Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Condition: Small Lymphocytic Leukemia (SLL); Chronic Lymphocytic Leukemia (CLL)
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Duvelisib; Ibrutinib
Intervention description: twice daily as tolerated until disease progression; daily for the first six 28-day cycles
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: P13K Inhibitor; PLCG2 Mutations; BTK Mutations; Myeloid Cells and Myeloid Derived Suppressor Cells (MDSCs); T and Leukemic B Cells Aggregate

Summary:

      Background:

      Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers often
      treated with the drug ibrutinib. For some people, ibrutinib stops working. Researchers want
      to see if adding another drug can help.

      Objective:

      To test how people with ibrutinib-resistant CLL respond to duvelisib.

      Eligibility:

      People ages 18 and older with CLL or SLL that is no longer responding to ibrutinib or has
      developed mutations that could stop it from working

      Design:

      Participants will be screened with:

        -  Medical history

        -  Physical exam

        -  Heart tests

        -  Blood and urine tests

        -  CT scan. For this, participants will have a dye injected into a vein. They will lie in a
           machine that takes pictures of the body.

        -  Bone marrow biopsy. For this, a needle injected into the participant s bone will remove
           marrow.

        -  Optional lymph node biopsy. For this, the participants whole lymph node or part of it
           will be removed through the skin.

        -  Optional lymphapheresis. For this, the participants blood is removed through a vein in
           one arm, the white blood cells separated out, and the blood returned through a vein in
           the other arm.

      Participants will take duvelisib twice daily by mouth. They will continue ibrutinib at their
      current dose for the first 6 months. They will continue to take duvelisib until their CLL/SLL
      stops responding or they develop intolerable side effects.

      Participants will take an antibiotic and antiviral medication. They may take steroids.

      Participants will have blood tests every 2 weeks during the first 2 months.

      Participants will have monthly follow-up visits during the first 6 months and every 3 months
      thereafter. These will include repeats of some of the screening tests.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Age greater than or equal to 18 years

          -  Diagnosis of CLL or SLL as defined by the following:

               -  CLL: clonal B cells greater than or equal to 5,000 cells/uL in the peripheral
                  blood.

               -  SLL: lymphadenopathy with histopathological evaluation consistent with SLL,
                  absence of cytopenia caused by clonal marrow infiltrate, and <5,000 B cells/uL in
                  the peripheral blood

               -  Immunophenotype: co-expression of CD5, CD19, CD20, and CD23. CD23 negative cases
                  may be included if there is an absence of t(11;14).

          -  Current treatment with ibrutinib for CLL.

          -  Mutations in BTK and/or PLCG2 (from a Clinical Laboratory Improvement Amendments
             (CLIA)-certified laboratory) with measurable disease characterized by at least 1 of
             the following:

               -  Lymphadenopathy: greater than or equal to 1 lymph node measuring greater than or
                  equal to 1.5 cm in the greatest diameter

               -  Splenomegaly: spleen measuring > 13 cm in craniocaudal length

               -  Lymphocytosis: greater than or equal to 5,000 B cells/ L

               -  Bone marrow infiltration: CLL comprising greater than or equal to 30% of all
                  cells

        or

        Progressive disease characterized by at least 1 of the following when compared with nadir
        values:

          -  Lymphadenopathy: appearance of any new enlarged lymph nodes (greater than or equal to
             1.5 cm) or an increase by greater than or equal to 50% in greatest determined diameter
             of any previous site (greater than or equal to 1.5 cm).

          -  Splenomegaly: an increase in the cranio-caudal dimension of the spleen by greater than
             or equal to 2 cm from nadir, on imaging or physical exam.

          -  Lymphocytosis: an increase in the number of blood lymphocytes by greater than or equal
             to 50% over nadir with greater than or equal to 5,000 cells/uL B cells not
             attributable to redistribution of leukemia cells from lymphoid tissues to the blood
             related to treatment with kinase inhibitor.

          -  Cytopenia: occurrence of cytopenia directly attributable to CLL and unrelated to
             autoimmune cytopenia or treatment, as documented by a decrease of Hb levels greater
             than or equal to 2 g/dL or <10 g/dL, or by a decrease of platelet counts greater than
             or equal to 50% or <100,000/uL, if the marrow biopsy is consistent with the cytopenia
             resulting from increased marrow infiltration of clonal CLL cells.

               -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or
                  equal to 2.

               -  Adequate organ function as defined below

        Hematological:

          -  Absolute neutrophil count (ANC) greater than or equal to 1000/uL

          -  Platelets greater than or equal to 75,000/uL

        Renal:

        -Serum creatinine < 2.0 mg/dL

        Hepatic:

          -  Serum total bilirubin less than or equal to 1.5 X ULN except subjects with Gilbert's
             Syndrome

          -  AST (SGOT) and ALT (SGPT) less than or equal to 3.0 X ULN

          -  For women of childbearing potential (WCBP): negative serum beta human chorionic
             gonadotropin (beta-hCG) pregnancy test within 7 days before first treatment (WCBP
             defined as a sexually mature woman who has not undergone surgical sterilization or who
             has not been naturally postmenopausal for at least 12 consecutive months for women >55
             years of age)

          -  Willingness of male and female subjects who are not surgically sterile or
             postmenopausal to use medically acceptable methods of birth control for the duration
             of the study treatment and 3 months after the last dose of duvelisib

          -  Willingness and ability to participate in all required evaluations and procedures in
             this study protocol including swallowing capsules without difficulty

          -  Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent and authorization to use protected health information (in accordance
             with national and local subject privacy regulations)

        EXCLUSION CRITERIA:

          -  Richter transformation of CLL into an aggressive lymphoma

          -  History or concurrent condition of interstitial lung disease of any severity and/or
             severely impaired lung function

          -  Prior history of drug-induced colitis or pneumonitis

          -  Known hypersensitivity to any of the study drugs

          -  Major surgery within 4 weeks prior to screening

          -  Central nervous system (CNS) non-Hodgkin lymphoma (NHL); lumbar puncture not required
             unless CNS involvement is clinically suspected

          -  Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., subjects
             with detectable viral load)

          -  Infection with hepatitis B or hepatitis C:

               -  Subjects with a positive hepatitis B surface antigen (HBsAg)) will be excluded

               -  Subjects with or hepatitis C antibody (HCV Ab) will be excluded, unless they have
                  received curative treatment for hepatitis C virus (HCV) and have undetectable
                  viral RNA by PCR.

               -  Subjects with a positive hepatitis B core antibody (HBcAb) must have negative
                  hepatitis B virus (HBV) deoxyribonucleic acid (DNA) to be eligible, must receive
                  prophylaxis with entecavir (or equivalent) concomitant with duvelisib treatment,
                  and must be periodically monitored for HBV reactivation by institutional
                  guidelines

          -  Investigators who strongly believe that a positive HBcAb is false due to passive
             immunization from previous immunoglobulin infusion therapy should consider the
             risk-benefit for the patient given the potential for reactivation

          -  Infection with human immunodeficiency virus (HIV): Subjects must be receiving
             antiretroviral therapy, have undetectable HIV RNA viral load and CD4 cell count
             greater than or equal to 200/uL to be eligible, must continue antiretroviral therapy
             concomitant with duvelisib treatment, and must be periodically monitored for
             suppression of viral load and potential drug-drug interactions between antiretroviral
             therapy and duvelisib

          -  Infection with human T-lymphotropic virus type 1

          -  History of tuberculosis treatment within the 2 years prior to randomization

          -  History of chronic liver disease, veno-occlusive disease, alcohol abuse, or illicit
             drug use

          -  Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic
             steroids >20 mg of prednisone (or equivalent) once daily (QD)

          -  Ongoing treatment for systemic bacterial, fungal, or viral infection at screening

        NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically
        excluded if all other inclusion/exclusion criteria are met

          -  Administration of a live or live attenuated vaccine within 6 weeks of randomization

          -  Concurrent administration of medications or foods that are strong inhibitors or
             inducers of cytochrome P450 3A (CYP3A). No prior use within 2 weeks before the start
             of study intervention.

          -  Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV),
             or herpes zoster (VZV) at screening

          -  Baseline left ventricular ejection fraction (LVEF) < 45 percent

          -  Baseline QT interval corrected with Fridericia's method (QTcF) > 500 ms

        NOTE: criterion does not apply to subjects with a right or left bundle branch block (BBB)

          -  Subjects with clinically significant medical condition of malabsorption, inflammatory
             bowel disease, chronic conditions which manifest with diarrhea, refractory nausea,
             vomiting, or any other condition that will interfere significantly with drug
             absorption

          -  Female subjects who are pregnant or breastfeeding

          -  Concurrent active malignancy that requires treatment except malignancies treated with
             antihormonal therapy alone, nonmelanoma skin cancer, or carcinoma in situ of the
             cervix.

          -  History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia
             requiring medication or a pacemaker within the last 6 months prior to screening

          -  Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function,
             unstable pulmonary condition, uncontrolled diabetes and inflammatory GI diseases such
             as Crohn s Disease) or any important medical illness or abnormal laboratory finding
             that would, in the investigator's judgment, increase the risk to the subject
             associated with his or her participation in the study