Treatment of Orelabrutinib+Hi-CVP Regimen for Previously Untreated MZL

This is an investigator-initiated, prospective, open-label, multicenter Phase II clinical trial evaluating the efficacy and safety of orelabrutinib in combination with anti-CD20 monoclonal antibody-CVP (rituximab or zebetutamab-cyclophosphamide-vincristine-prednisone) followed by orelabrutinib monotherapy maintenance in treatment-naïve patients with marginal zone lymphoma (MZL) .

The study aims to address the unmet clinical need for a highly effective, chemotherapy-free frontline regimen in MZL. While current standard immunochemotherapy regimens-such as bendamustine plus rituximab (BR) or R-CVP-demonstrate meaningful response rates, they are associated with high incidences (60-70%) of Grade 3-4 adverse events, compromising quality of life and long-term tolerability . Building upon promising retrospective data showing 90% ORR and 30% CR with orelabrutinib plus rituximab in frontline MZL , and robust single-agent activity in relapsed/refractory MZL (ORR 68.9%, CR 11.1%) , this trial introduces a novel sequential strategy:

Induction phase: 6 cycles of orelabrutinib (150 mg orally once daily) combined with anti-CD20 monoclonal antibody (375 mg/m² IV), cyclophosphamide (750 mg/m² IV), vincristine (1.4 mg/m² IV, max 2 mg), and prednisone (100 mg IV Days 1-5), administered per 3-week cycle ; Maintenance phase: 18 cycles (1.5 years) of orelabrutinib monotherapy (150 mg QD), extended up to 2 years total treatment duration.

A key scientific innovation lies in the prospective, serial assessment of measurable residual disease (MRD) using next-generation sequencing (NGS) of peripheral blood at three critical timepoints: baseline, end of induction, and 1 year after initiation of maintenance therapy . This exploratory objective seeks to determine whether MRD negativity correlates with prolonged progression-free survival (PFS), overall survival (OS), and critically, prevention of progression within 2 years (POD24)-the strongest prognostic factor in MZL, associated with median survival of only 3-5 years . While MRD has established predictive value in CLL and FL , its role in MZL remains investigational, with only limited retrospective evidence (e.g., 5-year PFS of 74.8% vs. 31.4% in MRD-negative vs. MRD-positive splenic MZL) .

The primary endpoint is the 2-year complete response rate (CR24), with secondary endpoints including ORR and CR at end of induction, 2-year PFS and OS, and MRD dynamics . The study plans to enroll 65 patients across multiple centers, with the lead site-National Cancer Center/CICAMS-enrolling 36 participants . Eligibility requires confirmed CD20⁺ MZL (nodal, extranodal, or splenic), measurable disease, ECOG PS 0-2, and fulfillment of NCCN-defined treatment indications . Exclusion criteria include CNS involvement, active HBV/HCV infection, significant cardiovascular comorbidities (e.g., QTc ≥450/470 ms, LVEF <50%), recent thromboembolic events, or major surgery within 4 weeks .

Safety monitoring adheres strictly to NCI-CTCAE v5.0, with comprehensive AE/SAE collection from first dose through ≥30 days post-last dose, and mandatory 24-hour reporting of SAEs to the sponsor (Beijing Innocare Pharma) and ethics committee

. All procedures comply with the Declaration of Helsinki (1996), China's Good Clinical Practice (GCP) regulations, and require prior approval by the Ethics Committee of The First Affiliated Hospital of Nanchang University . Data will be managed via validated EDC systems, analyzed using SAS 9.3+, and archived for ≥5 years per GCP requirements .

The trial is sponsored by the National Cancer Center/CICAMS, with drug supply provided by Beijing Innocare Pharma (orelabrutinib) and financial support from Zhejiang Borun Biopharmaceutical Co., Ltd. (zebetutamab) . It represents a collaborative effort involving CICAMS' Langfang and Shenzhen branches .

Inclusion criteria

• Age 18 years or older
• ECOG performance status (PS) 0-2
• Expected survival of at least 12 weeks
• CD20-positive marginal zone lymphoma confirmed according to WHO 2022 lymphoma classification standards, including the three subtypes: nodal MZL, extranodal MZL, and splenic MZL
• Measurable lesions by contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI)
• Meet the NCCN guideline criteria for MZL treatment and have not previously received systemic therapy for MZL (excluding hormone therapy and anti-infective treatment)
• Main organ function within normal limits, meeting the following criteria (excluding abnormalities caused by lymphoma):

• Hematology test standards:

• ANC ≥ 1.0 × 10^9/L
• PLT ≥ 75 × 10^9/L (for patients with confirmed bone marrow involvement: ≥ 50 × 10^9/L)
• Hb ≥ 80 g/L
• Biochemistry test standards:

• TBIL < 2 × ULN
• ALT and AST < 2.5 × ULN (for patients with liver involvement, ALT and AST < 5 × ULN)
• Endogenous creatinine clearance ≥ 40 ml/min (Cockcroft-Gault formula)
• Women of childbearing potential must use reliable contraception or have a negative pregnancy test (blood or urine) within 7 days prior to enrollment and agree to use appropriate contraception during the trial and for 8 weeks after the last dose of the study drug. For men, agreement to use appropriate contraception during the trial and for 8 weeks after the last dose of the study drug or previous surgical sterilization is required
• Subjects voluntarily agree to participate in this study, sign the informed consent form, have good compliance, and cooperate with follow-up

Exclusion criteria

• Patients with central nervous system involvement
• Patients with a history of or concurrent untreated malignant tumors, except for cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, and superficial bladder cancer
• Patients with the following cardiovascular diseases: myocardial ischemia or myocardial infarction of grade II or above, uncontrolled arrhythmias (including QTc interval ≥450 ms for men, ≥470 ms for women); heart failure of NYHA class III-IV, or left ventricular ejection fraction (LVEF) <50% as indicated by cardiac ultrasonography; 4. Coagulation dysfunction (INR >1.5 or prothrombin time (PT) > ULN + 4 seconds, or APTT >1.5 ULN), bleeding tendency, or currently receiving thrombolytic or anticoagulant therapy
• Arterial or venous thrombotic events occurring within 12 months prior to enrollment, such as cerebrovascular events (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, or pulmonary embolism
• Known genetic or acquired bleeding or thrombotic disorders (e.g., hemophilia, coagulation disorders)
• Major surgery or severe traumatic injury, fracture, or ulceration within 4 weeks prior to enrollment
• Factors significantly affecting oral drug absorption, such as dysphagia, chronic diarrhea, or intestinal obstruction
• Active infections requiring antimicrobial treatment (e.g., antibacterial or antiviral drugs, excluding chronic hepatitis B antiviral therapy or antifungal treatments); 10. Active hepatitis B (HBV DNA ≥2000 IU/mL or 104 copies/mL) or hepatitis C (HCV antibody positive and HCV RNA above the detection limit of the assay)
• History of substance abuse of psychiatric drugs that cannot be discontinued or mental disorders
• Participation in another anti-tumor drug clinical trial within 4 weeks prior to enrollment
• Treatment with strong CYP3A4 inhibitors within 7 days prior to enrollment, or treatment with strong CYP3A4 inducers within 12 days prior to enrollment
• Pregnant or breastfeeding women; patients of childbearing potential who are unwilling or unable to use effective contraception
• Other conditions that the investigator deems may affect the conduction of the clinical study or the assessment of study results