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

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ClinicalTrials.gov Identifier: NCT03336333
Recruitment Status : Active, not recruiting
First Posted : November 8, 2017
Results First Posted : November 7, 2023
Last Update Posted : November 9, 2023
Sponsor:
Information provided by (Responsible Party):
BeiGene

Study Description
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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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Drug: Zanubrutinib Drug: Bendamustine Drug: Rituximab Drug: Venetoclax Phase 3

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 590 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : October 31, 2017
Actual Primary Completion Date : May 7, 2021
Estimated Study Completion Date : September 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1: Bendamustine + Rituximab
Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B)
 Drug: Bendamustine
Administered intravenously (IV) at a dose of 90 mg/m^2/day on the first 2 days of each cycle for 6 cycles.
Other Name: Treanda, Ribomustin, and Levact

Drug: Rituximab
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
Other Name: Rituxan, MabThera
Experimental: Cohort 1: Zanubrutinib
Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A)
 Drug: Zanubrutinib
Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
Other Names:
  • BGB-3111
  • BRUKINSA
Experimental: Cohort 1a (China only): Bendamustine + Rituximab
Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only)
 Drug: Bendamustine
Administered intravenously (IV) at a dose of 90 mg/m^2/day on the first 2 days of each cycle for 6 cycles.
Other Name: Treanda, Ribomustin, and Levact

Drug: Rituximab
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
Other Name: Rituxan, MabThera
Experimental: Cohort 1a (China only): Zanubrutinib
Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only)
 Drug: Zanubrutinib
Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
Other Names:
  • BGB-3111
  • BRUKINSA
Experimental: Cohort 2: Zanubrutinib
Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C)
 Drug: Zanubrutinib
Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
Other Names:
  • BGB-3111
  • BRUKINSA
Experimental: Cohort 3: Venetoclax + 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)
 Drug: Zanubrutinib
Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
Other Names:
  • BGB-3111
  • BRUKINSA

Drug: Venetoclax
400 mg tablets administered orally once daily.
Other Name: Venclexta, Venclyxto


Outcome Measures
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Primary Outcome Measures :
  1. Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR) [ Time Frame: 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 :
  1. Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR [ Time Frame: 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.

  2. Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups [ Time Frame: Up to 5 years ]
  3. Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR [ Time Frame: Up to 5 years ]
    OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason.

  4. Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR [ Time Frame: 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.

  5. Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups [ Time Frame: Up to 5 years ]
  6. Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) [ Time Frame: 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.

  7. Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) [ Time Frame: Up to 5 years ]
  8. Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire [ Time Frame: Up to 5 years ]
  9. 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. [ Time Frame: Up to 5 years ]
  10. Cohort 2: Overall Response Rate (ORR) [ Time Frame: Up to 5 years ]
  11. Cohort 2: Progression-free Survival (PFS) [ Time Frame: Up to 5 years ]
  12. Cohort 2: Duration of Response (DOR) [ Time Frame: Up to 5 years ]
  13. Cohort 3: Overall Response Rate (ORR) [ Time Frame: Up to 5 years ]
  14. Cohort 3: Progression-free Survival (PFS) [ Time Frame: Up to 5 years ]
  15. Cohort 3: Duration of Response (DOR) [ Time Frame: Up to 5 years ]
  16. Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4) [ Time Frame: Up to 5 years ]
  17. Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 5 years ]
  18. Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F [ Time Frame: Predose up to 12 hours postdose ]
  19. Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) [ Time Frame: Predose up to 12 hours postdose ]
  20. Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib [ Time Frame: Predose up to 12 hours postdose ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03336333


Locations
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Sponsors and Collaborators
BeiGene
Investigators
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Study Director: Study Director BeiGene
  Study Documents (Full-Text)

Documents provided by BeiGene:
Study Protocol  [PDF] February 10, 2021
Statistical Analysis Plan  [PDF] May 13, 2021

More Information
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Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: BeiGene
ClinicalTrials.gov Identifier: NCT03336333    
Other Study ID Numbers: BGB-3111-304
2017-001551-31 ( EudraCT Number )
CTR20190416 ( Registry Identifier: Center for drug evaluation, NMPA )
First Posted: November 8, 2017    Key Record Dates
Results First Posted: November 7, 2023
Last Update Posted: November 9, 2023
Last Verified: November 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by BeiGene:
zanubrutinib
BTK inhibitor
bendamustine
rituximab
 venetoclax
BGB-3111
Phase 3
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hematologic Diseases
Leukemia, B-Cell
Chronic Disease
Disease Attributes
Pathologic Processes
 Rituximab
Venetoclax
Bendamustine Hydrochloride
Zanubrutinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors