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.

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.

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.