xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05976763</url>
    </required_header>
    <id_info>
      <org_study_id>A052101</org_study_id>
      <secondary_id>NCI-2023-03577</secondary_id>
      <nct_id>NCT05976763</nct_id>
    </id_info>
    <brief_title>Testing Continuous Versus Intermittent Treatment With the Study Drug Zanubrutinib for Older Patients With Previously Untreated Mantle Cell Lymphoma</brief_title>
    <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</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Alliance for Clinical Trials in Oncology</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Cancer Institute (NCI)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
    </sponsors>
    <source>Alliance for Clinical Trials in Oncology</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This phase III trial tests whether continuous or intermittent zanubrutinib after achieving a&#xD;
        complete remission (CR) with rituximab works in older adult patients with mantle cell&#xD;
        lymphoma (MCL) who have not received treatment in the past (previously untreated). Rituximab&#xD;
        is a monoclonal antibody that may interfere with the ability of cancer cells to grow and&#xD;
        spread. Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes&#xD;
        needed for cell growth. When zanubrutinib is used in MCL, the current standard of care is to&#xD;
        continue administering the drug indefinitely until disease progression. This continuous&#xD;
        treatment comes with clinical as well as financial toxicity, which could be especially&#xD;
        detrimental in older patients. For patients who achieve a CR after initial zanubrutinib plus&#xD;
        rituximab therapy, it may be safe and equally effective to stop treatment and restart&#xD;
        zanubrutinib upon disease progression rather than continuing indefinitely in previously&#xD;
        untreated older adult patients with MCL.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        PRIMARY OBJECTIVE:&#xD;
  &#xD;
        I. To compare time to first progression or death (progression free survival [PFS]1) with&#xD;
        continuous treatment (Arm A) and time to second progression or death (PFS2) with intermittent&#xD;
        treatment that is restarted at first progression (Arm B).&#xD;
  &#xD;
        KEY SECONDARY OBJECTIVE:&#xD;
  &#xD;
        I. To compare overall survival between patients who achieve a complete remission (CR) with&#xD;
        induction therapy subsequently treated with continuous treatment versus (vs.) intermittent&#xD;
        treatment as part of maintenance therapy.&#xD;
  &#xD;
        SECONDARY OBJECTIVES:&#xD;
  &#xD;
        I. To determine overall response rate (ORR) and CR rate to induction therapy with&#xD;
        zanubrutinib and rituximab in previously untreated MCL.&#xD;
  &#xD;
        II. To determine adverse events during induction and post-induction in each study arm (Arm A&#xD;
        and B) by Common Terminology Criteria for Adverse Events (CTCAE) 5.0.&#xD;
  &#xD;
        III. To determine PFS1, event free survival (EFS) and overall survival (OS) in each study arm&#xD;
        (A and B).&#xD;
  &#xD;
        IV. To determine the overall response rate (ORR) and complete response rate (CR) after&#xD;
        restarting zanubrutinib, following the first progression, in the intermittent treatment arm&#xD;
        (Arm B).&#xD;
  &#xD;
        V. To compare burden of symptomatic adverse events (AEs) as assessed by Patient-Reported&#xD;
        Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE) between patients&#xD;
        randomized to Arm A versus Arm B.&#xD;
  &#xD;
        QUALITY OF LIFE PRIMARY OBJECTIVE:&#xD;
  &#xD;
        I. To compare health-related quality of life (QOL) at 12 cycles post-randomization as&#xD;
        assessed by the Functional Assessment of Cancer Therapy (FACT) Lymphoma Symptom Index-18&#xD;
        (FLYMSI-18) total score between patients randomized to Arm A versus Arm B.&#xD;
  &#xD;
        QUALITY OF LIFE SECONDARY OBJECTIVES:&#xD;
  &#xD;
        I. To compare health-related QOL at other time points as assessed by the FLYMSI-18 total&#xD;
        score between patients randomized to Arm A versus Arm B.&#xD;
  &#xD;
        II. To compare burden of symptomatic AEs as assessed by PRO-CTCAE between patients randomized&#xD;
        to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment.&#xD;
  &#xD;
        QUALITY OF LIFE EXPLORATORY OBJECTIVES:&#xD;
  &#xD;
        I. To compare the geriatric functional and cognitive PRO as assessed by Elderly Functional&#xD;
        Index (EFLI) and Neurology (Neuro) QOL in Arm A versus Arm B.&#xD;
  &#xD;
        II. To compare cognitive function at various time points as assessed by the Neuro-QOL between&#xD;
        patients randomized to continuous (Arm A) versus intermittent (Arm B) zanubrutinib treatment.&#xD;
  &#xD;
        EXPLORATORY OBJECTIVES:&#xD;
  &#xD;
        I. To evaluate the completion rate of a lymphoma-specific patient assessment of life survey&#xD;
        (PALS) with patient directed questions on life, health, and social determinants of health&#xD;
        (SDH) and assess the impact of the survey collected data on outcomes for all enrolled&#xD;
        patients (study arms A and B).&#xD;
  &#xD;
        II. To evaluate minimal residual disease (MRD) in those patients who achieve a CR after&#xD;
        induction therapy (arms A and B) and how detectable MRD status changes after continued&#xD;
        therapy vs. discontinuation of therapy (i.e. arms A vs. B).&#xD;
  &#xD;
        OUTLINE:&#xD;
  &#xD;
        INDUCTION THERAPY: Patients receive zanubrutinib orally (PO) and rituximab intravenously (IV)&#xD;
        on study. Patients undergo bone marrow biopsy and fluciclovine F18 (FDG) positron emission&#xD;
        tomography (PET)/ computed tomography (CT) or CT throughout the trial. Patients may also&#xD;
        undergo esophagogastroduodenoscopy (EGD) and/or colonoscopy on study as clinically indicated.&#xD;
        Patients may optionally undergo blood sample collection throughout the trial.&#xD;
  &#xD;
        MAINTENANCE THERAPY: Patients achieving a CR after induction therapy are randomized to 1 of 2&#xD;
        arms.&#xD;
  &#xD;
        ARM A: Patients receive zanubrutinib PO until first disease progression on study. Patients&#xD;
        undergo CT or magnetic resonance imaging (MRI) or FDG PET/CT throughout the trial. Patients&#xD;
        may optionally undergo blood sample collection throughout the trial.&#xD;
  &#xD;
        ARM B: Patients undergo observation until first disease progression and then receive&#xD;
        zanubrutinib PO until second disease progression on study. Patients undergo CT or MRI or FDG&#xD;
        PET/CT throughout the trial. Patients may optionally undergo blood sample collection&#xD;
        throughout the trial.&#xD;
  &#xD;
        After completion of study treatment, patients are followed within 30 days and every 6 months&#xD;
        for 10 years.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 8, 2023</start_date>
    <completion_date type="Anticipated">August 31, 2038</completion_date>
    <primary_completion_date type="Anticipated">August 31, 2038</primary_completion_date>
    <phase>Phase 3</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Progression-free survival (PFS) 1 (Arm A)</measure>
      <time_frame>Time from randomization until the earlier of first progression or death from any cause, assessed up to 10 years</time_frame>
      <description>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.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Progression-free survival (PFS) 2 (Arm B)</measure>
      <time_frame>Time from randomization until the earlier of second progression or death from any cause, assessed up to 10 years</time_frame>
      <description>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.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Overall survival (OS) (Arms A and B)</measure>
      <time_frame>Time from randomization until death from any cause, assessed up to 10 years</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of adverse events</measure>
      <time_frame>Up to 10 years</time_frame>
      <description>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.&#xD;
  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.&#xD;
  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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall response rate (ORR, complete + partial remission)</measure>
      <time_frame>up to 10 years</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Complete response rate (CR)</measure>
      <time_frame>Up to 10 years</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Event-free survival (EFS) 1</measure>
      <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.</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Event-free survival (EFS) 2</measure>
      <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.</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">421</enrollment>
    <condition>Mantle Cell Lymphoma</condition>
    <arm_group>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>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.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Zanubrutinib</intervention_name>
      <description>Given PO</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Rituximab</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Patient Observation</intervention_name>
      <description>Undergo observation</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Bone Marrow Biopsy</intervention_name>
      <description>undergo bone marrow biopsy</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Fludeoxyglucose F-18</intervention_name>
      <description>Given IV</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Positron Emission Tomography</intervention_name>
      <description>Undergo PET</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
      <other_name>PET</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Computed Tomography</intervention_name>
      <description>Undergo CT</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
      <other_name>CAT Scan</other_name>
      <other_name>CT Scan</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Magnetic Resonance Imaging</intervention_name>
      <description>Undergo MRI</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
      <other_name>MRI</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Esophagogastroduodenoscopy</intervention_name>
      <description>Undergo EGD</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
      <other_name>EGD</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Colonoscopy</intervention_name>
      <description>Undergo colonoscopy</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Biospecimen Collection</intervention_name>
      <description>Undergo blood sample collection</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Questionnaire Administration</intervention_name>
      <description>Ancillary studies</description>
      <arm_group_label>ARM B (Observation)</arm_group_label>
      <arm_group_label>Arm A (Zanubrutinib)</arm_group_label>
      <arm_group_label>Induction therapy (Zanubrutinib, rituximab)</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  • Histologically confirmed mantle cell lymphoma with cyclin D1 (BCL1) expression by&#xD;
               immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ&#xD;
               hybridization (FISH) as confirmed by the enrolling center&#xD;
  &#xD;
                 -  Any stage allowed (stage I-IV)&#xD;
  &#xD;
                      -  Presence of measurable disease, defined as &gt;= 1 nodal lesion that is &gt; 1.5&#xD;
                         cm in longest diameter or &gt;= 1 extranodal lesion that is &gt; 1 cm in longest&#xD;
                         diameter&#xD;
  &#xD;
                      -  Steroids for management of mantle cell lymphoma are allowed up to a dose of&#xD;
                         prednisone 100mg/day (or equivalent) for up to 7 days&#xD;
  &#xD;
                      -  No prior systemic treatment for mantle cell lymphoma&#xD;
  &#xD;
                      -  No prior radiation treatment for stage I MCL&#xD;
  &#xD;
                      -  No prior exposure to a BTK inhibitor or anti-CD20 monoclonal antibody&#xD;
  &#xD;
                      -  No prior stem cell transplant&#xD;
  &#xD;
                      -  Age &gt;= 70 years OR age &gt;= 60 to &lt; 70 years with comorbidities precluding&#xD;
                         autologous stem cell transplantation (autoSCT) including at least one of the&#xD;
                         following: a) cardiac ejection fraction (EF) &lt; 45%, b) diffusing capacity&#xD;
                         for carbon monoxide &lt; 60% predicted; c) creatinine clearance &lt; 70 but &gt;&#xD;
                         30ml/minute (min); d) Eastern Cooperative Oncology Group (ECOG) performance&#xD;
                         status of 2, which poses an unacceptable risk of toxicity for high-dose&#xD;
                         therapy and stem cell transplantation; or e) Cumulative Illness Rating&#xD;
                         Scales (CIRS) total score &gt; 6&#xD;
  &#xD;
                      -  ECOG Performance Status 0-2&#xD;
  &#xD;
                      -  Absolute neutrophil count (ANC) &gt;= 750/mm^3 (without growth factor support&#xD;
                         within 7 days)&#xD;
  &#xD;
                      -  Platelet count &gt;= 75,000/mm^3 (or &gt;= 50,000/mm^3 for patients with bone&#xD;
                         marrow involvement of lymphoma) without growth factor support or transfusion&#xD;
                         within 7 days&#xD;
  &#xD;
                      -  Creatinine clearance &gt;= 30 mL/ min determined by either: a) Estimation using&#xD;
                         the Cockcroft-Gault equation or b) Measurement by nuclear medicine scan or&#xD;
                         24 hour urine collection&#xD;
  &#xD;
                      -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN) (unless documented&#xD;
                         Gilbert's syndrome)&#xD;
  &#xD;
                      -  Aspartate transferase (AST) / alanine transaminase (ALT) =&lt; 3 x ULN&#xD;
  &#xD;
                      -  Patients should not be considered candidates for stem cell transplant or&#xD;
                         must have declined a stem cell transplant strategy&#xD;
  &#xD;
                      -  No clinically significant cardiovascular disease including the following&#xD;
  &#xD;
                 -  Unstable angina within 3 months before registration&#xD;
  &#xD;
                 -  New York Heart Association class III or IV congestive heart failure&#xD;
  &#xD;
                 -  History of clinically significant arrhythmias (eg, sustained ventricular&#xD;
                    tachycardia, ventricular fibrillation, torsades de pointes)&#xD;
  &#xD;
                 -  QT correction formula (QTcF) &gt; 480 msecs based on Fredericia's formula&#xD;
  &#xD;
                 -  History of Mobitz II second-degree or third-degree heart block without a&#xD;
                    permanent pacemaker in place&#xD;
  &#xD;
                      -  Human immunodeficiency virus (HIV)-infected patients on effective&#xD;
                         anti-retroviral therapy with undetectable viral load within 6 months are&#xD;
                         eligible for this trial&#xD;
  &#xD;
                      -  No active Hepatitis B or Hepatitis C infection. Patients with prior&#xD;
                         hepatitis B virus (HBV) exposure (positive HBV core antibody and/or surface&#xD;
                         antigen) are eligible if they have no detectable viral load, and are taking&#xD;
                         appropriate prophylactic antiviral therapy to prevent reactivation. Patients&#xD;
                         with history of hepatitis C virus (HCV) are eligible if they have an&#xD;
                         undetectable HCV viral load&#xD;
  &#xD;
                      -  Patients with a prior or concurrent malignancy whose natural history or&#xD;
                         treatment does not have the potential to interfere with the safety or&#xD;
                         efficacy assessment of the investigational regimen are eligible for this&#xD;
                         trial&#xD;
  &#xD;
                      -  No history of severe bleeding disorder such as hemophilia A, hemophilia B,&#xD;
                         von Willebrand disease, or history of spontaneous bleeding requiring blood&#xD;
                         transfusion or other medical intervention&#xD;
  &#xD;
                      -  No history of stroke or intracranial hemorrhage within 6 months prior to&#xD;
                         registration&#xD;
  &#xD;
                      -  No disease significantly affecting gastrointestinal function such as&#xD;
                         malabsorption syndrome, resection of the stomach or small bowel, bariatric&#xD;
                         surgery procedures, symptomatic inflammatory bowel disease, or partial or&#xD;
                         complete bowel obstruction. Patient must be able to swallow pills&#xD;
  &#xD;
                      -  Potential trial participants should have recovered from major surgery&#xD;
  &#xD;
                      -  No vaccination with a live vaccine within 35 days prior to registration&#xD;
  &#xD;
                      -  No hypersensitivity to zanubrutinib or rituximab or any of the other&#xD;
                         ingredients of the study drugs&#xD;
  &#xD;
                      -  Chronic concomitant treatment with strong inhibitors of CYP3A4 is not&#xD;
                         allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue&#xD;
                         the drug for 14 days prior to registration on the study.&#xD;
  &#xD;
                      -  Chronic concomitant treatment with strong CYP3A4 inducers is not allowed.&#xD;
                         Patients must discontinue the drug 14 days prior to the start of study&#xD;
                         treatment&#xD;
  &#xD;
                      -  Avoid use of moderate CYP3A4 inhibitors, PGP inhibitors, and moderate CYP3A4&#xD;
                         inducers&#xD;
  &#xD;
                      -  Archival tissue must be available for submission in all patients for&#xD;
                         histopathology review, though participation in correlative substudies is&#xD;
                         optional&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>60 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Anne Meaden, MD</last_name>
      <phone>919-966-9268</phone>
      <email>anne_beaven@med.unc.edu</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Destin Carlisle</last_name>
      <phone>773-702-8824</phone>
      <email>dcarlisle@bsd.uchicago.edu</email>
    </overall_contact_backup>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>July 26, 2023</study_first_submitted>
    <study_first_submitted_qc>July 26, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 4, 2023</study_first_posted>
    <last_update_submitted>September 13, 2023</last_update_submitted>
    <last_update_submitted_qc>September 13, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lymphoma</mesh_term>
      <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Rituximab</mesh_term>
      <mesh_term>Zanubrutinib</mesh_term>
      <mesh_term>Fluorodeoxyglucose F18</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Undecided</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05976763
  org study id: A052101
  secondary id: NCI-2023-03577
  nct id: NCT05976763
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  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.
  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.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: 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
  description: 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.
  measure: 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
  description: 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.
  measure: Overall survival (OS) (Arms A and B)
  time frame: Time from randomization until death from any cause, assessed up to 10 years
  description: 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.
  measure: Incidence of adverse events
  time frame: Up to 10 years
  description: 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.
  measure: Overall response rate (ORR, complete + partial remission)
  time frame: up to 10 years
  description: 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.
  measure: Complete response rate (CR)
  time frame: Up to 10 years
  description: 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.
  measure: 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.
  description: 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.
  measure: 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.
  description: 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.
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  arm group type: Experimental
  description: 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.
  arm group label: Arm A (Zanubrutinib)
  arm group type: Experimental
  description: 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.
  arm group label: ARM B (Observation)
  arm group type: Active Comparator
  description: 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.
  intervention type: Drug
  intervention name: Zanubrutinib
  description: Given PO
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  intervention type: Biological
  intervention name: Rituximab
  description: Given IV
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  intervention type: Other
  intervention name: Patient Observation
  description: Undergo observation
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  intervention type: Procedure
  intervention name: Bone Marrow Biopsy
  description: undergo bone marrow biopsy
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  intervention type: Other
  intervention name: Fludeoxyglucose F-18
  description: Given IV
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  intervention type: Procedure
  intervention name: Positron Emission Tomography
  description: Undergo PET
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  other name: PET
  intervention type: Procedure
  intervention name: Computed Tomography
  description: Undergo CT
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  other name: CAT Scan
  other name: CT Scan
  intervention type: Procedure
  intervention name: Magnetic Resonance Imaging
  description: Undergo MRI
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  other name: MRI
  intervention type: Procedure
  intervention name: Esophagogastroduodenoscopy
  description: Undergo EGD
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  other name: EGD
  intervention type: Procedure
  intervention name: Colonoscopy
  description: Undergo colonoscopy
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  intervention type: Procedure
  intervention name: Biospecimen Collection
  description: Undergo blood sample collection
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  intervention type: Other
  intervention name: Questionnaire Administration
  description: Ancillary studies
  arm group label: ARM B (Observation)
  arm group label: Arm A (Zanubrutinib)
  arm group label: Induction therapy (Zanubrutinib, rituximab)
  criteria: 
  gender: All
  minimum age: 60 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Anne Meaden, MD
  phone: 919-966-9268
  email: anne_beaven@med.unc.edu
  last name: Destin Carlisle
  phone: 773-702-8824
  email: dcarlisle@bsd.uchicago.edu
  responsible party type: Sponsor
  mesh term: Lymphoma
  mesh term: Lymphoma, Mantle-Cell
  mesh term: Rituximab
  mesh term: Zanubrutinib
  mesh term: Fluorodeoxyglucose F18
  sharing ipd: Undecided