Evaluating Mosunetuzumab for Clearance of Detectable Minimal Residual Disease for the Treatment of Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Previously Treated with BTKi and/or BCL2i

Inclusion Criteria

• Subjects must meet 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines for the diagnosis of CLL or SLL
• Recent completion of treatment or ongoing treatment for CLL/SLL as follows: * BTKi arm: On continuous BTKi therapy for > 12 months, including > 2 months at a stable dose. ** BTKis include ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib. Up to 5 subjects on pirtobrutinib are allowed on the BTKi arm. No limits for other BTKis. ** The BTKi is the first- or second-line therapy for CLL. ** Prior exposure to BTKi + anti-CD20 mAb is allowed as long as the mAb has been stopped before starting study therapy. This combination is considered one line of therapy (LOT). ** Prior exposure to the combination of a BCL2i + BTKi +/- anti-CD20 mAb is allowed. The combination is considered one LOT. *** If BTKi was continued after the triplet combination, the subject is eligible for the BTKi arm. *** If all three agents of the triplet combination stopped before the study therapy, the subject is eligible for the BCL2i arm. *** If BCL2i was continued after the combination, the subject is not eligible. * BCL2i arm: Completed BCL2i-based therapy < 12 months of enrollment. ** BCL2i-based therapy must be the most recent CLL therapy prior to enrollment. ** BCL2i must have been given for at least 6 months for patients who were intolerant to a BCL2i and stopped the treatment without disease progression. For all others, at least 12 cycles of BCL2i therapy are required. ** BCL2i-based therapy should have been given as first- or second-line therapy for CLL. ** BCL2i-based regimens include venetoclax plus obinutuzumab (VO) or rituximab (VR), and the combination of a BTKi + a BCL2i +/- anti-CD20mAb. *** If BCL2i was continued after the combination, the subject is not eligible
• Detectable minimal residual disease (MRD) of >= 10^-4 in peripheral blood (PB) or bone marrow (BM) based on NGS-based method (ClonoSEQ). * Note: Discordance between PB and BM MRD has been reported in CLL. Detectable MRD in either one of these samples is eligible
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN) or ≤ 5 × ULN with documented liver involvement or hemolysis (completed within 30 days prior to starting study therapy)
• Total bilirubin =< 1.5 x ULN or =< 3 x ULN with documented liver involvement, hemolysis, and/or Gilbert's disease (completed within 30 days prior to starting study therapy)
• Serum creatinine calculated creatinine clearance ≥ 30 ml/min/1.73m^2 using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) equation or using 24-hour urine collection (completed within 30 days prior to starting study therapy)
• Absolute neutrophil count (ANC) ≥ 0.75 × 10^9/L * Independent of growth factor support within 7 days of screening assessment
• Hemoglobin (HGB) ≥ 8 g/dL * Independent of transfusion within 7 days of screening assessment
• Platelet count (PLT) ≥ 50 × 10^9/L * Independent of transfusion within 7 days of screening assessment
• Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 x ULN (must be completed within 30 days prior to starting study therapy)
• Partial thromboplastin time (PTT) or activated PTT ≤ 1.5 x ULN (must be completed within 30 days prior to starting study therapy)
• Women of child-bearing potential must agree to remain abstinent or use highly effective contraception (defined as contraceptive measures that result in a failure rate of < 1% per year) during the treatment period and for at least 3 months after the last dose of study therapy and tocilizumab
• Men with female sexual partners of childbearing potential should agree to remain abstinent or use contraceptive measures which include a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 1 month after the last dose of study therapy and 2 months after the last dose of tocilizumab. Men should refrain from donating sperm during the same period. Women should not donate oocytes. 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
• Ability to take oral medications
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Bulky disease with any lymph node > 5cm or absolute lymphocyte count > 100,000 /microL
• Clinical progression of CLL at the time of enrollment
• Prior treatment with chimeric antigen receptor T-cell therapy within 30 days of starting study therapy, or radioimmunotherapy within 12 weeks of starting study therapy
• History of solid organ or allogeneic stem cell transplantation
• Ongoing significant toxicity (grade 3 or higher adverse events) from prior BCL2i- or BTKi- -based therapy at the time of enrollment
• Known or suspected Richter’s transformation or known central nervous system (CNS) involvement of CLL
• History of bleeding disorders (e.g. von Willebrand’s disease, hemophilia)
• Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. * Note: Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no residual neurologic deficits as judged by the investigator are allowed. * Note: Participants with a history of epilepsy who have had no seizures in the past 2 years with or without anti-epileptic medications can be eligible only for the expansion cohort
• Significant cardiovascular disease defined as: * Uncontrolled arrhythmia; OR * Note: Patients with atrial fibrillation are eligible if they are adequately rate controlled. * Note: Patients with pacemakers are eligible if they had no history of fainting or clinically relevant arrhythmias while using the pacemaker. * Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; OR * Ejection fraction (EF) < 40% by any methods in the 12 months of enrollment; OR * Unstable angina or acute coronary syndrome including myocardial infarction within 6 months of enrollment
• Patients with significant pulmonary disease such as uncontrolled obstructive pulmonary disease, history of bronchospasm, uncontrolled idiopathic, autoimmune, or drug-induced interstitial lung disease (ILD), or uncontrolled drug induced or auto-immune pneumonitis
• Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis
• For patients with history of other malignancies with life expectancy of < 2 years. The study allows enrollment of patients with the following types of cancer in remission and life expectancy of 2 years or longer: * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated carcinoma in situ without evidence of disease. * Low-risk prostate cancer on active surveillance. * Current adjuvant hormonal therapy for breast or prostate cancer treated with curative intent > 2 years before starting study therapy
• Patients who are receiving any other investigational agents
• Concurrent systemic immunosuppression (e.g. azathioprine, methotrexate, cyclosporine, tacrolimus, anti-TNF agents, anti-CD20 monoclonal antibody) within 30 days of starting study therapy or administration of > 20 mg of prednisone or equivalent daily within 14 days of study therapy
• Vaccinated with live vaccine within 4 weeks of starting study therapy
• Major surgery within 4 weeks of starting study therapy. If a subject had major surgery greater than 4 weeks prior to the first dose, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study therapy
• Ongoing or recent infection (e.g. bacterial, viral, fungal, parasitic, or other infection) requiring intravenous antimicrobials within 4 weeks of starting study therapy. Prophylactic antibiotics are allowed if there is no evidence of active infection and the antibiotics is not included on the list of the prohibited medications
• Known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
• Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the mosunetuzumab. Patients with previous reactions to other anti-CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are not excluded
• Concurrent treatment with warfarin or other vitamin K antagonists for anticoagulation. * Note: Other antiplatelet and anticoagulants are allowed
• Patients who have tested positive for HIV are excluded due to potential drug-drug interactions between anti retroviral medications and pirtobrutinib and risk of opportunistic infections with both HIV and irreversible BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result should be negative for enrollment
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection: * HBV: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with negative HBsAg and positive hepatitis B core antibody (anti-HBc) require HBV deoxyribonucleic acid (DNA) PCR. Patients with positive HBV DNA PCR will be excluded. Patients with negative HBsAg, positive anti-HBc and undetectable HBV DNA are eligible and will receive prophylaxis with entecavir to prevent HBV reactivation during study therapy. HBV DNA should be monitored every 3 months during HBV prophylaxis. Refer to section 5.4 for HBV monitoring and prophylaxis. * HCV: Patients with positive hepatitis C antibody require HCV RNA PCR. Patients with positive HCV RNA will be excluded.
• History of progressive multifocal leukoencephalopathy (PML)
• Positive SARS-CoV-2 test within 7 days prior to enrollment. Either a rapid antigen test (self-testing at home) or a PCR test is allowed
• Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment
• Active uncontrolled autoimmune disease, including, but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis * Patients with a remote history of, or well-controlled, autoimmune disease with a treatment‑free interval from immunosuppressive therapy for 12 months may be eligible to enroll if judged to be safe by the investigator. * Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible. * Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. * Patients with history of autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) are eligible as long as treatment regimens (e.g. new therapy, dose escalation of existing therapy) remained stable within 4 weeks of starting study therapy
• Significant co-morbid condition or disease which in the judgement of the principal investigator would place the patient at undue risk or interfere with the study