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

Phase 3

Active, not recruiting

Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma

Interventions: Drug: Bendamustine
Drug: Zanubrutinib
Drug: Rituximab
Drug: Venetoclax

Registration Number: NCT03336333

Lead Sponsor: BeiGene

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 590

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1: Bendamustine + Rituximab	Rituximab	Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B)
Cohort 1: Bendamustine + Rituximab	Bendamustine	Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B)
Cohort 1a (China only): Bendamustine + Rituximab	Rituximab	Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only)
Cohort 1: Zanubrutinib	Zanubrutinib	Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A)
Cohort 1a (China only): Bendamustine + Rituximab	Bendamustine	Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only)
Cohort 1a (China only): Zanubrutinib	Zanubrutinib	Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only)
Cohort 2: Zanubrutinib	Zanubrutinib	Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C)
Cohort 3: Venetoclax + Zanubrutinib	Zanubrutinib	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)
Cohort 3: Venetoclax + Zanubrutinib	Venetoclax	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)

Primary Outcome Measures

Name	Time	Method
Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR)	Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021)	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).

Secondary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)	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 2: Progression-free Survival (PFS)	Up to 5 years
Cohort 2: Duration of Response (DOR)	Up to 5 years
Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR	Up to 5 years	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.
Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)	Up to 5 years	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.
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: Overall Survival (OS) Between Treatment Groups as Determined by the ICR	Up to 5 years	OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason.
Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups	Up to 5 years
Cohort 3: Duration of Response (DOR)	Up to 5 years
Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR	Up to 5 years	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.
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 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12)	Predose up to 12 hours postdose
Cohort 3: Overall Response Rate (ORR)	Up to 5 years
Cohort 2: Overall Response Rate (ORR)	Up to 5 years
Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib	Predose up to 12 hours postdose
Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups	Up to 5 years
Cohort 3: Progression-free Survival (PFS)	Up to 5 years
Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4)	Up to 5 years
Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F	Predose up to 12 hours postdose

Trial Locations

Locations (158): Augusta University
🇺🇸
Augusta, Georgia, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Research Medical Center
🇺🇸
Kansas City, Missouri, United States
Washington University
🇺🇸
Saint Louis, Missouri, United States
Comprehensive Cancer Centers of Nevada
🇺🇸
Las Vegas, Nevada, United States
Summit Medical Group
🇺🇸
Florham Park, New Jersey, United States
Icahn School of Medicine At Mount Sinai
🇺🇸
New York, New York, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
University of Rochester
🇺🇸
Rochester, New York, United States
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Augusta University
🇺🇸Augusta, Georgia, United States