would adverselyaffect the participant's participation in this study or interpretation of studyoutcomes.

11. History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigenreceptor-modified Tcell (CAR-T) therapy within 60 days of enrollment or presence ofany of the following, regardless of prior SCT and/or CAR-T therapy timing:

• active graft versus host disease (GVHD);

• cytopenia from incomplete blood cell count recovery post-transplant;

• need for anti-cytokine therapy for toxicity from CAR-T therapy; residualsymptoms of neurotoxicity > Grade 1 from CAR-T therapy;

• ongoing immunosuppressive therapy (> 20 mg prednisone or equivalent daily).

12. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA],idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced orexisting therapy was escalated within the 4 weeks prior to study enrollment tomaintain adequate blood counts.

13. Participants who experienced grade >3 arrhythmia on prior treatment with BTKinhibitor.

14. Significant cardiovascular disease, defined as any of the following:

15. Unstable angina or acute coronary syndrome within the past 2 months.

16. History of myocardial infarction within 6 months prior to planned start ofstudy treatment.

17. Documented left ventricular ejection fraction (LVEF) by any method of ≤ 45% inthe 12 months prior to planned start of study treatment.

18. ≥ Grade 3 New York Heart Association (NYHA) functional classification system ofheart failure.

19. uncontrolled or symptomatic arrhythmias

20. Prolongation of the QT interval corrected (QTc - see Appendix 3) for heart rateusing Fredericia's Formula (QTcF) > 470 msec on an EKG during screening.

21. QTcF is calculated using Fredericia's Formula (QTcF = QT/(RR^0.33)

22. Correction of suspected drug-induced QTcF prolongation or prolongation due toelectrolyte abnormalities can be attempted at the Investigator's discretion,and only if clinically safe to do so with either discontinuation of theoffending drug or switch to another drug not known to be associated with QTcFprolongation or electrolyte supplementation.

23. Correction of QTc for underlying bundle branch block (BBB) permissible.Participants with pacemakers are eligible if they have no history of faintingor clinically relevant arrhythmias while using the pacemaker

24. Hepatitis B or hepatitis C testing indicating active/ongoing infection based onscreening laboratory tests as defined as:

25. Hepatitis B virus (HBV): Participants with positive hepatitis B surface antigen (HBsAg) are excluded. Participants with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation. Participants who are hepatitis B PCR positive will beexcluded.

26. Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis Cantibody result, participant will need to have a negative result for hepatitisC ribonucleic acid (RNA) . Participants who are hepatitis C RNA positive willbe excluded.

27. Evidence of other clinically significant uncontrolled condition(s) including, butnot limited to, uncontrolled systemic infection (viral, bacterial, parasitic orfungal) or other clinically significant active disease process which in the opinionof the Principal Investigator may pose a risk for patient participation. Screeningfor chronic conditions is not required.

28. Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Forparticipants with unknown HIV status, HIV testing will be performed at screening andresult must be negative for enrollment.

29. Known active CMV infection. Participants with unknown or negative status areeligible.

30. Vaccination with live vaccine within 28 days prior to enrollment

31. Clinically significant active malabsorption syndrome or other condition likely toaffect gastrointestinal (GI) absorption of the oral administered study treatments.

32. Active other malignancy unless in remission and with life expectancy > 2 years. withexception of participants diagnosed with basal cell or squamous cell carcinoma ofthe skin or carcinoma "in situ" of the cervix or breast who are eligible even ifdiagnosed within 2 years. If Participants have another malignancy that was treatedwithin the last 2 years, such participants may be enrolled, if the likelihood ofrequiring 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 CancerCenter, and after consultation with the Principal Investigator.

33. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers. Awashout period of at least 5 half-lives of these agents following discontinuationbefore study entry is required (treatment with moderate CYP3A4 inhibitors orinducers is not excluded). Because of their effect on CYP3A4, use of any of thefollowing within 7 days of study therapy start or planned use during studyparticipation is prohibited i. Grapefruit or grapefruit products ii. Seville orangesor products from Seville oranges iii. Star fruit.

34. Current treatment with the following P-gp inhibitors: amiodarone, clarithromycin,cyclosporine, erythromycin, ketoconazole, and verapamil. A washout period of atleast 5 half-lives of the inhibitor before study entry is required.

35. Participants that are pregnant or plan to become pregnant during the study or within 1 month of the last dose of study treatment.

25. Participants that are lactating or plan to breastfeed during the study or within 1 week of the last dose of study treatment.