Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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 delta 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 CLL 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 six 28-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.

Official Title
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Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Conditions
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Small Lymphocytic Leukemia (SLL), Chronic Lymphocytic Leukemia (CLL)

Intervention / Treatment
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* Drug: Duvelisib
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma<br>Duvelisib with ibrutinib will be administered for the first six 28-day (± 7) cycles followed by duvelisib alone until disease progression or intolerance. Duvelisib is an orally administered at 15 mg twice a day (dose level 1) or 25 mg twice day (dose level 2). Subjects will continue the same dose of ibrutinib prior to study enrollment for the first six 28-day cycles. Ibrutinib is an orally administered and provided as 140 mg white opaque capsules or tablets in 4 strengths: 140 mg, 280 mg, 420 mg, and 560 mg. | Drug: Duvelisib<br>* twice daily as tolerated until disease progression<br>* Other names: Copiktra;Drug: Ibrutinib<br>* daily for the first six 28-day cycles<br>* Other names: Imbruvica;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Overall Response Rate (ORR) | Overall response rate with modification for treatment-related lymphocytosis. Response is defined below and followed iwCLL 2008 guidelines and incorporated clarifications for lymphocytosis associated with kinase inhibitors. Complete Response: Lymph Nodes = None greater or equal to 1.5 cm; Spleen &/or liver size = Spleen less than 13 cm &/or liver size normal; Blood Lymphocytes = less than 4000/μL. Partial Response: Lymph Nodes, Spleen and/or liver size, plus Blood Lymphocytes = Decrease greater than or equal to 50%. Partial Remission with Lymphocytosis: Lymph Nodes and Spleen and/or liver size = Decrease greater than or equal to 50%; Blood Lymphocytes = Increase or decrease greater than 50%. Progressive Disease: Lymph Nodes = Increase ≥ 50% or any new lesion > 1.5 cm; Spleen and/or liver size = Increase ≥ 50% or new splenomegaly; Blood Lymphocytes = Increase ≥ 50% and > 5000/μL B cells. Stable Disease: Lymph Nodes, Spleen and/or liver size plus Blood Lymphocytes =Change of -49% to +49% | After 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression-free Survival | Number of participants with progression-free survival as defined as time from treatment initiation to progression of disease or death from any cause. | From Day 1 to progression of disease or death from any cause, which ever came first, assessed up to approximately 6 months | 
| Participant Overall Survival | Participant overall survival as defined as time from treatment initiation to death from any cause | From Day 1 to death from any cause, which ever came first, assessed up to approximately 6 months | 
| Duration of Response in Days | Duration of response in days as defined as time from initial response to progression of disease. | From initial response [12 weeks or later] to progression of disease | 
| Number of Participants Who Achieved Best Response | Number of participants who achieved best response [complete response is better than partial response is better than stable disease]. Complete Response: Lymph Nodes = None greater or equal to 1.5 cm; Spleen &/or liver size = Spleen less than 13 cm &/or liver size normal; Blood Lymphocytes = less than 4000/μL. Partial Response: Lymph Nodes, Spleen and/or liver size, plus Blood Lymphocytes = Decrease greater than or equal to 50%. Partial Remission with Lymphocytosis: Lymph Nodes and Spleen and/or liver size = Decrease greater than or equal to 50%; Blood Lymphocytes = Increase or decrease greater than 50%. Progressive Disease: Lymph Nodes = Increase ≥ 50% or any new lesion > 1.5 cm; Spleen and/or liver size = Increase ≥ 50% or new splenomegaly; Blood Lymphocytes = Increase ≥ 50% and > 5000/μL B cells. Stable Disease: Lymph Nodes, Spleen and/or liver size plus Blood Lymphocytes =Change of -49% to +49% | After greater than or equal to 3 cycles [12 weeks] of treatment, up to 6 months | 
| Safety of Duvelisib Plus Ibrutinib Combination and Duvelisib Monotherapy | Safety as defined by number of dose limiting toxicities during first cycle of duvelisib plus ibrutinib combination and serious adverse events while participants are taking duvelisib plus ibrutinib combination followed by duvelisib monotherapy. | From time of informed consent to 30 days after last dose of duvelisib plus ibrutinib combination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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P13K Inhibitor, PLCG2 Mutations, BTK Mutations, Myeloid Cells and Myeloid Derived Suppressor Cells (MDSCs), T and Leukemic B Cells Aggregate