Time-limited Triplet Combination of Pirtobrutinib, Venetoclax, and Obinutuzumab for Patients With Treatment-naïve Chronic Lymphocytic Leukemia (CLL) or Richter Transformation (RT)

Inclusion Criteria

• •1. Patients with a diagnosis of previously untreated CLL/SLL meeting iwCLL 2018 indication for treatment (cohort 1) or with a diagnosis of previously untreated or relapsed/refractory RT arising from CLL (cohort 2). Previously untreated patients with RT must have received prior therapy for CLL.
• •2. At least 18 years of age
• •3. Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2
• •4. Adequate hepatic function
• •1. 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)
• •2. ALT and AST ≤3.0 x ULN, or ≤5.0 x ULN if documented disease involvement of liver
• •5. Adequate renal function
• •a. Creatinine clearance ≥ 50 ml/min (calculated using CKD-EPI formula)
• •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. Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visit for the duration of study participation
• •8. Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 6 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 during the study and for 6 months following the last dose of study drug
• •10. Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment
• •11. Concurrent use of warfarin or another vitamin K antagonist
• •12. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers. A washout period of at least 5 half-lives of these agents following discontinuation and prior to study entry is required (treatment with moderate CYP3A4 inhibitors or inducers is not excluded)
• •a. Because of their effect on CYP3A4, use of any of the following within 7 days of study therapy start or planned use during study participation is prohibited
• •i. Grapefruit or grapefruit products
• •ii. Seville oranges or products from Seville oranges
• •iii. Star fruit 13. Current treatment with the following P-gp inhibitors: amiodarone, clarithromycin, cyclosporine, erythromycin, ketoconazole, and verapamil. A washout period of at least 5 half-lives of the inhibitor before study entry is required.
• •14\. Known central nervous system involvement by CLL/SLL/RT 15. 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.
• •16\. Prior therapy restrictions
• •a. Cohort 1 (CLL/SLL)
• •i. Prior receipt of anti-CD20 monoclonal antibody therapy for non-malignant indication, including for autoimmune phenomenon ii. Prior receipt of systemic therapy for CLL/SLL
• •b. Cohort 2 (RT)
• •i. Patients who experienced a major bleeding event or grade ≥3 arrythmia on prior treatment with a BTK inhibitor ii. History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within 60 days of first dose of study drugs or presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing:
• •1. Active graft versus host disease (GVHD)
• •2. Cytopenia from incomplete blood cell count recovery post-transplant
• •3. Need for anti-cytokine therapy for toxicity from CAR-T therapy or residual symptoms of neurotoxicity \> Grade 1 from CAR-T therapy
• •4. Ongoing immunosuppressive therapy (\> 20 mg prednisone or equivalent daily) including GVHD prophylaxis/treatment (calcineurin inhibitors or ruxolitinib)
• •iii. Patients are required to have the following washout periods prior to planned Cycle 1 Day 1 (C1D1). In addition, prior treatment-related AEs must have recovered to Grade ≤ 1 with the exception of alopecia and Grade 2 peripheral neuropathy.
• •1\. Targeted agents, investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter
• •1. Immunoconjugated antibody treatment within 10 weeks prior to randomization
• •2. Broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study enrollment
• •3. Palliative limited field radiation must be completed 7 days prior to study enrollment.
• •iv. Prior therapy with venetoclax and obinutuzumab is allowed but Richter should not have developed while actively receiving venetoclax or obinutuzumab (active therapy implies having received venetoclax or obinutuzumab within the prior 3 months)
• •17\. Known hypersensitivity to any component or excipient of study drugs
• •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