Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
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 participant s whole lymph node or part of it
 will be removed through the skin.

 -  Optional lymphapheresis. For this, the participant s 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.
Background:

 -  In chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), ibrutinib
 resistance is predominantly caused by somatic mutations in BTK and PLCG2. Virtually all
 patients with detectable mutations eventually develop progressive disease. Patients who
 discontinue ibrutinib often have rapidly progressive disease that can be difficult to
 control. These observations suggest that BTK inhibitors still exert at least a partial
 anti-tumor effect. Outcomes after ibrutinib discontinuation are poor. Early detection of
 BTK and PLCG2 mutations represents an opportunity for preemptive intervention to
 eliminate the resistant clone.

 -  Duvelisib is a dual PI3K-gamma and zeta inhibitor. Duvelisib monotherapy improved
 progression-free survival and overall response rate compared to ofatumumab and had a
 manageable safety profile in subjects with previously treated CLL/SLL. Based on these
 results, duvelisib received US approval for CLL/SLL after at least 2 prior therapies.

 -  This study will assess duvelisib in patients who develop disease progression or BTK
 and/or PLCG2 mutations on ibrutinib. Duvelisib will overlap with ibrutinib for the first
 six 28-day cycles to prevent disease acceleration often seen in patients who discontinue
 ibrutinib.

 Primary Objective:

 -To investigate the rate of overall response to duvelisib in patients with
 ibrutinib-resistant CLL.

 Key Eligibility Criteria:

 -  Patients on current treatment for CLL/SLL with ibrutinib and at least one of the
 following:

 -  BTK and/or PLCG2 mutations

 -  Progressive CLL per iwCLL guidelines

 -  Patients with known Richter transformation will be excluded.

 Design:

 -  This is a single-center, single-arm, open-label phase 2 study with a safety lead-in
 cohort.

 -  Treatment plan: Duvelisib will be administered with ibrutinib for the first six28-day
 cycles then

 duvelisib monotherapy will be administered continuously until disease progression or
 intolerance.

 Study Duration: 5 years.

 Participant Duration: until disease progression or intolerance.
-  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 antiretrovial
 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