A Study of Duvelisib in Combination With Rituximab and Bendamustine vs Placebo in Combination With Rituximab and Bendamustine in Subjects With Previously-Treated Indolent Non-Hodgkin Lymphoma (BRAVURA)

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of duvelisib in combination with bendamustine and rituximab (DBR) vs placebo in combination with bendamustine and rituximab (PBR) in subjects with previously-treated indolent non-Hodgkin lymphoma (iNHL).

Detailed Description
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Study IPI-145-22 is an international, multicenter, randomized, double-blind, placebo-controlled, two-arm Phase 3 study designed to evaluate efficacy and safety of DBR vs PBR in subjects with previously-treated iNHL (including follicular lymphoma [FL], small lymphocytic lymphoma [SLL] and marginal zone lymphoma [MZL]). Approximately 600 subjects will receive 25 mg of duvelisib or placebo, orally BID for 28 day continuous cycles, in combination with 375 mg/m2 of rituximab given on Day 1 of Cycles 1-6 and 90 mg/m2 of bendamustine given on Day 1 and Day 2 of Cycles 1-6. Subjects will receive duvelisib until disease progression or unacceptable toxicity.

Official Title
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A Phase 3, Randomized, Double-blind Study of Duvelisib Administered in Combination With Rituximab and Bendamustine vs Placebo Administered in Combination With Rituximab and Bendamustine in Subjects With Previously-Treated Indolent Non-Hodgkin Lymphoma

Conditions
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Indolent Non-Hodgkin's Lymphoma, Follicular Lymphoma, Small Lymphocytic Lymphoma, Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: Duvelisib
* Drug: Placebo
* Drug: Rituximab
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of iNHL with one of the following histologic sub-types and grade: Follicular lymphoma (FL)Grade 1, 2, or 3a Small lymphocytic lymphoma (SLL) Marginal zone lymphoma (MZL)( splenic, nodal, or extranodal) Have received the following systemic treatments for iNHL: an anti-CD20 antibody; and chemotherapy At least 1 measurable disease lesion > 1.5 cm in at least one dimension by computed tomography (CT)/CT-PET or magnetic resonance imaging (MRI) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (corresponds to Karnofsky Performance Status [(KPS) ≥60%]) Exclusion Criteria: Clinical evidence of transformation to a more aggressive subtype of lymphoma or grade 3B FL Refractory to bendamustine + rituximab therapy or single-agent bendamustine 120 mg/m2, with refractory defined as: - Progression of disease while receiving or within 6 months of completing treatment Severe allergic or anaphylactic reaction to any monoclonal antibody therapy, murine protein, or known hypersensitivity to any of the study drugs Received prior allogeneic transplant Received prior treatment with a phosphoinositide-3-kinase (PI3K) inhibitor Infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). History of tuberculosis treatment within the two years prior to randomization History of chronic liver disease, veno-occlusive disease, or alcohol abuse Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic steroids > 20 mg of prednisone (or equivalent) daily (QD) Ongoing treatment for systemic bacterial, fungal, or viral infection at screening Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster (VZV) at screening Concurrent active malignancy other than adequately treated non-melanoma skin cancer or lentigo maligna without evidence of invasive disease or adequately treated cervical carcinoma in situ without evidence of disease History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or a pacemaker within the last 6 months prior to screening History of progressive multifocal leukoencephalopathy

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duvelisib + Rituximab + Bendamustine<br>Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules. Bendamustine is administered as an intravenous (IV) infusion and is supplied for injection in single-use vials at two strengths, 25 mg and 100 mg. Rituximab is administered as an IV infusion and is supplied in single-use vials at two strengths, 100 mg and 500 mg. | Drug: Duvelisib<br>* Duvelisib (25 mg BID) administered orally in 28-day continuous treatment cycles<br>* Other names: IPI-145;Drug: Rituximab<br>* IV infusion of rituximab (375 mg/m2) on Day 1 of Cycles 1-6.<br>* Other names: MabThera;Drug: Bendamustine<br>* IV infusion of bendamustine (90 mg/m2) on Day 1 and Day 2 of Cycles 1-6.<br>* Other names: Levact;|
| Placebo Comparator: Placebo + Rituximab + Bendamustine<br>Placebo is administered orally and supplied as formulated capsules to match the active 5 mg and 25 mg capsules of duvelisib. Bendamustine is administered as an IV infusion and is supplied for injection in single-use vials at two strengths, 25 mg and 100 mg. Rituximab is administered as an IV infusion and is supplied in single-use vials at two strengths, 100 mg and 500 mg. | Drug: Placebo<br>* Matching placebo (25 mg BID) administered orally in 28-day continuous treatment cycles<br>Drug: Rituximab<br>* IV infusion of rituximab (375 mg/m2) on Day 1 of Cycles 1-6.<br>* Other names: MabThera;Drug: Bendamustine<br>* IV infusion of bendamustine (90 mg/m2) on Day 1 and Day 2 of Cycles 1-6.<br>* Other names: Levact;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) |  | From date of enrollment until the date of first documentation of progression or date of death from any cause, whatever came first, assessed up to 78 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CRR) |  | Every 3-6 Cycles (each cycle is 28 days) from date of randomization, until date of first documented progression. Subjects will be evaluated for progression through the primary analysis of the study or 5 years from randomization, whichever is later. | 
| Overall Response Rate (ORR) |  | Every 3-6 Cycles (each cycle is 28 days) from date of randomization, until date of first documented progression. Subjects will be evaluated for progression through the primary analysis of the study or 5 years from randomization, whichever is later. | 
| Overall Survival (OS) |  | Every 6 months for up to 5 years from date of randomization | 
| Duration of Response (DOR) |  | Every 3-6 Cycles (each cycle is 28 days) from date of randomization, until date of first documented progression. Subjects will be evaluated for progression through the primary analysis of the study or 5 years from randomization, whichever is later. | 
| Safety (Treatment- emergent adverse events (TEAEs) and changes in safety laboratory values) |  | Continuous from informed consent until 30 days from last dose | 
| Pharmacokinetics (PK) | Evaluate the Duvelisib concentration in plasma sample. | Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (PK) | Evaluate IPI-656 (metabolite) concentration in plasma sample. | Cycle 1 and Cycle 2 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 3, iNHL, Follicular Lymphoma, FL, PI3K, Small Lymphocytic Lymphoma, SLL, Marginal Zone Lymphoma, MZL