A Phase II Clinical Study of Zanubrutinib Combined With Four Cycles of CD20 Monoclonal Antibody and Reduced-Dose Bendamustine in the Treatment of Untreated Waldenström Macroglobulinemia (ZBR in WM)

This study is a prospective phase II clinical trial designed to evaluate the deep response rate of the ZBR regimen (zanubrutinib combined with reduced-dose bendamustine and CD20 Monoclonal Antibody ) in treatment-naïve symptomatic Waldenström macroglobulinemia (WM) patients. Eligible patients will receive four cycles of the ZBR regimen, followed by zanubrutinib monotherapy for an additional eight months. The assessment period spans from the initiation of treatment until 12 months after treatment completion, with efficacy evaluations conducted every three cycles. Patients will be withdrawn from the study if they experience disease progression (PD) or show no response to treatment. Minimal residual disease (MRD) assessments will be performed at the end of the 3rd and 6th treatment cycles, as well as 12 months after treatment completion, involving evaluations of both bone marrow and peripheral blood MRD rates

Study Overview

• Status: Not yet recruiting
• Conditions: Waldenström Macroglobulinemia (WM)
• Intervention / Treatment: Drug: Zaunbrutinib, Bendamustine and Rituximab for induction therapy; Drug: Zanubrutinib mono therapy for maintenance treatment

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shuhua Yi, Dr; Phone Number: +86-022-23608109; Email: yishuhua@ihcams.ac.cn
• Study Contact Backup: Name: Wenjie Xiong; Phone Number: +86-022-23608123; Email: xiongwenjie@ihcams.ac.cn

Study Locations

• China
  • China
    • Tianjin, China, China, 300020
      • China Institute of Hematology and Blood Diseases Hospital ,Chinese Academy of Medical Sciences
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300020
      • Institute of Hematology & Blood Diseases Hospital, China

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Male or female patients aged ≥18 years.
• 2. Must meet the diagnostic criteria for Waldenström's Macroglobulinemia (WM).
• 3. Patients must be treatment-naïve or not have received standard prior therapy, as defined by the following conditions: a) No prior combined chemotherapy with regimens such as BR, RCD, BCD, CHOP, or COP. b) No prior therapy with fludarabine-containing regimens. c) Treatment with chlorambucil or cyclophosphamide (alone or in combination with glucocorticoids) for less than 4 weeks. d) Failure to achieve a minimal response (MR) from the above treatments. e) If any of the above treatments were previously administered, a washout period of at least 2 weeks must be completed before study treatment initiation.
• 4. Presence of indications for WM treatment, meeting at least one of the following criteria: a) Symptomatic hyperviscosity. b) Symptomatic peripheral neuropathy. c) Amyloidosis. d) Cold agglutinin disease; cryoglobulinemia. e) Disease-related cytopenia (Hemoglobin <100 g/L or Platelet count <100×10^9/L). f) Massive lymphadenopathy. g) Presence of constitutional symptoms: persistent/recurrent fever (>38°C) for over 2 weeks unrelated to infection, drenching night sweats, and/or unintentional weight loss >10% within 6 months. h) Rapid disease progression, defined as a >50% increase in lymph node size within 2 months, and/or lymphocyte doubling time <6 months, and/or rapid decline in hemoglobin or platelet counts not due to autoimmune causes. i) Evidence of histologic transformation.
• 5. ECOG Performance Status score of ≤2.
• 6. Laboratory values meeting the following criteria within the screening period: Absolute Neutrophil Count (ANC) ≥ 0.75 × 10^9/L; Platelet count ≥ 50 × 10^9/L; Total Bilirubin ≤ 2 × Upper Limit of Normal (ULN); Alanine Aminotransferase (ALT) / Aspartate Aminotransferase (AST) ≤ 3 × ULN; Calculated creatinine clearance ≥ 30 mL/min (using Cockcroft-Gault formula)
• 7. Life expectancy of ≥ 6 months.

Exclusion Criteria:

• 1. Diagnosis or treatment for any malignancy other than B-cell non-Hodgkin lymphoma (B-NHL) within the past year (including active central nervous system lymphoma).
• 2. Clinical evidence of transformation to large cell lymphoma.
• 3.Pre-existing severe hepatic or renal impairment unrelated to lymphoma: ALT > 3 × ULN; AST > 3 × ULN; Total Bilirubin > 2 × ULN; Estimated creatinine clearance < 30 mL/min
• 4.Any other severe concurrent medical condition that would, in the investigator's judgment, compromise the patient's ability to participate in the study (e.g., uncontrolled diabetes, gastric ulcer, significant cardiac or pulmonary disease, etc.). The final determination rests with the investigator.
• 5. Known history of human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotic therapy. Note: Active HBV infection is defined by ALL of the following criteria: a. HBV DNA ≥ 2000 IU/mL; b. ALT ≥ 2 × ULN; c. Hepatitis not attributable to other causes such as the underlying disease or drugs. Patients with initially active HBV who convert to an inactive carrier state after antiviral therapy may be enrolled if they receive adequate concomitant antiviral prophylaxis.
• 6. Symptomatic central nervous system dysfunction or involvement (Bing-Neel syndrome).
• 7. Major surgery within 14 days prior to the first dose of study drug or anticipated requirement for major surgery during the study treatment period (excluding lymph node biopsy).
• 8. Inability to swallow capsules, or conditions significantly affecting gastrointestinal function (e.g., malabsorption syndrome, status post-gastrectomy or small bowel resection, symptomatic inflammatory bowel disease, ulcerative colitis, partial or complete intestinal obstruction).
• 9. Requirement for concurrent strong Cytochrome P450 (CYP) 3A inhibitors.
• 10. Pregnancy or lactation. Women of childbearing potential unwilling to use effective contraception during the study period.
• 11. Known hypersensitivity to any of the study drugs or their excipients.

Withdrawal Criteria

• 1. Disease progression during treatment (after ≥2 cycles of therapy) or failure to achieve at least a minimal response (MR) after 6 cycles of therapy.
• 2. Occurrence of intolerable adverse events or complications.
• 3. Patient's voluntary decision to withdraw consent for continued treatment.
• 4. Pregnancy during the study.
• 5. Investigator's judgment that the patient should discontinue treatment for any other reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental: ZBR

Drug: Zaunbrutinib, Bendamustine and Rituximab for induction therapy; Patients in the experimental group will receive treatment in 4-week cycles, totaling 4 cycles of zanubrutinib + bendamustine + CD20 Monoclonal Antibody therapy, followed by 8 months of zanubrutinib monotherapy maintenance. Specific regimen: Zanubrutinib: Oral administration starts on Day 1 of Cycle 1 and continues continuously at 160 mg twice daily. Bendamustine: Intravenous infusion at 70 mg/m² on Days 1-2 of Cycles 1-4. CD20 Monoclonal Antibody: Intravenous infusion at 375 mg/m² on Day 0 of Cycles 1-4. After completing the 4-cycle combination therapy, a systematic efficacy evaluation will be conducted.; Drug: Zanubrutinib mono therapy for maintenance treatment; Patients will then continue with zanubrutinib monotherapy maintenance for 8 months before treatment discontinuation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best deep response rate(≥VGPR)	defined as the rate of very good partial response VGPR or CR	up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD Negativity Rate at End of Treatment	MRD Negativity Rate at End of Treatment	up to the end of treatment
Duration of Response	The length of time between the achievement of criteria for response to treatment (first documented complete or partial response) and the first documented relapse or progression.	up to 3 years
Objective Response Rate (ORR)	Response Rate (ORR) is defined as the proportion of subjects who achieve CR ,VGPR, PR or MR at the end of Treatment	up to 1 year
Complete Response (CR) Rate	To assess CR rate at the end of treatment	up to 1 year
Major Response Rate (MRR, ≥ Partial Response)	Response Rate (ORR) is defined as the proportion of subjects who achieve CR or PR at the end of Treatment	up to 1 year
Time to First Response	Time to First Observed Response During Treatment	up to 1 year
Time to Best Response	Time to the Best Response	up to the end of treatment
Progression-Free Survival (PFS)	The time from the enrollment of a subject to the occurrence of (in any way) progression of disease or Death for any reason. patients with indeterminate recurrence or Death at the last follow-up, defined as the date of the last Investigation	up to 3 years
Overall Survival (OS) Rate	The time from subject enrollment to Death caused by any reason. for patients lost to follow-up, the time of the last follow-up; for patients still alive at the end of study, the date of the end of follow-up.	up to 3 years
Time to Next Treatment (TTNT)	Time from the initiation of the current treatment regimen to the start of the next line of therapy	up to 3 years
Treatment-Related Adverse Events (AEs)	Incidence of adverse events, serious adverse events and significant adverse event	up to 3 years

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Shuhua Yi, Institute of Hematology & Blood Diseases Hospital, China

Study record dates

Study Major Dates

• Study Start (Estimated): December 30, 2025
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: November 14, 2025
• First Submitted That Met QC Criteria: November 21, 2025
• First Posted (Actual): December 2, 2025

Study Record Updates

• Last Update Posted (Actual): December 2, 2025
• Last Update Submitted That Met QC Criteria: November 21, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: bendamustine; zanubrutinib
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Waldenstrom Macroglobulinemia; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Therapeutics; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Butyrates; Antibodies, Monoclonal, Murine-Derived; Combined Modality Therapy; Bendamustine Hydrochloride; Rituximab; Neoadjuvant Therapy
• Other Study ID Numbers: IIT2025111

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