Umbralisib Plus Ublituximab (U2) in Progressive CLL After Novel Therapy
Condition: Chronic Lymphocytic Leukemia; CLL Progression; CLL/SLL
MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell; Disease Progression
Intervention: Umbralisib; Ublituximab
Intervention description: Lead-in cycle of 28 days (Cycle -1) of umbralisib monotherapy, 800mg oral daily
Continued 800mg oral daily dosing in all subsequent cycles (combination therapy cycles 1-6, then continued monotherapy cycle 7 and beyond); -Co-administered on days 1 and 2 (dose split over days 1 and 2), 8, 15 of cycle 1 then on day 1 for subsequent cycles 2-6
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CLL; progression

Summary:

      This study evaluates the efficacy and safety of umbralisib and ublituximab (U2) as salvage
      therapy in patients with chronic lymphocytic leukemia (CLL) who have progressed either on a
      BTK inhibitor (BTKi) or BCL-2 inhibitor. The study will evaluate this combination in two
      parallel cohorts and subjects will be assigned based on which class of novel agent-containing
      regimen was used prior. Cohort A will consist of patients who progress after BTKi containing
      regimens and Cohort B will consist of patients who progress after a BCL-2 containing regimen.
      Subjects who progress on a regimen containing both a BTKi and a BCL-2 inhibitor, will be
      enrolled in cohort B. Each cohort will be evaluated independently of each other.
    

Eligibility criteria:

        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.