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

NCT04209621 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 20001620-H-0016
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Small Lymphocytic Leukemia (SLL); Chronic Lymphocytic Leukemia (CLL)

Keywords

P13K Inhibitor; PLCG2 Mutations; BTK Mutations; Myeloid Cells and Myeloid Derived Suppressor Cells (MDSCs); T and Leukemic B Cells Aggregate

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Number of Participants With Progression-free Survival

  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

  From Day 1 to death from any cause, which ever came first, assessed up to approximately 6 months

• Duration of Response in Days

  From initial response [12 weeks or later] to progression of disease

• Number of Participants Who Achieved Best Response

  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

  From time of informed consent to 30 days after last dose of duvelisib plus ibrutinib combination

Study Arms (1)

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

OTHER

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; Drug: Ibrutinib

Interventions

Duvelisib DRUG

twice daily as tolerated until disease progression

Also known as: Copiktra

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

Ibrutinib DRUG

daily for the first six 28-day cycles

Also known as: Imbruvica

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

duvelisib; ibrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Sun, Clare, M.D. Principal Investigator, NIH, NHLBI
• Organization: National Institutes of Health (NIH) / The National Heart, Lung, and Blood Institute (NHLBI)

clare.sun@nih.gov

301.402.1806

Study Officials

• Clare C Sun, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Clinician

Study Record Dates

• First Submitted: December 21, 2019
• First Posted: December 24, 2019
• Study Start: July 31, 2020
• Primary Completion: January 22, 2021
• Study Completion: January 22, 2021
• Last Updated: March 9, 2022
• Results First Posted: March 9, 2022

Record last verified: 2022-02

Locations

US (1)