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

Phase 2

Terminated

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

Interventions: Drug: Duvelisib
Drug: Ibrutinib

Registration Number: NCT04209621

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

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.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma	Duvelisib	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.
Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma	Ibrutinib	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.

Primary Outcome Measures

Name	Time	Method
Participant Overall Response Rate (ORR)	After 12 weeks	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%

Secondary Outcome Measures

Name	Time	Method
Participant Overall Survival	From Day 1 to death from any cause, which ever came first, assessed up to approximately 6 months	Participant overall survival as defined as time from treatment initiation to death from any cause
Duration of Response in Days	From initial response [12 weeks or later] to progression of disease	Duration of response in days as defined as time from initial response to progression of disease.
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	Number of participants with progression-free survival as defined as time from treatment initiation to progression of disease or death from any cause.
Number of Participants Who Achieved Best Response	After greater than or equal to 3 cycles [12 weeks] of treatment, up to 6 months	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%
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	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.