Inclusion Criteria:

• Patients must sign the ICF and be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• Patients must be ≥ 18 years of age, inclusive, at the time of signing the informed consent.
• Patients must have confirmed diagnosis of CLL/SLL that meets the iwCLL criteria (Hallek et al 2018, Appendix 6 ). The prior documented CLL or SLL diagnosis that meets the iwCLL criteria (Hallek et al 2018) will be eligible.
• Patient must have received ≥ 1 prior therapy for CLL/SLL. For each line of therapy, patients must receive at least 2 cycles of this therapy. For patients who received a BCL2i, only those with CLL/SLL who received BCL2i in the first-line setting with fixed-duration therapy, have a remission for ≥ 3 years, and have a time interval of ≥ 2 years from the last dose of BCL2i to screening, are eligible.
• Indication for CLL/SLL therapy is met per the IWCLL 2018 criteria, modified as follows:
  • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Hemoglobin concentrations < 11 g/dL or platelet counts < 100 x 109 cells/L are generally regarded as indications for treatment.
  • Massive/progressive, or symptomatic splenomegaly.
  • Massive/progressive or symptomatic lymphadenopathy.
  • Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period, or LDT < 6 months. NOTE: LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts < 30 x 109 cells/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (eg, infections and steroid administration) should be excluded.
  •  Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, and spine).
  • Disease-related symptoms as defined by any of the following:
    • Unintentional weight loss ≥ 10% within the previous 6 months.
    • Significant fatigue (cannot work or unable to perform usual activities). NOTE: Patients with significant fatigue cannot have an ECOG Performance Status score of 0.
    • Fevers ≥ 100.5°F or ≥ 38.0°C for ≥ 2 weeks without evidence of infection.
    • Night sweats for ≥ 1 month without evidence of infection.
• ECOG Performance Status score 0, 1, or 2.
• Adequate marrow function as defined by:
  • Absolute neutrophil count ≥ 1.0 x 109 cells/L with an exception for patients with bone marrow involvement, in which case the absolute neutrophil count must be ≥ 0.75 x 109 cells/L (without growth factor support within the past 7 days).
  • Platelet counts ≥ 75 x 109 cells/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be ≥ 30 x 109 cells/L (without growth factor support or transfusion within the past 7 days).
  • Hemoglobin > 75 g/L (may be posttransfusion).
•  Adequate liver function as indicated by AST and ALT ≤ 2.5 x ULNs value; serum total bilirubin ≤1.5 x ULN (unless documented Gilbert syndrome). 9. Adequate renal function is defined as a creatinine clearance ≥ 30 mL/min, directly measured with a 24-hour urine collection or calculated according to CKD-EPI calculation .
• Life expectancy > 6 months.
• Female patients of childbearing potential must be willing to use a highly effective method of birth control and refrain from egg donation for the duration of the study and for ≥ 90 days after the last dose of sonrotoclax, > 30 days after last dose of venetoclax, > 12 months after the last dose of rituximab, or > 18 months after last dose of obinutuzumab, whichever is longer. They must also have a negative serum pregnancy test result ≤ 7 days before randomization (Section 8.3.5) Note: a woman is considered of childbearing potential (ie, fertile, following menarche and until becoming postmenopausal) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy
• Nonsterile male patients must be willing to use a highly effective method of birth control and refrain from sperm donation for the duration of the study and for ≥ 90 days after the last dose of sonrotoclax, > 30 days after last dose of venetoclax, > 12 months after the last dose rituximab, or > 18 months after last dose of obinutuzumab whichever is longer. Note: A sterile male patient is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. Male patients with known “low sperm counts” (consistent with “subfertility”) are not to be considered sterile for purposes of this study

Exclusion Criteria:

• Known active prolymphocytic leukemia or currently suspected Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation).
• Patients who have active symptomatic COVID-19 infection.
• Patients who are unable to comply with the requirements of the protocol.
• Known central nervous system involvement by CLL/SLL.
• Prior autologous stem cell transplant < 3 months after transplant; or prior CAR-T therapy < 3 months after cell infusion Note: Patients who received autologous transplant or CAR-T therapy more than 3 months after transplant or cell infusion without clear complications will be eligible.
• Prior allogeneic stem cell transplant with active GVHD, requiring immunosuppressive drugs for treatment of GVHD, or have taken calcineurin inhibitors within 4 weeks prior to consent.
• Received any of the following agents within the defined days below prior to the first dose of the study drug, or has not recovered to at least Grade 2 or better clinically significant adverse effect(s)/toxicity(s) of the previous therapy:
  • Received anticancer therapy including chemotherapy or radiation therapy within 14 days prior to the first dose of the study drug.
  • Received targeted inhibitors within the 5 half-lives of the specific agent prior to the first dose of the study drug.
  • Received mAb directed to cancer within 28 days prior to the first dose of the study drug.
  • Received corticosteroid more than equivalent prednisone dose of 60 mg daily for antineoplastic intent within 5 days prior to the first dose of the study drug unless it is used to control BTKi withdrawal flare.
• Patients with a history of confirmed progressive multifocal leukoencephalopathy .
• Severe or debilitating pulmonary disease, defined as diffusing lung capacity for carbon monoxide < 60% and/or respiratory failure requiring assisted ventilation.
• Clinically significant cardiovascular disease including the following:
  • Myocardial infarction within 6 months before screening.
  • Unstable angina within 3 months before screening.
  • New York Heart Association class III or IV congestive heart failure (Appendix 15).
  • History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes).
  • QTcF > 480 msecs based on Fridericia’s formula. NOTE: QTcF value should be calculated as the numerical average of up to 3 separate readings for eligibility.
  • History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.
  • Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing an average systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening.
• Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring active treatment. If this immune cytopenia is controlled, patients will be eligible.
• History of prior or active malignancy within the past 18 months, except for conditions as listed below and as long as patients have recovered from the acute side effects incurred because of previous therapy:
  • Malignancies treated with curative intent and with no known active disease present for ≥ 3 years before randomization.
  • Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated cervical carcinoma in situ without evidence of disease.
  • Localized prostate cancer with Gleason score ≤ 6 or controlled prostate cancer with androgen deprivation treatment.
  • Treated early-stage breast cancer with or without hormonal therapy.
• Active fungal, bacterial, and/or viral infection requiring systemic therapy at the time of study treatment initiation.
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products.
• Hypersensitivity to sonrotoclax, obinutuzumab, venetoclax, rituximab, or any of its excipients (eg, trehalose) that prohibit to use these agents per investigator’s opinion
• Any patient who is pregnant or breastfeeding will not be eligible for the study.
• Vaccination with a live vaccine for a ≤ 4 weeks before enrollment. Note: Inactivated vaccines (eg, seasonal vaccines for influenza) are allowed. Intranasal vaccines are live vaccines and are not allowed ≤ 4 weeks before the first dose of the study treatment.
• Patients with underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study treatment, will affect the explanation of drug toxicity or AEs, or will result in insufficient or impaired compliance with study conduct.
• Positive serologic status reflecting active hepatitis B or C infection or positive HIV serology as follows:
  • Presence of HBsAg.
  • Patients with presence of HBcAb, in the absence of HBsAg, with detectable HBV DNA. NOTE: The limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL (Section 8.1.2). Patients with the presence of HBcAb but undetectable HBV DNA and if they are willing to undergo HBV DNA monitoring per protocol requirement for HBV reactivation (every cycle for patients receiving no prophylactic antiviral therapy or 12 weeks for patients receiving prophylactic antiviral therapy) are eligible.
  • Patients with the presence of HCV antibody and HCV RNA detectable (NOTE: The limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL; Section 8.1.2). Patients with the presence of HCVAb and undetectable HCV RNA and if willing to undergo HCV RNA monitoring per protocol requirement for HCV reactivation (every cycle) are eligible.
  • Positive HIV antibody.
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in the study.
• Unable to swallow capsules or tablets or diseases significantly affecting the GI function, such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• Receiving treatment with any moderate or strong CYP3A4 inhibitor (≤ 7 days or 5 half-lives, whichever is shorter), or strong CYP3A4 inducer (≤ 14 days or 5 half-lives, whichever is shorter) before the first dose of sonrotoclax/venetoclax, or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a strong CYP3A inducer.
• 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.
• Antineoplastic therapy with Chinese traditional medicine or antibody‑based therapies within 4 weeks of the start of the study drug.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/16/2024. Questions regarding updates should be directed to the study team contact.