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

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ClinicalTrials.gov Identifier: NCT05976763
Recruitment Status : Recruiting
First Posted : August 4, 2023
Last Update Posted : April 9, 2024
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Drug: Zanubrutinib Biological: Rituximab Other: Patient Observation Procedure: Bone Marrow Biopsy Other: Fludeoxyglucose F-18 Procedure: Positron Emission Tomography Procedure: Computed Tomography Procedure: Magnetic Resonance Imaging Procedure: Esophagogastroduodenoscopy Procedure: Colonoscopy Procedure: Biospecimen Collection Other: Questionnaire Administration Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 421 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 8, 2023
Estimated Primary Completion Date : August 31, 2038
Estimated Study Completion Date : August 31, 2038

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Induction therapy (Zanubrutinib, rituximab)
Patients receive zanubrutinib PO and rituximab IV on study. Patients undergo bone marrow biopsy and FDG PET/CT or CT throughout the trial. Patients may also undergo EDG and/or colonoscopy on study as clinically indicated. Patients may optionally undergo blood sample collection throughout the trial.
 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
Other Name: PET

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT Scan
  • CT Scan

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Name: MRI

Procedure: Esophagogastroduodenoscopy
Undergo EGD
Other Name: EGD

Procedure: Colonoscopy
Undergo colonoscopy

Procedure: Biospecimen Collection
Undergo blood sample collection

Other: Questionnaire Administration
Ancillary studies
Experimental: Arm A (Zanubrutinib)
Patients receive zanubrutinib PO until first 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.
 Drug: Zanubrutinib
Given PO

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
Other Name: PET

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT Scan
  • CT Scan

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Name: MRI

Procedure: Esophagogastroduodenoscopy
Undergo EGD
Other Name: EGD

Procedure: Colonoscopy
Undergo colonoscopy

Procedure: Biospecimen Collection
Undergo blood sample collection

Other: Questionnaire Administration
Ancillary studies
Active Comparator: ARM B (Observation)
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.
 Drug: Zanubrutinib
Given PO

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
Other Name: PET

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT Scan
  • CT Scan

Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Name: MRI

Procedure: Esophagogastroduodenoscopy
Undergo EGD
Other Name: EGD

Procedure: Colonoscopy
Undergo colonoscopy

Procedure: Biospecimen Collection
Undergo blood sample collection

Other: Questionnaire Administration
Ancillary studies


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free survival (PFS) 1 (Arm A) [ Time Frame: Time from randomization until the earlier of first progression or death from any cause, assessed up to 10 years ]
    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.

  2. Progression-free survival (PFS) 2 (Arm B) [ Time Frame: Time from randomization until the earlier of second progression or death from any cause, assessed up to 10 years ]
    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.


Secondary Outcome Measures :
  1. Overall survival (OS) (Arms A and B) [ Time Frame: Time from randomization until death from any cause, assessed up to 10 years ]
    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.

  2. Incidence of adverse events [ Time Frame: Up to 10 years ]

    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.


  3. Overall response rate (ORR, complete + partial remission) [ Time Frame: up to 10 years ]
    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.

  4. Complete response rate (CR) [ Time Frame: Up to 10 years ]
    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.

  5. Event-free survival (EFS) 1 [ Time Frame: 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. ]
    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.

  6. Event-free survival (EFS) 2 [ Time Frame: 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. ]
    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.


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

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
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): NCT05976763


Contacts
Layout table for location contacts
Contact: Anne Beaven, MD 919-966-9268 anne_beaven@med.unc.edu
Contact: Destin Carlisle 773-702-8824 dcarlisle@bsd.uchicago.edu

Locations
Show Show 138 study locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
More Information
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Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT05976763    
Other Study ID Numbers: A052101
NCI-2023-03577 ( Other Identifier: NCI Clinical Trial Reporting Program )
First Posted: August 4, 2023    Key Record Dates
Last Update Posted: April 9, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Zanubrutinib
 Fluorodeoxyglucose F18
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Radiopharmaceuticals
Molecular Mechanisms of Pharmacological Action
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors