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:
  • 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), 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 (as long as initial ALC was ≥ 30,000/μL); 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/mm3 (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 30 days 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 therapy started at least 7 days prior to Cycle 1, Day 1 (prednisone ≤ 10 mg daily or equivalent) is allowed as clinically warranted. Topical or inhaled corticosteroids are permitted.
• Autologous hematologic stem cell transplant within 6 months of study entry. Prior allogeneic hematologic stem cell transplant is excluded.
• Evidence of chronic active Hepatitis B (HBV, not including subjects with prior hepatitis B vaccination; or positive surface Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), cytomegalovirus (CMV), or known history of HIV. Subjects with positive HBc antibody or HCV antibody are eligible only if PCR is negative for HBV DNA or HCV RNA. Antiviral prophylaxis for HBV reactivation should be considered for HBc antibody positive subjects at investigator discretion.
• Known histological transformation from CLL to an aggressive lymphoma such as Richter’s Transformation. Prolymphocytic leukemia is also excluded.
• History of CLL with CNS involvement.
• Prior exposure to any PI3K inhibitor (e.g. idelalisib, duvelisib, umbralisib (TGR-1202), etc.) or venetoclax (ABT-199, GDC-0199).
• Inability to swallow and retain oral medications.
• No 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 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 (NY Heart Association functional classification III-IV);
  • 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-gp inhibitors, or narrow therapeutic index P-gp substrates.
• Malignancy within 3 years of study enrollment except for adequately treated basal, squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized prostate cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the most recent one being within 4 weeks of study entry.
• Women who are pregnant or lactating.