Pirtobrutinib in Combination with Obinutuzumab for the Treatment of Previously Untreated Chronic Lymphocytic Leukemia

Inclusion Criteria

• Subjects must meet 2018 iwCLL guidelines for the diagnosis of CLL or small lymphocytic lymphoma (SLL)
• Presence of measurable disease (absolute lymphocyte count [ALC] > 5,000/uL, palpable or measurable lymph nodes >= 1.5cm on imaging, OR bone marrow involvement of CLL >= 30%)
• No prior systemic therapy for CLL or SLL. Exception: The study allows prior treatment with corticosteroids or anti-CD20 monoclonal antibody for palliation of symptoms or the treatment of autoimmune cytopenia as long as the patient does not meet the exclusion criterion “concurrent systemic immunosuppression”
• Subjects must currently have an indication for treatment as defined by the following 2018 iwCLL guidelines: * Massive or progressive or symptomatic splenomegaly; OR * Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR * Significant fatigue (i.e. Eastern Cooperative Oncology Group [ECOG] performance status 2 or worse, cannot work or unable to perform usual activities); OR * Fever >= 100.5 Fahrenheit (F) for 2 or more weeks without evidence of infection; OR * Night sweats for >= 1 month without evidence of infection; OR * Presence of weight loss >= 10% over the preceding 6 months; OR * Progressive lymphocytosis with an increase of >= 50% over a 2-month period or lymphocyte doubling time of < 6 months; OR * Evidence of progressive marrow failure as manifested by the development of or worsening of anemia and/or thrombocytopenia; OR * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids and another standard therapy such as rituximab; OR * Symptomatic or functional extranodal involvement
• Age >= 18 years (CLL is extremely rare in persons < 18 years of age)
• 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
• Total bilirubin =< 1.5 × ULN or =< 3 × ULN with documented liver involvement, hemolysis, and/or Gilbert’s disease
• Serum creatinine calculated creatinine clearance >= 30 ml/min/1.73m^2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or using 24-hour urine collection
• 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 transfusions within 7 days of screening assessment)
• Platelet count (PLT) >= 50 × 10^9/L (independent of transfusions within 7 days of screening assessment)
• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN
• Partial thromboplastin time (PTT) or activated PTT =< 1.5 x ULN
• 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 1 month after the last dose of study therapy. 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. 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

• Known or suspected Richter’s transformation or known central nervous system (CNS) involvement
• History of bleeding disorders (e.g. von Willebrand’s disease, hemophilia)
• History of stroke or intracranial hemorrhage within 6 months of starting study therapy
• Significant cardiovascular disease defined as: * Uncontrolled or symptomatic arrhythmia; OR ** Note: Patients with atrial fibrillation are allowed as long as 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 prior to study therapy; OR * Unstable angina or acute coronary syndrome including myocardial infarction within 3 months or study therapy
• 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. cyclosporine, tacrolimus, anti-CD20 monoclonal antibody) < 28 days of study therapy or administration of > 20 mg of prednisone or equivalent daily < 7 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 requiring intravenous antimicrobials at time of screening. 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
• History of severe allergic reactions to compounds of similar chemical or biological composition to pirtobrutinib. 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 human T cell leukemia virus (HTLV)
• 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) polymerase chain reaction (PCR). Patients with positive HBV DNA PCR will be excluded. Patients with negative HBsAg, positive anti-HBc and undetectable HBV DNA can be enrolled and will receive prophylaxis with entecavir to prevent HBV reactivation. HBV DNA should be monitored every three months during HBV prophylaxis * HCV: Patients with positive hepatitis C antibody require HCV ribonucleic acid (RNA) PCR. Patients with positive HCV RNA will be excluded
• Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
• Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug
• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
• 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