Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL

Inclusion Criteria: * Confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) per International Workshop on CLL (iwCLL) 2018 criteria.1 * Participants must have an indication for treatment as defined by iwCLL 2018 criteria.1 * Participants must have measurable disease, defined as lymphocytosis \> 5,000 / μL, or palpable or CT measurable lymphadenopathy ≥ 1.5 cm, or bone marrow involvement ≥ 30%. * For enrollment to Cohort 1: Participants must have relapsed or refractory disease as per iwCLL 2018 criteria,1 and must have received no more than 2 prior lines of anti-cancer therapy. * For enrollment to Cohort 2: Participants must have previously untreated disease (i.e. must not have received any prior systemic therapy for CLL or SLL). * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of umbralisib, acalabrutinib, and ublituximab in participants \< 18 years of age and CLL is extremely rare in this population, children are excluded from this study. * ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A). * Participants must have adequate organ and marrow function as defined below: * Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (unless due to hemolysis or Gilbert's disease, in which ≤ 3 × institutional ULN is acceptable) * AST (SGOT) and ALT (SGPT) ≤ 2.5 × institutional ULN, OR * AST (SGOT) and ALT (SGPT) ≤ 5 × institutional ULN if there is hemolysis or documented disease involvement in the liver * Calculated creatinine clearance ≥ 30 mL/min (as calculated by the Cockcroft-Gault formula) * Platelet count ≥ 50,000/mcL, unless there is bone marrow involvement with disease * PT-INR or aPTT ≤ 2 × institutional ULN * Absolute neutrophil count (ANC) ≥ 750 mm3 * Hemoglobin (Hgb) \> 8 g/dL * Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. * The effects of umbralisib, acalabrutinib, or ublituximab on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use highly effective methods of contraception. 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. Men and women treated on this protocol must agree to use highly effective contraception prior to the study, for the duration of study participation, and 4 months after completion of umbralisib, acalabrutinib, or ublituximab administration. * Ability to understand and the willingness to sign a written informed consent document. * Ability to swallow and retain oral medication. * Participants must be able to receive prophylactic anti-pneumocystis jiroveci pneumonia (PJP) and anti-viral therapy Exclusion Criteria: * Participants with progressive or refractory disease while receiving either a BTK inhibitor or PI3K inhibitor. Prior exposure to either a BTK inhibitor, PI3K inhibitor, or both is acceptable as long as the participant's disease did not progress during active therapy with the agent(s). * Participants who have undergone a major surgical procedure within 28 days of the first dose of study drug. If a participant had major surgery greater than 28 days prior to the first dose of study drug, they must have recovered adequately from any adverse event and/or complications from the intervention prior to the first dose (as judged by the treating investigator). For enrollment to Cohort 1: receipt of prior BTK inhibitor treatment within 7 days, or any other anti-cancer therapy (e.g. chemotherapy, immunotherapy, radiation, biologic therapy or any investigational agent) within 21 days of the first dose of study drug. * Participants who are receiving any other investigational agents. * History of prior allogeneic stem cell transplant. * History of autologous hematologic stem cell transplant within 6 months of the first dose of study drug. * Participants with known Richter's transformation, or histological transformation from CLL to large cell lymphoma. * Participants with known CNS involvement, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with no known history of CNS leukemia are not required to undergo CT scan or lumbar puncture (LP) for trial eligibility unless the participant is symptomatic as judged by the treating investigator. * Participants with uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). * Participants with active clinically significant bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease). * Participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (other anticoagulants are permitted). * Participants with a history of significant cerebrovascular disease/event within 6 months before the first dose of study drug, including stroke or intracranial hemorrhage. * Participants with uncontrolled intercurrent illness, including but not limited to: unstable angina pectoris, cardiac arrhythmia, or poorly controlled and clinically significant atherosclerotic vascular disease (including patients who required angioplasty, cardiac or vascular stenting within 6 months prior to the first dose of study agent), myocardial infarction within 6 months of screening, congestive heart failure, or patients with Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Note: participants with controlled, asymptomatic atrial fibrillation are permitted to enroll on study. Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion. * Individuals with a history of a different malignancy are ineligible with the following exceptions: individuals who have been treated and are disease-free for a minimum of 2 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence. Additionally, individuals with the following cancers are eligible if diagnosed and curatively treated within the past 2 years: basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ. Prostate cancer on observation, with stable PSA for 6 months, is also eligible. * Participants who require ongoing immunosuppressive therapy including systemic corticosteroids (prednisone or equivalent ≤ 10 mg daily is permitted). Topical, inhaled, and ophthalmologic steroids are permitted. * Participants with a history of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis). * Participants with irritable bowel syndrome (IBS) with greater than 3 loose stools per day at baseline. * Participants with evidence of ongoing systemic bacterial, fungal, or viral infection, except localized fungal infections of the skin or nails. NOTE: participants may be receiving prophylactic antiviral or antibacterial therapies at the treating investigator's discretion. Use of anti-pneumocystis and antiviral prophylaxis is required. * Participants with a known history of progressive multifocal leukoencephalopathy (PML). * Participants with evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B vaccination or positive serum Hepatitis B antibody), chronic active Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of human immunodeficiency virus (HIV): * If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA by PCR (see Appendix B). Subjects with positive HBc antibody and negative HBV DNA by PCR are eligible but serial monitoring of HBV DNA by PCR is required, see Section 5.4. Subjects with positive HBV DNA by PCR are not eligible. * Participants with positive HBsAg are to be excluded. * If HCV antibody is positive, the subject must be evaluated for the presence of HCV RNA by PCR. Subjects with positive HCV antibody and negative HCV RNA by PCR are eligible. Subjects with positive HCV RNA by PCR are not eligible. * If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence of CMV DNA by PCR. Subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by PCR are eligible, anti-viral prophylaxis should be considered per treating investigator discretion. * History of allergic reactions attributed to study drugs including active product or excipients, or compounds of similar chemical or biologic composition to acalabrutinib, umbralisib, or ublituximab, including participants with a history of anaphylaxis (excluding infusion-related reactions) in association with previous anti-CD20 administration. * Participants requiring concomitant treatment with any medications or substances that are strong inhibitors or inducers of CYP3A4 at the time of study enrollment. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product. * Participants requiring concomitant treatment with proton pump inhibitors (e.g.omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) at the time of study enrollment. Note: participants receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids prior to the first dose of study medication are eligible. * Participants with psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study because acalabrutinib, umbralisib, and ublituximab are anti-cancer agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with acalabrutinib, umbralisib, or ublituximab, breastfeeding must be discontinued prior to the initiation of study treatment. A negative serum pregnancy test is required for women of childbearing potential within 3 days prior to Cycle 1 Day 1.