Umbralisib Plus Ublituximab (U2) in Progressive CLL After Novel Therapy

Inclusion Criteria: * confirmed diagnosis of CLL based upon 2018 International Workshop on CLL (IWCLL) criteria. * Patient must have progressed on a BTK or BCL-2 containing regimen as the prior line of therapy. Patients who were treated with a regimen containing both classes of novel agents will be allowed to enroll and will be enrolled into Cohort B. Patients who receive a temporizing non-experimental treatment such as an anti-CD20 monoclonal antibody, corticosteroid including high dose methylprednisolone after progression on a BTK or BCL-2 inhibitor will be considered for enrollment after discussion with the study sponsor. * Age ≥18 years * ECOG performance status ≤2 * Patient must have adequate bone marrow function and meet the below thresholds: * Absolute neutrophil count of ≥ 750 cell/μL in absence of G-CSF for 7 days prior to enrollment. * Platelet count of ≥ 30,000 cells/μL, or ≥ 20,000 cells/μL if there is bone marrow involvement) * Patient must have adequate organ function and meet the thresholds below: * Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Subjects with bilirubin exceeding this limit due to Gilbert's disease are eligible * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no liver involvement or ≤5 x the ULN if known liver involvement * Creatinine clearance \>30 ml/min/1.73m2 as calculated by the MDRD equation * Ability to swallow and retain oral medication. * Females who are not of child-bearing potential, and females of child-bearing potential (FCBP) who have a negative serum pregnancy test within 3 days prior to initial trial treatment. Males of reproductive potential may not participate unless they agree to use medically acceptable contraception. FCBP and all male partners, and male subjects must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last dose of study drug * Willingness and ability to comply with trial and follow-up procedures, and give written informed consent Exclusion Criteria: * Patient has had prior exposure to a PI3K inhibitor at any point in treatment history * Patient has discontinued the BTK or BCL2 inhibitor due to intolerance. Intolerance will be defined as discontinuing prior BTKi or BCL-2 therapy for any reason without evidence of progression. Patients who were re-challenged after discontinuation for therapeutic reasons will be allowed if the toxicity did not recur or was managed without indication for discontinuation. Patients who progress on BTKi or BCL-2 therapy who were on a reduced dose due to an AE/intolerance are eligible as long as progression has been documented on that reduced dose. * Patient has clinical or radiographic evidence of, or has biopsy proven Richter's transformation or prolymphocytic leukemia. * Patient has undergone an allogeneic stem cell transplant. * Patient has received an autologous hematologic stem cell transplant within 6 months of study entry. * Prior history of 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. * Patient is known to be positive for HIV. * Patient has history of hepatitis C infection, active infection with hepatitis B or active cytomegalovirus (CMV) as determined by PCR. * Patient has previous exposure to a BTK inhibitor therapy within 14 days of initiating study treatment on Cycle 1 Day 1, or previous exposure to anti-cancer therapy including chemotherapy, radiotherapy, or investigational therapy, including other targeted small molecule agents within 21 days of initiating study treatment on Cycle 1 Day 1. * Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails. * History of anaphylaxis (excluding infusion related reactions) in association with previous anti-CD20 administration. * Inflammatory bowel disease (such as Crohn's disease or ulcerative colitis). * Malabsorption syndromes. * Irritable bowel syndrome with greater than 3 loose stools per day as a baseline. * Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as: * Symptomatic, or history of documented congestive heart failure (New York Heart Association functional classification III-IV)\[see Appendix: NYHA Classifications\] * Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, CHF, or myocardial infarction within 6 months of enrollment. * 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 or vascular stenting within 6 months of enrollment. * Females who are pregnant or lactating.