Testing Continuous Versus Intermittent Treatment With the Study Drug Zanubrutinib for Older Patients With Previously Untreated Mantle Cell Lymphoma

Mantle Cell Lymphoma Clinical Trial

Official title:

A Randomized Phase 3 Trial of Continuous vs. Intermittent Maintenance Therapy With Zanubrutinib as Upfront Treatment in Older Patients With Mantle Cell Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05976763
• Other study ID #: A052101
• Secondary ID: NCI-2023-03577
• Status: Recruiting
• Phase: Phase 3
• Start date: September 8, 2023
• Est. completion date: August 31, 2038

Study information

• Verified date: April 2024
• Source: Alliance for Clinical Trials in Oncology
• Contact: Anne Beaven, MD
• Phone: 919-966-9268
• Email: anne_beaven[@]med.unc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase III trial tests whether continuous or intermittent zanubrutinib after achieving a complete remission (CR) with rituximab works in older adult patients with mantle cell lymphoma (MCL) who have not received treatment in the past (previously untreated). Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. When zanubrutinib is used in MCL, the current standard of care is to continue administering the drug indefinitely until disease progression. This continuous treatment comes with clinical as well as financial toxicity, which could be especially detrimental in older patients. For patients who achieve a CR after initial zanubrutinib plus rituximab therapy, it may be safe and equally effective to stop treatment and restart zanubrutinib upon disease progression rather than continuing indefinitely in previously untreated older adult patients with MCL.

Description:

PRIMARY OBJECTIVE: I. To compare time to first progression or death (progression free survival [PFS]1) with continuous treatment (Arm A) and time to second progression or death (PFS2) with intermittent treatment that is restarted at first progression (Arm B). KEY SECONDARY OBJECTIVE: I. To compare overall survival between patients who achieve a complete remission (CR) with induction therapy subsequently treated with continuous treatment versus (vs.) intermittent treatment as part of maintenance therapy. SECONDARY OBJECTIVES: I. To determine overall response rate (ORR) and CR rate to induction therapy with zanubrutinib and rituximab in previously untreated MCL. II. To determine adverse events during induction and post-induction in each study arm (Arm A and B) by Common Terminology Criteria for Adverse Events (CTCAE) 5.0. III. To determine PFS1, event free survival (EFS) and overall survival (OS) in each study arm (A and B). IV. To determine the overall response rate (ORR) and complete response rate (CR) after restarting zanubrutinib, following the first progression, in the intermittent treatment arm (Arm B). V. To compare burden of symptomatic adverse events (AEs) as assessed by Patient-Reported Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE) between patients randomized to Arm A versus Arm B. QUALITY OF LIFE PRIMARY OBJECTIVE: I. To compare health-related quality of life (QOL) at 12 cycles post-randomization as assessed by the Functional Assessment of Cancer Therapy (FACT) Lymphoma Symptom Index-18 (FLYMSI-18) total score between patients randomized to Arm A versus Arm B. QUALITY OF LIFE SECONDARY OBJECTIVES: I. To compare health-related QOL at other time points as assessed by the FLYMSI-18 total score between patients randomized to Arm A versus Arm B. II. To compare burden of symptomatic AEs as assessed by PRO-CTCAE between patients randomized to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment. QUALITY OF LIFE EXPLORATORY OBJECTIVES: I. To compare the geriatric functional and cognitive PRO as assessed by Elderly Functional Index (EFLI) and Neurology (Neuro) QOL in Arm A versus Arm B. II. To compare cognitive function at various time points as assessed by the Neuro-QOL between patients randomized to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment. EXPLORATORY OBJECTIVES: I. To evaluate the completion rate of a lymphoma-specific patient assessment of life survey (PALS) with patient directed questions on life, health, and social determinants of health (SDH) and assess the impact of the survey collected data on outcomes for all enrolled patients (study arms A and B). II. To evaluate minimal residual disease (MRD) in those patients who achieve a CR after induction therapy (arms A and B) and how detectable MRD status changes after continued therapy vs. discontinuation of therapy (i.e. arms A vs. B). OUTLINE: INDUCTION THERAPY: Patients receive zanubrutinib orally (PO) and rituximab intravenously (IV) on study. Patients undergo bone marrow biopsy and fluciclovine F18 (FDG) positron emission tomography (PET)/ computed tomography (CT) or CT throughout the trial. Patients may also undergo esophagogastroduodenoscopy (EGD) and/or colonoscopy on study as clinically indicated. Patients may optionally undergo blood sample collection throughout the trial. MAINTENANCE THERAPY: Patients achieving a CR after induction therapy are randomized to 1 of 2 arms. ARM A: Patients receive zanubrutinib PO until first disease progression on study. Patients undergo CT or magnetic resonance imaging (MRI) or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial. ARM B: Patients undergo observation until first disease progression and then receive zanubrutinib PO until second disease progression on study. Patients undergo CT or MRI or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial. After completion of study treatment, patients are followed within 30 days and every 6 months for 10 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 421
• Est. completion date: August 31, 2038
• Est. primary completion date: August 31, 2038
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

• • Histologically confirmed mantle cell lymphoma with cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH) as confirmed by the enrolling center
• Any stage allowed (stage I-IV)
• Presence of measurable disease, defined as >= 1 nodal lesion that is > 1.5 cm in longest diameter or >= 1 extranodal lesion that is > 1 cm in longest diameter
• Steroids for management of mantle cell lymphoma are allowed up to a dose of prednisone 100mg/day (or equivalent) for up to 7 days
• No prior systemic treatment for mantle cell lymphoma
• No prior radiation treatment for stage I MCL
• No prior exposure to a BTK inhibitor or anti-CD20 monoclonal antibody
• No prior stem cell transplant
• Age >= 70 years OR age >= 60 to < 70 years with comorbidities precluding autologous stem cell transplantation (autoSCT) including at least one of the following: a) cardiac ejection fraction (EF) < 45%, b) diffusing capacity for carbon monoxide < 60% predicted; c) creatinine clearance < 70 but > 30ml/minute (min); d) Eastern Cooperative Oncology Group (ECOG) performance status of 2, which poses an unacceptable risk of toxicity for high-dose therapy and stem cell transplantation; or e) Cumulative Illness Rating Scales (CIRS) total score > 6
• ECOG Performance Status 0-2
• Absolute neutrophil count (ANC) >= 750/mm^3 (without growth factor support within 7 days)
• Platelet count >= 75,000/mm^3 (or >= 50,000/mm^3 for patients with bone marrow involvement of lymphoma) without growth factor support or transfusion within 7 days
• Creatinine clearance >= 30 mL/ min determined by either: a) Estimation using the Cockcroft-Gault equation or b) Measurement by nuclear medicine scan or 24 hour urine collection
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless documented Gilbert's syndrome)
• Aspartate transferase (AST) / alanine transaminase (ALT) =< 3 x ULN
• Patients should not be considered candidates for stem cell transplant or must have declined a stem cell transplant strategy
• No clinically significant cardiovascular disease including the following
• Unstable angina within 3 months before registration
• New York Heart Association class III or IV congestive heart failure
• History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
• QT correction formula (QTcF) > 480 msecs based on Fredericia's formula
• History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• No active Hepatitis B or Hepatitis C infection. Patients with prior hepatitis B virus (HBV) exposure (positive HBV core antibody and/or surface antigen) are eligible if they have no detectable viral load, and are taking appropriate prophylactic antiviral therapy to prevent reactivation. Patients with history of hepatitis C virus (HCV) are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• No history of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
• No history of stroke or intracranial hemorrhage within 6 months prior to registration
• No disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. Patient must be able to swallow pills
• Potential trial participants should have recovered from major surgery
• No vaccination with a live vaccine within 35 days prior to registration
• No hypersensitivity to zanubrutinib or rituximab or any of the other ingredients of the study drugs
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment
• Avoid use of moderate CYP3A4 inhibitors, PGP inhibitors, and moderate CYP3A4 inducers
• Archival tissue must be available for submission in all patients for histopathology review, though participation in correlative substudies is optional

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma

Intervention

Drug:
• Zanubrutinib
Given PO

Biological:
• Rituximab
Given IV

Other:
• Patient Observation
Undergo observation

Procedure:
• Bone Marrow Biopsy
undergo bone marrow biopsy

Other:
• Fludeoxyglucose F-18
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET
• Computed Tomography
Undergo CT
• Magnetic Resonance Imaging
Undergo MRI
• Esophagogastroduodenoscopy
Undergo EGD
• Colonoscopy
Undergo colonoscopy
• Biospecimen Collection
Undergo blood sample collection

Other:
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Augusta University Medical Center	Augusta	Georgia
United States	Nebraska Medicine-Bellevue	Bellevue	Nebraska
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Alliance for Clinical Trials in Oncology	Boston	Massachusetts
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Northwest Cancer Center - Main Campus	Crown Point	Indiana
United States	Carle at The Riverfront	Danville	Illinois
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Northwest Oncology LLC	Dyer	Indiana
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Beaumont Hospital - Farmington Hills	Farmington Hills	Michigan
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Smilow Cancer Hospital Care Center at Glastonbury	Glastonbury	Connecticut
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Smilow Cancer Hospital Care Center at Greenwich	Greenwich	Connecticut
United States	Smilow Cancer Hospital Care Center - Guilford	Guilford	Connecticut
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Northwest Cancer Center - Hobart	Hobart	Indiana
United States	Saint Mary Medical Center	Hobart	Indiana
United States	Saint Catherine Hospital	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	City of Hope at Irvine Lennar	Irvine	California
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Community Medical Hospital	Missoula	Montana
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	The Community Hospital	Munster	Indiana
United States	Women's Diagnostic Center - Munster	Munster	Indiana
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Froedtert and MCW Moorland Reserve Health Center	New Berlin	Wisconsin
United States	Yale University	New Haven	Connecticut
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Medicine-Village Pointe	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Saint Alphonsus Medical Center-Ontario	Ontario	Oregon
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Rhode Island Hospital	Providence	Rhode Island
United States	University of Rochester	Rochester	New York
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Memorial Hospital East	Shiloh	Illinois
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Smilow Cancer Hospital Care Center at Long Ridge	Stamford	Connecticut
United States	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Carle Cancer Center	Urbana	Illinois
United States	Northwest Cancer Center - Valparaiso	Valparaiso	Indiana
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut
United States	Smilow Cancer Hospital Care Center - Waterford	Waterford	Connecticut
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Wilmot Cancer Institute at Webster	Webster	New York
United States	Smilow Cancer Hospital Care Center - Westerly	Westerly	Rhode Island
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS) 1 (Arm A)	Hazard ratios on the treatment effect will be estimated using a stratified cox proportional hazards model, stratified on age and mantle cell lymphoma (MCL) International Prognostic Index (IPI) score. The primary analysis for non-inferiority will be based on an intent-to-treat (ITT) analysis and will include all randomized patients in the analyses, regardless of eligibility or treatment status. Sensitivity analyses will also be done in an ancillary manner to evaluate and compare our endpoints using a modified ITT approach, and exclude from the analysis those classified as ineligible as well as those who withdraw right after randomization prior to any treatment/observation monitoring.	Time from randomization until the earlier of first progression or death from any cause, assessed up to 10 years
Primary	Progression-free survival (PFS) 2 (Arm B)	Hazard ratios on the treatment effect will be estimated using a stratified cox proportional hazards model, stratified on age and MCL IPI score. The primary analysis for non-inferiority will be based on an ITT analysis and will include all randomized patients in the analyses, regardless of eligibility or treatment status. Sensitivity analyses will also be done in an ancillary manner to evaluate and compare our endpoints using a modified ITT approach, and exclude from the analysis those classified as ineligible as well as those who withdraw right after randomization prior to any treatment/observation monitoring.	Time from randomization until the earlier of second progression or death from any cause, assessed up to 10 years
Secondary	Overall survival (OS) (Arms A and B)	Kaplan-Meier methodology will be used to estimate the distributions of OS by treatment arm and log-rank test statistics will be used to compare these distributions between the two treatment arms. Cox Proportional Hazards models may be used to further evaluate covariates of interest with OS, including assessment of treatment effects when adjusting for other known risk factors in the model.	Time from randomization until death from any cause, assessed up to 10 years
Secondary	Incidence of adverse events	Will be evaluated and captured using the CTCAE 5.0, where the type and severity grade of each adverse event will be collected and tabulated within each of the treatment arms. Perceived attribution to study treatment will also be captured.; The analysis population for this secondary endpoint will include all patients who are registered and randomized on the study and receive at least one dose of study treatment. Adverse events will be monitored continuously throughout the course of the study as well as analyzed at the time of the final primary endpoint analysis.; Summary statistics and frequency tables will be used to describe the distributions of adverse events. Rates of adverse events occurring in compared across the treatment arms with chi-squared tests Tolerability will also be evaluated, summarizing rates of dose delays or modifications, reasons patients end treatment, and time to end of active treatment.	Up to 10 years
Secondary	Overall response rate (ORR, complete + partial remission)	Will be assessed using Lugano criteria. ORR to induction is defined as the number of patients with complete or partial remission at the end of induction divided by the number of patients who receive at least one dose of the induction regimen. ORR to restart of zanubrutinib is only defined for Arm B, as the number of patients with complete or partial remission after restart of zanubrutinib divided by the number of patients that restart zanubrutinib after first disease progression following randomization. The frequencies and rates of tumor response categories will be summarized by treatment arm for response to induction as well as response to restart of zanubrutinib (Arm B only). ORR to induction and ORR to restart of zanubrutinib (Arm B only) with 95% exact binomial confidence intervals will be calculated by treatment arm. To compare the association of treatment arm and ORR to induction, chi-squared or Fisher's Exact test will be used, whichever is more appropriate at final analysis.	up to 10 years
Secondary	Complete response rate (CR)	Will be assessed using Lugano criteria. CR to induction is defined as the number of patients with complete remission at the end of induction divided by the number of eligible patients who receive at least one dose of the induction regimen. CR to restart of zanubrutinib is only defined for Arm B, as the number of patients with complete remission after restart of zanubrutinib divided by the number of eligible patients that restart zanubrutinib after first disease progression following randomization. CR to induction and CR to restart of zanubrutinib (Arm B patients only) with 95% exact binomial confidence intervals will be calculated by treatment arm. To compare the association of treatment arm and CR to induction, chi-squared or Fisher's Exact test will be used, whichever is more appropriate at the time of the final analysis.	Up to 10 years
Secondary	Event-free survival (EFS) 1	For EFS1, patients without an event will be censored at the last known clinical assessment. Any patient who goes to transplant will be censored at the last known clinical assessment prior to transplant. Kaplan-Meier methodology will be used to estimate the distribution of EFS. Cox Proportional Hazards models may be used to further evaluate covariates of interest with EFS.	Time from randomization (Arms A and B) until the earlier of first progression, start of an alternative MCL therapy, or death from any cause, assessed up to 10 years.
Secondary	Event-free survival (EFS) 2	For EFS2, patients without an event will be censored at the last known clinical assessment. Any patient who goes to transplant will be censored at the last known clinical assessment prior to transplant. Kaplan-Meier methodology will be used to estimate the distribution of EFS. Cox Proportional Hazards models may be used to further evaluate covariates of interest with EFS.	Time from randomization (Arm B) until the earlier of second progression, start of an alternative MCL therapy, or death from any cause, assessed up to 10 years.