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
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Condition or disease | Intervention/treatment | Phase |
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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 |
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 |
Arm | Intervention/treatment |
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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.
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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:
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.
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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:
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.
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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:
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 |
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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Ages Eligible for Study: | 60 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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• 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
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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
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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
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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
Contact: Anne Beaven, MD | 919-966-9268 | anne_beaven@med.unc.edu | |
Contact: Destin Carlisle | 773-702-8824 | dcarlisle@bsd.uchicago.edu |
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 |
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 |
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 |