A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL

Study Overview
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Brief Summary
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To compare efficacy between zanubrutinib versus bendamustine and rituximab in patients with previously untreated CLL/SLL, as measured by progression free survival assess by Independent Central Review.

Detailed Description
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This is a global phase 3, open label, randomized study of zanubrutinib versus bendamustine plus rituximab (B+R) in participants with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), including participants without del(17p) [Cohort 1] and participants with del(17p) [Cohort 2 and Cohort 3]. Participants in Cohort 1 are randomized 1:1 to zanubrutinib (Arm A) or bendamustine plus rituximab (Arm B). Randomization will be stratified by age, Binet stage, immunoglobulin variable region heavy chain (IGHV) mutational status, and geographic region. Participants in Cohort 2 will receive treatment with zanubrutinib. Participants in Cohort 3 will receive treatment with zanubrutinib and venetoclax.

Official Title
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An International, Phase 3, Open-Label, Randomized Study of BGB-3111 Compared With Bendamustine Plus Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Zanubrutinib
* Drug: Bendamustine
* Drug: Rituximab
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) Confirmed diagnosis of CD20-positive CLL or SLL, requiring treatment Measurable disease by imaging Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Life expectancy ≥ 6 months Adequate bone marrow function Adequate renal and hepatic function Key Exclusion Criteria: Previous systemic treatment for CLL/SLL Requires ongoing need for corticosteroid treatment Known prolymphocytic leukemia or history of or suspected Richter's transformation. Clinically significant cardiovascular disease Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix of breast, or localized Gleason score 6 prostate cancer History of severe bleeding disorder History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug Severe or debilitating pulmonary disease Inability to swallow capsules or disease affecting gastrointestinal function Active infection requiring systemic treatment Known central nervous system involvement by leukemia or lymphoma Underlying medical condition that will render the administration of study drug hazardous or obscure interpretation of toxicity or AEs Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C infection Major surgery ≤ 4 weeks prior to start of study treatment Pregnant or nursing females Vaccination with live vaccine within 35 days prior to the first dose of study drug. Ongoing alcohol or drug addiction Known hypersensitivity to zanubrutinib, bendamustine, rituximab, or venetoclax (as applicable) or any other ingredients of the study drugs Requires ongoing treatment with strong cytochrome P450 (CYP3A) inhibitor or inducer Concurrent participation in another therapeutic clinical study NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Bendamustine + Rituximab<br>Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B) | Drug: Bendamustine<br>* Administered intravenously (IV) at a dose of 90 mg/m^2/day on the first 2 days of each cycle for 6 cycles.<br>* Other names: Treanda, Ribomustin, and Levact;Drug: Rituximab<br>* Administered intravenously (IV) at a dose of 375 mg/m^2 on day 0 of cycle 1, and at a dose of 500 mg/m^2 on day 1 of cycles 2 to 6<br>* Other names: Rituxan, MabThera;|
| Experimental: Cohort 1: Zanubrutinib<br>Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A) | Drug: Zanubrutinib<br>* Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)<br>* Other names: BRUKINSA;|
| Experimental: Cohort 1a (China only): Bendamustine + Rituximab<br>Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only) | Drug: Bendamustine<br>* Administered intravenously (IV) at a dose of 90 mg/m^2/day on the first 2 days of each cycle for 6 cycles.<br>* Other names: Treanda, Ribomustin, and Levact;Drug: Rituximab<br>* Administered intravenously (IV) at a dose of 375 mg/m^2 on day 0 of cycle 1, and at a dose of 500 mg/m^2 on day 1 of cycles 2 to 6<br>* Other names: Rituxan, MabThera;|
| Experimental: Cohort 1a (China only): Zanubrutinib<br>Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only) | Drug: Zanubrutinib<br>* Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)<br>* Other names: BRUKINSA;|
| Experimental: Cohort 2: Zanubrutinib<br>Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C) | Drug: Zanubrutinib<br>* Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)<br>* Other names: BRUKINSA;|
| Experimental: Cohort 3: Venetoclax + Zanubrutinib<br>Approximately 110 participants, 50 without del17p and 60 with del[17p] or TP53 mutation will receive zanubrutinib plus venetoclax; Participants will also receive zanubrutinib starting on Cycle 1 Day 1 then daily for a minimum of 27 cycles, or until unacceptable toxicity or disease progression, whichever occurs first. Participants will receive venetoclax starting Cycle 4 Day 1 according to a 5-week dose-up schedule then daily until unacceptable toxicity, disease progression, or for a maximum of 24 cycles. Each cycle is 28 days. (Arm D) | Drug: Zanubrutinib<br>* Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)<br>* Other names: BRUKINSA;Drug: Venetoclax<br>* 400 mg tablets administered orally once daily.<br>* Other names: Venclexta, Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR) | PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the ICR per 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with small lymphocytic lymphoma (SLL). | Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR | ORR in Cohort 1 is defined as the percentage of participants who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by the ICR. | Up to 5 years | 
| Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups |  | Up to 5 years | 
| Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR | OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason. | Up to 5 years | 
| Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR | Duration of response in Cohort 1 determined using the iwCLL criteria with modification for treatment related lymphocytosis (in participants with CLL) and the Lugano Classification for non-Hodgkin lymphoma (NHL; in participants with SLL), is defined as the time from the date that criteria for response (ie, partial response with lymphocytosis [PR-L] or better) are first met to the date that disease progression is objectively documented or death, whichever occurs first. | Up to 5 years | 
| Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups |  | Up to 5 years | 
| Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) | PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the investigator per iwCLL guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL. | Up to 5 years | 
| Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) |  | Up to 5 years | 
| Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire |  | Up to 5 years | 
| Cohort 1: Patient-reported Outcomes as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Questionnaire. |  | Up to 5 years | 
| Cohort 2: Overall Response Rate (ORR) |  | Up to 5 years | 
| Cohort 2: Progression-free Survival (PFS) |  | Up to 5 years | 
| Cohort 2: Duration of Response (DOR) |  | Up to 5 years | 
| Cohort 3: Overall Response Rate (ORR) |  | Up to 5 years | 
| Cohort 3: Progression-free Survival (PFS) |  | Up to 5 years | 
| Cohort 3: Duration of Response (DOR) |  | Up to 5 years | 
| Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4) |  | Up to 5 years | 
| Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Up to 5 years | 
| Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F |  | Predose up to 12 hours postdose | 
| Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) |  | Predose up to 12 hours postdose | 
| Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib |  | Predose up to 12 hours postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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zanubrutinib, BTK inhibitor, bendamustine, rituximab, venetoclax, BGB-3111, Phase 3