The Efficacy and Safety of ZR2 Versus R-miniCHOP in the Treatment of Unfit or Frail de Novo Diffuse Large B-cell Lymphoma Patients Aged Older Than or Equal to 70 Years

Study Overview
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Brief Summary
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A multicenter, prospective, randomized, open-label, controlled trial to evaluate the efficacy and safety of zanubrutinib, rituximab and lenalidomide (ZR2) versus rituximab combined with low-dose CHOP (R-miniCHOP) in the treatment of unfit or frail de novo diffuse large B-cell lymphoma patients aged older than or equal to 70 years

Detailed Description
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This study will evaluate the efficacy and safety of ZR2 versus R-miniCHOP in the treatment of unfit or frail de novo diffuse large B-cell lymphoma patients aged older than or equal to 70 years. Subjects will be randomly assigned 1:1 to ZR2 or R-miniCHOP regimen. The stratification will be performed according to international prognostic index (0-2 / 3-5). Patients in ZR2 group will receive 6 cycles of zanubrutinib 160mg bid, day 1-21, orally, lenalidomide 25mg qd, day 2-11, orally, rituximab 375mg/m², day 1, intravenously, every 21 days. Patients in R-miniCHOP group will receive rituximab 375 mg/m² on day 1, cyclophosphamide 400 mg/m², doxorubicin 25 mg/m², and vincristine 1 mg on day 2, and prednisone 40 mg/m² on days 2-6, every 21 days.

Official Title
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The Efficacy and Safety of Zanubrutinib, Rituximab and Lenalidomide (ZR2) Versus Rituximab Combined With Low-dose CHOP (R-miniCHOP) in the Treatment of Unfit or Frail de Novo Diffuse Large B-cell Lymphoma Patients Aged Older Than or Equal to 70 Years: A Multicenter, Prospective, Randomized, Open-label, Controlled Trial

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: six courses of zanubrutinib, rituximab and lenalidomide
* Drug: six courses of rituximab combined with low-dose CHOP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must satisfy all of the following criteria to be enrolled in the study: Histologically-confirmed diffuse large B-cell lymphoma (without central nervous system involvement) Eastern Cooperative Oncology Group performance status 0-3 Aged ≥ 80 years old or aged 70-79 with comprehensive geriatric assessment stratified as unfit or frail International normalized ratio and activated partial thromboplastin time are both 1.5 times lower than the upper limits of normal (ULN). At least 1 measurable site of disease (defined as lymph nodes with the long diameters longer than 1.5cm, or extra-nodal sites with the long diameters longer than 1.0cm; meanwhile, any lesion site with at least 2 measurable vertical diameters) Life expectancy of at least 3 months determined by researchers The patient or his or her legal representative must provide written informed consent prior to any special examination or procedure for the research. Anti-lymphoma drugs have not been used before (except glucocorticoids). Exclusion criteria Presence of any of the following criteria will exclude a patient from enrollment: Uncontrolled cardio- and cerebro-vascular disease, blood clotting disorders, connective tissue diseases, serious infectious diseases and other diseases Laboratory measures meet the following criteria at screening (unless caused by lymphoma): Neutrophils<1.5×10^9/L Platelets<80×10^9/L (Platelets<50×10^9/L in case of bone marrow involvement) ALT or AST is 2 times higher than the upper limits of normal (ULN), AKP and bilirubin are 1.5 times higher than the ULN. Creatinine is 1.5 times higher than the ULN or eGFR is lower than 40ml/min/1.73m^2 (according to Cockcroft-Gault Equation or MDRD Equation). HIV-infected patients Left ventricular ejection fraction<50% Patients with HbsAg positive are required to have HBV DNA<1.0×10^3 IU/ml before entering the group. In addition, if the patient is HBsAg negative but HBcAb positive (regardless of HBsAb status), HBV DNA test is also required, and HBV DNA<1.0×10^3 IU/ml is required before entering the group. Other anti-tumor treatments (lymphoma or other types of tumors) are currently in progress. Patients with psychiatric disorders or patients who are known or suspected to be unable to fully comply with the study protocol Require treatment with strong/moderate CYP3A inhibitors or inducers. History of stroke or intracranial hemorrhage within 6 months prior to start of therapy Inability to swallow capsules or presence of diseases that significantly affect gastrointestinal function, such as malabsorption syndrome, post-bariatric surgery, inflammatory bowel disease and complete or incomplete intestinal obstruction Other medical conditions determined by the researchers that may affect the study

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZR2<br>six courses of zanubrutinib, rituximab and lenalidomide | Drug: six courses of zanubrutinib, rituximab and lenalidomide<br>* Patients in ZR2 group will receive 6 cycles of zanubrutinib 160mg bid, day 1-21, orally, lenalidomide 25mg qd, day 2-11, orally, rituximab 375mg/m², day 1, intravenously, every 21 days.<br>|
| Active Comparator: R-miniCHOP<br>six courses of rituximab combined with low-dose CHOP | Drug: six courses of rituximab combined with low-dose CHOP<br>* Patients in R-miniCHOP group will receive rituximab 375 mg/m² on day 1, cyclophosphamide 400 mg/m², doxorubicin 25 mg/m², and vincristine 1 mg on day 2, and prednisone 40 mg/m² on days 2-6, every 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression-free survival was defined as the time from the date of randomization until the date of the first documented day of disease progression or relapse, using 2014 Lugano criteria, or death from any cause, whichever occurred first. | Baseline up to data cut-off (up to approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate | Percentage of participants with complete response was determined on the basis of investigator assessments according to 2014 Lugano criteria. | At the end of Cycle 6 (each cycle is 21 days) | 
| Overall survival | Overall survival was defined as the time from the date of randomization to the date of death from any cause. | Baseline up to data cut-off (up to approximately 2 years) | 
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0 | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | From enrollment to study completion, a maximum of 4 years | 
| Percentage of Participants Achieving Meaningful Improvement in European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) | Quality of Life will be assessed by EORTC QLQ-C30 (Verison 3.0). | Day 1 of Cycles 1 and 4 (Cycle length=21 days); 30 days after treatment completion | 
| Percentage of Participants Achieving Meaningful Improvement in EORTC QLQ-ELD14 (Elderly Module) | Quality of Life will be assessed by EORTC QLQ-ELD14. | Day 1 of Cycles 1 and 4 (Cycle length=21 days); 30 days after treatment completion | 
| Percentage of Participants Achieving Meaningful Improvement in Functional Assessment of Cancer Therapy-Lymphoma Lymphoma Subscale (FACT-Lym LymS) | Quality of Life will be assessed by FACT-Lym LymS. | Day 1 of Cycles 1 and 4 (Cycle length=21 days); 30 days after treatment completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lenalidomide, Rituximab, R-miniCHOP, Diffuse Large B-Cell Lymphoma, Elderly patients, Zanubrutinib