Application of Orelabrutinib With or Without CD20 Monoclonal Antibody in Previously Untreated Marginal Zone Lymphoma

Application of Orelabrutinib With or Without CD20 Monoclonal Antibody in Previously Untreated Marginal Zone Lymphoma:A Phase II, Prospective, Multicenter, Single-Arm Clinical Study

This study focuses on treatment-naïve marginal zone lymphoma (MZL) patients and aims to investigate the efficacy and safety of orelabrutinib combined with or without CD20 monoclonal antibody.

This is a single-arm study without a control group. All subjects will receive orelabrutinib treatment but will be stratified based on disease stage and clinical characteristics into the following two groups:

1. Stage I MZL Patient Group (Monotherapy Group) Treatment regimen: Orelabrutinib monotherapy. Dosage and administration: Orelabrutinib 150mg, once daily (qd), taken continuously for 21 days per treatment cycle (d1-d21), for a total of 6 cycles (C1-C6).

   Target population: Patients with Ann Arbor Stage I gastric MALT MZL, including H. pylori-negative patients or those with unsatisfactory response after anti-H. pylori therapy, as well as other Stage I MZL patients unsuitable for local radiotherapy.

   Sample size: 50 cases.

2. Stage II-IV MZL Patient Group (Combination Therapy Group) Treatment regimen: Orelabrutinib combined with a CD20 monoclonal antibody. Dosage and administration: Orelabrutinib 150mg, once daily (qd), taken continuously for 21 days per treatment cycle (d1-d21), for a total of 6 cycles (C1-C6). CD20 monoclonal antibody (either Rituximab 375mg/m², intravenous infusion, Day 1 of each cycle, C1-C6; or Obinutuzumab 1000mg, intravenous infusion, on Days 1, 8, and 15 of Cycle 1 [C1], and on Day 1 of Cycles 2-6 [C2-C6]).

Target population: Patients with Ann Arbor Stage II-IV non-gastric MALT MZL, nodal MZL, splenic marginal zone lymphoma (SMZL), and other Stage II-IV MZL patients unsuitable for local radiotherapy.

Sample size: 38 cases.

Study Overview

• Status: Recruiting
• Conditions: Marginal Zone Lymphoma(MZL)
• Intervention / Treatment: Drug: Orelabrutinib

Detailed Description

This study focuses on treatment-naïve marginal zone lymphoma (MZL) patients and aims to investigate the efficacy and safety of orelabrutinib combined with or without CD20 monoclonal antibody. Given the current lack of a standard first-line treatment regimen for MZL, and the limited efficacy and significant side effects associated with commonly used immunochemotherapy regimens, chemotherapy-free approaches have attracted considerable attention. As a domestically developed new-generation BTK inhibitor, orelabrutinib exhibits high selectivity and a favorable safety profile, and demonstrates synergistic effects with CD20 monoclonal antibodies. The study enrolls treatment-naïve MZL patients at different stages, administering either orelabrutinib monotherapy or combination therapy with a CD20 monoclonal antibody. Efficacy indicators, such as overall response rate and complete response rate, are closely monitored, with tumor changes assessed through regular imaging and laboratory examinations. Meanwhile, all types of adverse reactions are documented in detail to evaluate safety. Long-term follow-up is conducted to track progression-free survival and overall survival, comprehensively analyzing whether this combination regimen can emerge as a highly effective, low-toxicity, chemotherapy-free option.

This is a single-arm study without a control group. All subjects will receive orelabrutinib treatment but will be stratified based on disease stage and clinical characteristics into the following two groups:

1. Stage I MZL Patient Group (Monotherapy Group) Treatment regimen: Orelabrutinib monotherapy. Dosage and administration: Orelabrutinib 150mg, once daily (qd), taken continuously for 21 days per treatment cycle (d1-d21), for a total of 6 cycles (C1-C6).

   Target population: Patients with Ann Arbor Stage I gastric MALT MZL, including H. pylori-negative patients or those with unsatisfactory response after anti-H. pylori therapy, as well as other Stage I MZL patients unsuitable for local radiotherapy.

   Sample size: 50 cases.

2. Stage II-IV MZL Patient Group (Combination Therapy Group) Treatment regimen: Orelabrutinib combined with a CD20 monoclonal antibody. Dosage and administration: Orelabrutinib 150mg, once daily (qd), taken continuously for 21 days per treatment cycle (d1-d21), for a total of 6 cycles (C1-C6). CD20 monoclonal antibody (either Rituximab 375mg/m², intravenous infusion, Day 1 of each cycle, C1-C6; or Obinutuzumab 1000mg, intravenous infusion, on Days 1, 8, and 15 of Cycle 1 [C1], and on Day 1 of Cycles 2-6 [C2-C6]).

Target population: Patients with Ann Arbor Stage II-IV non-gastric MALT MZL, nodal MZL, splenic marginal zone lymphoma (SMZL), and other Stage II-IV MZL patients unsuitable for local radiotherapy.

Sample size: 38 cases.

• Study Type: Interventional
• Enrollment (Estimated): 88
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Liang Wang, MD; Phone Number: +86 15013009093; Email: wangliangtrhos@126.com
• Study Contact Backup: Name: Wei Zhang, MD; Phone Number: +86 13681473557; Email: vv1223@vip.sina.com

Study Locations

• China
  • Beijing, China
    • Not yet recruiting
    • Peking Union Medical College Hospital
    • Contact: Wei Zhang, PhD; Phone Number: +86 13681473557; Email: vv1223@vip.sina.com
  • Beijing, China
    • Recruiting
    • Beijing Tongren Hospital
    • Contact: Liang Wang, PhD; Phone Number: +86 15013009093; Email: wangliangtrhos@126.com
  • Beijing, China
    • Not yet recruiting
    • The First Affiliated Hospital of China Medical University
    • Contact: Xiaojing Yan, PhD; Phone Number: +86 13889128302; Email: yanxiaojingpp@hotmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥ 18 years;
• Pathologically confirmed marginal zone lymphoma;
• Presence of evaluable lesions;
• Meets indications for treatment: Fulfills the GELF criteria OR has disease-related clinical symptoms/organ function impairment;
• Patients who are unsuitable for local radiotherapy, refuse local radiotherapy, or have disease progression after local therapy. Cases considered unsuitable for local radiotherapy include the following:

Gastric MALT MZL, Ann Arbor stage I, that is H. pylori-negative, or H. pylori-positive gastric MALT MZL (Ann Arbor stage I) with poor response to H. pylori eradication therapy;

Non-gastric MALT and nodal MZL in Ann Arbor non-contiguous stage II or stages III-IV;

SMZL;

Gastric MALT classified as Lugano II2, IIE, or IV stage;

Patient intolerance to radiotherapy;

Other MZL patients deemed unsuitable for local radiotherapy by the investigator.

• ECOG score of 0-3;
• Expected survival time ≥ 3 months;
• Ability to provide signed informed consent.

Exclusion Criteria:

• Currently diagnosed with another malignant tumor;
• Central nervous system involvement by lymphoma or transformation to a higher grade;
• Allergy to any of the investigational drugs;
• Active infection or uncontrolled HBV infection, HIV/AIDS, or other serious infectious diseases;
• Pregnancy, lactating women, or subjects of childbearing potential unwilling to use contraception;
• Other situations deemed by the investigator as unsuitable for participation in this trial.

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: Orelabrutinib-based treatments; This is a single-arm study without a control group. All subjects will receive orelabrutinib treatment but will be stratified based on disease stage and clinical characteristics into the following two groups: Stage I MZL Patient Group (Monotherapy Group) Treatment regimen: Orelabrutinib monotherapy. Dosage and administration: Orelabrutinib 150mg, once daily (qd), taken continuously for 21 days per treatment cycle (d1-d21), for a total of 6 cycles (C1-C6).; Stage II-IV MZL Patient Group (Combination Therapy Group) Treatment regimen: Orelabrutinib combined with a CD20 monoclonal antibody. Dosage and administration: Orelabrutinib 150mg, once daily (qd), taken continuously for 21 days per treatment cycle (d1-d21), for a total of 6 cycles (C1-C6). CD20 monoclonal antibody (either Rituximab 375mg/m², intravenous infusion, Day 1 of each cycle, C1-C6; or Obinutuzumab 1000mg, intravenous infusion, on Days 1, 8, and 15 of Cycle 1 [C1], and on Day 1 of Cycles 2-6 [C2-C6].

Drug: Orelabrutinib; Stage I MZL Patients:Treatment with Orelabrutinib monotherapy. Induction Phase: During Cycles 1-6 (C1-C6), Orelabrutinib 150mg is administered orally once daily (qd) on Days 1-21 (d1-d21) of each cycle.; Stage II-IV MZL Patients: Treatment with the Orelabrutinib plus CD20 monoclonal antibody regimen, divided into an induction phase and a maintenance phase. Induction Phase: During Cycles 1-6 (C1-C6), Orelabrutinib 150mg is administered orally once daily (150mg qd d1-d21/C1-C6). Concurrently, a CD20 monoclonal antibody is used: either Rituximab 375mg/m² intravenously (iv) on Day 1 of each cycle (d1/C1-C6); or Obinutuzumab, administered as 1000mg intravenously on Days 1, 8, and 15 of Cycle 1 (1000mg iv d1,d8,d15/C1), followed by 1000mg intravenously on Day 1 of Cycles 2-6 (1000mg iv d1/C2-C6). Maintenance Phase: If maintenance therapy is administered, during Cycles 7-30 (C7-C30), Orelabrutinib 150mg is administered orally once daily (qd) on Days 1-28 (d1-d28) of each cycle.; Other Names: Rituximab; Obinutuzumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Best Overall Response Rate (ORR): Efficacy is assessed every two treatment cycles. The best ORR achieved within the 6 treatment cycles serves as the primary endpoint.	From enrollment to the end of treatment at 21 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate	Best Complete Response Rate (CRR): Efficacy is assessed every two treatment cycles. The best CRR achieved within the 6 treatment cycles serves as a secondary endpoint.	From enrollment to the end of treatment at 21 weeks
2-Year Progression-Free Survival Rate	2-Year PFS (Progression-Free Survival) refers to the time interval from the date a patient begins treatment until either disease progression, relapse, or death from any cause reaches two years. If the patient does not experience disease progression and remains alive within the two-year period, they are considered to have achieved 2-year PFS. If disease progression or death occurs within the two years, 2-year PFS is not achieved.	From enrollment to 2 years
2-Year Overall Survival Rate	2-Year Overall Survival Rate (OS): OS is defined as the time from the date of study enrollment until the patient dies from any cause or is lost to follow-up.	From enrollment to 2 years
AE	Safety is evaluated according to the CTCAE v5.0 criteria. Toxicity assessments are performed during each treatment cycle, primarily focusing on hematological toxicities and non-hematological toxicities.	Through study completion, an average of 2.5 years

Collaborators and Investigators

• Sponsor: Beijing Tongren Hospital
• Investigators: Principal Investigator: Liang Wang, MD, Beijing Tongren Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2025
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: November 20, 2025
• First Submitted That Met QC Criteria: January 13, 2026
• First Posted (Actual): January 21, 2026

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Marginal Zone Lymphoma; Orelabrutinib; CD20 Monoclonal Antibody
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, B-Cell, Marginal Zone; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived; Rituximab; obinutuzumab; orelabrutinib
• Other Study ID Numbers: TREC2025-KY209

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: after the publishment of this study
• IPD Sharing Access Criteria: upon request to the PI after the publishment of this study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No