Inclusion Criteria: 

• B-cell CLL that warrants treatment consistent with iwCLL 2018 criteria for initiation of therapy with diagnosis established according to iwCLL 2018 criteria and documented within medical records. At least one of the following criteria must be met:
  • Evidence of progressive marrow failure as manifested by the onset or worsening of anemia and/or thrombocytopenia;
  • Massive (i.e., lower edge of spleen ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
  • Massive (i.e., ≥ 10 cm in the longest diameter) or progressive or symptomatic lymphadenopathy; or
  • Progressive lymphocytosis in the absence of infection, with an increase in blood absolute lymphocyte count (ALC) > 50% over a 2-month period or lymphocyte doubling time of < 6 months; or
  • Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs occurring in the absence of evidence of infection:
    • Unintentional weight loss of ≥ 10% within the previous 6 months; or
    • Significant fatigue (≥ Grade 2); or
    • Fevers > 100.5°F or 38.0°C for ≥ 2 weeks; or
    • Night sweats for > 1 month.
• Adequate organ system function, independent of growth factor or transfusion support, defined as follows:
  • Absolute neutrophil count (ANC) > 750/mm^3 (μL) / platelet count > 40,000/mm^3 (μL);
  • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome with bilirubin > 1.5 × ULN allowed per discussion with the Medical Monitor;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN if no liver involvement or ≤ 5 x the ULN if known liver involvement;
  • Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault formula).
• ECOG performance status ≤ 2.
• Male or female ≥ 18 years of age.
• Ability to swallow and retain oral medication.
• Female subjects who are not of child-bearing potential, and female subjects of child-bearing potential who have a negative serum pregnancy test within 3 days prior to Cycle 1, Day 1.  Female subjects of child-bearing potential, and male partners must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last dose of ublituximab or umbralisib or venetoclax. Men of reproductive potential may not participate unless they agree to use medically acceptable contraception.
• Willingness and ability to comply with trial and follow-up procedures and provide written informed consent.

Exclusion Criteria: 

• Subjects receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational drug within 21 days of Cycle 1, Day 1 (within 7 days of Cycle 1, Day 1 for prior BTK inhibitor):
  • Corticosteroid use within 1 week prior to first dose of study drug are excluded, with the exception of steroid use for adrenal replacement, inhaled steroid for asthma, topical steroid use or other locally administered corticosteroids. Patients requiring systemic steroids for leukemia control or white blood cell (WBC)-count lowering are excluded.
• Autologous hematologic stem cell transplant within 6 months of study entry.
• Prior allogeneic hematologic stem cell transplant.
• Evidence of chronic active Hepatitis B (HBV) infection as evidenced by a detectable hepatitis B surface antigen (HBsAg) (not including subjects with prior hepatitis B vaccination) or chronic Hepatitis C infection (HCV), cytomegalovirus (CMV), or known history of human immunodeficiency virus (HIV). Subjects with positive hepatitis B core antibody (HBc Ab) or hepatitis C virus antibody (HCV AB) or positive CMV by IgM or IgC are eligible only if PCR is negative for HBV DNA, HCV RNA or CMV.
• Known histological transformation from CLL to an aggressive lymphoma (e.g., Richter’s Transformation, prolymphocytic leukemia or DLBCL).
• History of CNS involvement with CLL.
• Prior exposure to any PI3K inhibitor (e.g. idelalisib, duvelisib, umbralisib (TGR-1202), etc.) or venetoclax (ABT-199, GDC-0199).
• Known barriers to commercially available venetoclax.
• Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails.
• Live virus vaccines within 4 weeks prior to or during study therapy.
• History of anaphylaxis (excluding infusion related reactions) in association with previous anti-CD20 monoclonal antibody administration.
• Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
  • Symptomatic, or history of documented congestive heart failure (New York Heart Association[NYHA] functional classification III-IV). Class 3 is defined as cardiac disease in which patients are comfortable at rest but marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain;
  • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of randomization;
  • Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion;
  • Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac/vascular stenting within 6 months of randomization.
• Requirement for use of strong or moderate CYP3A inhibitors, strong or moderate CYP3A inducers, P-glycoprotein(P-gp) inhibitors, or narrow therapeutic index P-gp substrates.
• Malignancy within three years of study enrollment except for adequately treated basal, squamous cell carcinoma or in situ carcinomas, superficial bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, or localized prostate cancer with a PSA <1.0 mg/dL on two consecutive measurements at least three months apart with the most recent one being within four weeks of study entry.
• Women who are pregnant or lactating.