A Randomized Phase 3 Trial of Continuous vs. Intermittent Maintenance Therapy With Zanubrutinib as Upfront Treatment in Older Patients With Mantle Cell Lymphoma
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 421
- 试验地点
- 238
- 主要终点
- Progression-free survival (PFS) 1 (Arm A)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •• Histologically confirmed mantle cell lymphoma with cyclin D1 (BCL1) expression by immunohistochemical stains and/or evidence of CCND1 rearrangement or t(11;14)(q13;q32) as confirmed by the enrolling center (such as by fluorescence in situ hybridization [FISH], polymerase chain reaction [PCR]/sequencing, karyotype). Patients with cyclin D1 and/or t(11;14) negative mantle cell lymphoma with an expression profile suggesting a diagnosis of mantle cell lymphoma [MCL] such as SOX11 expression are also eligible
- •Any stage allowed (stage I-IV)
- •Patient must have at least one objective measurable disease parameter by PET or CT. Measurable disease in the liver is required if the liver is the only site of lymphoma OR bone marrow involvement by MCL
- •Steroids for management of mantle cell lymphoma are allowed up to a dose of prednisone 100mg/day (or equivalent) for up to 7 days prior to registration
- •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 if thrombocytopenia is due to 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)
- •Known QT correction formula (QTcF) > 480 msecs based on Fredericia's formula (unless pacemaker in place)
- •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
- •Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study.
- •Patients on strong CYP3A4 inducers must discontinue the drug 14 days prior to registration.
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Positron Emission Tomography (Procedure)
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.
干预措施: Biospecimen Collection (Procedure)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
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.
干预措施: Questionnaire Administration (Other)
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.
干预措施: Esophagogastroduodenoscopy (Procedure)
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.
干预措施: Rituximab (Biological)
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.
干预措施: Fludeoxyglucose F-18 (Other)
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.
干预措施: Biospecimen Collection (Procedure)
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.
干预措施: Computed Tomography (Procedure)
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.
干预措施: Questionnaire Administration (Other)
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.
干预措施: Colonoscopy (Procedure)
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.
干预措施: Fludeoxyglucose F-18 (Other)
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.
干预措施: Fludeoxyglucose F-18 (Other)
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.
干预措施: Esophagogastroduodenoscopy (Procedure)
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.
干预措施: Computed Tomography (Procedure)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
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.
干预措施: Esophagogastroduodenoscopy (Procedure)
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.
干预措施: Colonoscopy (Procedure)
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.
干预措施: Biospecimen Collection (Procedure)
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.
干预措施: Questionnaire Administration (Other)
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.
干预措施: Zanubrutinib (Drug)
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.
干预措施: Patient Observation (Other)
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.
干预措施: Bone Marrow Biopsy (Procedure)
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.
干预措施: Positron Emission Tomography (Procedure)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
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.
干预措施: Zanubrutinib (Drug)
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.
干预措施: Colonoscopy (Procedure)
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.
干预措施: Patient Observation (Other)
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.
干预措施: Bone Marrow Biopsy (Procedure)
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.
干预措施: Patient Observation (Other)
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.
干预措施: Bone Marrow Biopsy (Procedure)
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.
干预措施: Positron Emission Tomography (Procedure)
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.
干预措施: Computed Tomography (Procedure)
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.
干预措施: Zanubrutinib (Drug)
结局指标
主要结局
Progression-free survival (PFS) 1 (Arm A)
时间窗: 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)
时间窗: 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.
次要结局
- Overall survival (OS) (Arms A and B)(Time from randomization until death from any cause, assessed up to 10 years)
- Incidence of adverse events(Up to 10 years)
- Overall response rate (ORR, complete + partial remission)(up to 10 years)
- Complete response rate (CR)(Up to 10 years)
- Event-free survival (EFS) 1(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.)
- Event-free survival (EFS) 2(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.)