A Study of Zanubrutinib Plus Anti-CD20 Versus Lenalidomide Plus Rituximab in Participants With Relapsed/Refractory Follicular or Marginal Zone Lymphoma

Study Overview
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Brief Summary
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The purpose of the study is to compare the efficacy of zanubrutinib plus obinutuzumab versus lenalidomide plus rituximab (R^2) in participants with relapsed/refractory (R/R) follicular lymphoma (FL), as measured by progression-free survival as determined by an independent review committee in accordance with the 2014 modification of the International Working Group on non-Hodgkin lymphoma (NHL) Criteria based on n positron emission tomography and computed tomography (PET/CT), and to compare the efficacy of zanubrutinib plus rituximab versus R^2 in participants with R/R marginal zone lymphoma (MZL), as measured by progression free survival (PFS) assessed by IRC in accordance with CT-based Lugano 2014 Criteria.

Official Title
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A Phase 3 Randomized, Open-Label Multicenter Study of Zanubrutinib (BGB-3111) Plus Anti-CD20 Antibodies Versus Lenalidomide Plus Rituximab in Patients With Relapsed/Refractory Follicular or Marginal Zone Lymphoma

Conditions
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Relapsed/Refractory Follicular Lymphoma, Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: Zanubrutinib
* Drug: Rituximab
* Drug: Lenalidomide
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed grade 1-3a FL or MZL Previously received ≥ 1 line of systemic therapy including anti-CD20 agent. Must have a documented failure to achieve at least partial response during the most recent systemic therapy or documented progressive disease after the most recent systemic therapy Need for systemic therapy for FL or MZL Measurable disease by computed tomography or magnetic resonance imaging Adequate bone marrow, liver and renal function Key Exclusion Criteria: Transformation to aggressive lymphoma Requiring ongoing need for corticosteroid treatment Clinically significant cardiovascular disease Prior malignancy within the past 2 years Active fungal, bacterial, and/or viral infection that requires systemic therapy 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: Follicular Lymphoma Arm A: Zanubrutinib plus Obinutuzumab<br>Participants will receive zanubrutinib and Obinutuzumab. Following the completion of the combination treatment, participants will continue receiving zanubrutinib monotherapy until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first. | Drug: Zanubrutinib<br>* Zanubrutinib will be administered orally as two 80-milligram (mg) capsules twice a day (160 mg twice a day or 320 mg once a day) continuously in repeated 28-day cycles.<br>* Other names: Brukinsa;Drug: Obinutuzumab<br>* Obinutuzumab will be administered at a dose of 1000 mg on Cycle 1 Days 1, 8, 15 and then on Cycles 2 to 6 Day 1.<br>|
| Active Comparator: Follicular Lymphoma Arm B: Lenalidomide plus Rituximab<br>Participants will receive lenalidomide and rituximab. | Drug: Rituximab<br>* Rituximab will be administered intravenously at a dose of 375 mg/meter squared on Days 1, 8, 15, and 22 of Cycle 1 and on Day 1 of Cycles 2 to 5. Each cycle is 28 days in length.<br>* Other names: Truxima;Drug: Lenalidomide<br>* Lenalidomide will be administered orally as 20-mg capsules once a day on Days 1 to 21 of each 28-day cycle for a total of 12 cycles.<br>* Other names: Revlimid;|
| Experimental: Marginal Zone Lymphoma Arm C: Zanubrutinib plus Rituximab<br>Participants will receive zanubrutinib and rituximab. Following the completion of the combination treatment, participants will continue receiving zanubrutinib monotherapy until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first. | Drug: Zanubrutinib<br>* Zanubrutinib will be administered orally as two 80-milligram (mg) capsules twice a day (160 mg twice a day or 320 mg once a day) continuously in repeated 28-day cycles.<br>* Other names: Brukinsa;Drug: Rituximab<br>* Rituximab will be administered intravenously at a dose of 375 mg/meter squared on Days 1, 8, 15, and 22 of Cycle 1 and on Day 1 of Cycles 2 to 5. Each cycle is 28 days in length.<br>* Other names: Truxima;|
| Active Comparator: Marginal Zone Lymphoma Arm D: Lenalidomide plus Rituximab<br>Participants will receive lenalidomide and rituximab. | Drug: Rituximab<br>* Rituximab will be administered intravenously at a dose of 375 mg/meter squared on Days 1, 8, 15, and 22 of Cycle 1 and on Day 1 of Cycles 2 to 5. Each cycle is 28 days in length.<br>* Other names: Truxima;Drug: Lenalidomide<br>* Lenalidomide will be administered orally as 20-mg capsules once a day on Days 1 to 21 of each 28-day cycle for a total of 12 cycles.<br>* Other names: Revlimid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival As Determined By An Independent Review Committee |  | Approximately 78 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival As Determined By Investigator Assessment |  | Approximately 87 months | 
| Duration Of Response As Determined By An Independent Review Committee And By Investigator Assessment . |  | Approximately 87 months | 
| Overall Response Rate As Determined By An Independent Review Committee And By Investigator Assessment |  | Approximately 87 months | 
| Complete Response Rate As Determined By An Independent Review Committee And By Investigator Assessment |  | Approximately 87 months | 
| Time To Response As Determined By An Independent Review Committee And By Investigator Assessment |  | Approximately 87 months | 
| Time to Next Ant-Lymphoma Treatment |  | Approximately 87 months | 
| Overall Survival |  | Approximately 87 months | 
| Health-related Quality Of Life (HRQoL) Using EORTC QLQ-C30) | HRQ0L assessed by The European Organization For Research On Treatment Of Cancer Quality Of Life Questionnaire-core 30 (EORTC QLQ-C30) consists of 30 questions that are associated with 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and 6 single symptom items ( dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The scores range from 0 to 100 and higher score indicates better quality of life. | Approximately 87 months | 
| HRQoL Using European Quality of Life 5 Dimension 5 Level Questionnaire [EQ 5D 5L) | The EQ-5D-5L is comprised of a descriptive module and a visual analogue scale. The EQ-5D-5L descriptive module comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The visual analogue scale records the respondent's self-rated health on a 0 to 100 scale, with 100 labeled the best health you can imagine and 0 labeled the worst health you can imagine. Higher scores indicate better quality of life. | Approximately 87 months | 
| HRQoL Using National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 [FLymSI 18) | The FLymSI-18 is comprised of 18 questions which cover 4 sub-scales: physical symptoms, emotional symptoms, side effects, and functional well-being. Scores are based on the 5-level Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and is divided into a total score. Higher score indicates better quality of life. | Approximately 87 months | 
| Number of Participants Experiencing Adverse Events (AEs) |  | From first dose to 28 days after the last dose of zanubrutinib or lenalidomide, 90 days after the last dose of obinutuzumab or rituximab, or until the date of confirmed disease progression, whichever comes later (Approximately 87 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Zanubrutinib, BGB-3111, Rituximab, Lenalidomide, Obinutuzumab