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

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

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

Study Overview

• Status: Recruiting
• Conditions: Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: six courses of zanubrutinib, rituximab and lenalidomide; Drug: six courses of rituximab combined with low-dose CHOP

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 280
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Weili Zhao; Phone Number: 610707 +862164370045; Email: zwl_trial@163.com
• Study Contact Backup: Name: Pengpeng Xu; Phone Number: 610707 +862164370045; Email: pengpeng_xu@126.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200020
      • Recruiting
      • Ruijin Hospital
      • Contact: Weili Zhao; Phone Number: 610707 +862164370045; Email: zwl_trial@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 68 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

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):

  1. Neutrophils<1.5×10^9/L
  2. Platelets<80×10^9/L (Platelets<50×10^9/L in case of bone marrow involvement)
  3. 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.
  4. 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZR2; six courses of zanubrutinib, rituximab and lenalidomide	Drug: six courses of zanubrutinib, rituximab and lenalidomide; 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.
Active Comparator: R-miniCHOP; six courses of rituximab combined with low-dose CHOP	Drug: six courses of rituximab combined with low-dose CHOP; 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.

What is the study measuring?

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
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
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)
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

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Collaborators: The First Affiliated Hospital of Nanchang University; Qilu Hospital of Shandong University; Hunan Cancer Hospital; First Affiliated Hospital of Fujian Medical University; The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; Shandong Provincial Hospital; The First Hospital of Jilin University; Henan Provincial People's Hospital; Wuhan Union Hospital, China; Sir Run Run Shaw Hospital; First Hospital of China Medical University; Northern Jiangsu Province People's Hospital; Ningbo No. 1 Hospital; The Affiliated Hospital of Xuzhou Medical University; Taizhou Hospital; The Second Affiliated Hospital of Dalian Medical University; Affiliated Hospital of Nantong University; Changzhou No.2 People's Hospital; Shanghai Fengxian District Central Hospital; Huai'an First People's Hospital; Huadong Hospital; National Naval Medical Center; The First People's Hospital of Changde City; YANCHENG NO.1 PEOPLE'S HOSPITAL; Wuxi Branch of Ruijin Hospital; The First People's Hospital of Kunshan; HARBIN THE FIRST HOSPITAL; THE FIRST AFFILIATED HOSPITAL; SUZHOU HONGCI HEMATOLOGY HOSPITAL

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2022
• Primary Completion (Anticipated): December 25, 2025
• Study Completion (Anticipated): December 25, 2025

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: December 16, 2021
• First Posted (Actual): January 5, 2022

Study Record Updates

• Last Update Posted (Actual): May 23, 2023
• Last Update Submitted That Met QC Criteria: May 20, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Rituximab; Lenalidomide; Elderly patients; Diffuse Large B-Cell Lymphoma; Zanubrutinib; R-miniCHOP
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Lenalidomide; Rituximab; Zanubrutinib
• Other Study ID Numbers: NHL-014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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