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

Orelabrutinib Combined With Anti-CD20 Monoclonal Antibody-CVP Regimen for the Treatment of Previously Untreated Marginal Zone Lymphoma:A Pospective, Multicenter, Open-label Phase II Clinical Study

In patients with previously untreated Marginal zone lymphoma (MZL), a treatment regimen of Orelabrutinib,Zuberitamab combined with Cyclophosphamide,Vincristine,Prednisoneacetatetablets is planned to be used.

Study Overview

• Status: Active, not recruiting
• Conditions: Marginal Zone Lymphoma(MZL)
• Intervention / Treatment: Drug: Orelabrutinib; Drug: Zuberitamab; Drug: Cyclophosphamide; Drug: Vincristine; Drug: Prednisoneacetatetablets

Detailed Description

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 .

• Study Type: Interventional
• Enrollment (Estimated): 65
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, beijing,

Participation Criteria

Eligibility Criteria

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

Description

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):

  1. Hematology test standards:

     1. ANC ≥ 1.0 × 10^9/L
     2. PLT ≥ 75 × 10^9/L (for patients with confirmed bone marrow involvement: ≥ 50 × 10^9/L)
     3. Hb ≥ 80 g/L

  2. Biochemistry test standards:

     1. TBIL < 2 × ULN
     2. ALT and AST < 2.5 × ULN (for patients with liver involvement, ALT and AST < 5 × ULN)
     3. 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

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: Patients with Marginal zone lymphoma who are treatment-naive; After the patient received one cycle of the anti-CD20 monoclonal antibody CVP regimen, obinutuzumab was added starting from the second cycle for combination therapy. After a total of five cycles of the obinutuzumab combined with the anti-CD20 monoclonal antibody CVP regimen, maintenance treatment with obinutuzumab monotherapy was administered for 18 cycles or until disease progression or unacceptable toxicity occurred.

Drug: Orelabrutinib; After the patient received one cycle of the anti-CD20 monoclonal antibody CVP regimen, obinutuzumab was added starting from the second cycle for combination therapy. After a total of five cycles of the obinutuzumab combined with the anti-CD20 monoclonal antibody CVP regimen, maintenance treatment with obinutuzumab monotherapy was administered for 18 cycles or until disease progression or unacceptable toxicity occurred.; Other Names: Orelabrutinib Tablets; Drug: Zuberitamab; After the patient received one cycle of the anti-CD20 monoclonal antibody CVP regimen, obinutuzumab was added starting from the second cycle for combination therapy. After a total of five cycles of the obinutuzumab combined with the anti-CD20 monoclonal antibody CVP regimen, maintenance treatment with obinutuzumab monotherapy was administered for 18 cycles or until disease progression or unacceptable toxicity occurred.; Other Names: Zebutumab; Drug: Cyclophosphamide; After the patient received one cycle of the anti-CD20 monoclonal antibody CVP regimen, obinutuzumab was added starting from the second cycle for combination therapy. After a total of five cycles of the obinutuzumab combined with the anti-CD20 monoclonal antibody CVP regimen, maintenance treatment with obinutuzumab monotherapy was administered for 18 cycles or until disease progression or unacceptable toxicity occurred.; Other Names: Cytoxan; Endoxan; Drug: Vincristine; After the patient received one cycle of the anti-CD20 monoclonal antibody CVP regimen, obinutuzumab was added starting from the second cycle for combination therapy. After a total of five cycles of the obinutuzumab combined with the anti-CD20 monoclonal antibody CVP regimen, maintenance treatment with obinutuzumab monotherapy was administered for 18 cycles or until disease progression or unacceptable toxicity occurred.; Other Names: VDS; Drug: Prednisoneacetatetablets; After the patient received one cycle of the anti-CD20 monoclonal antibody CVP regimen, obinutuzumab was added starting from the second cycle for combination therapy. After a total of five cycles of the obinutuzumab combined with the anti-CD20 monoclonal antibody CVP regimen, maintenance treatment with obinutuzumab monotherapy was administered for 18 cycles or until disease progression or unacceptable toxicity occurred.; Other Names: Decadron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-month complete remission rate	All visible tumor lesions have completely disappeared, no new lesions have appeared, and this has been maintained for at least 4 weeks at 24-month.	From enrollment to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR) at the end of induction therapy	The overall response rate (ORR) was defined as the cumulative proportion of patients attaining either a complete response (CR) or partial response (PR) at the end of induction therapy .	From enrollment to the end of induction treatment at 8 weeks
Complete remission rate (CRR) at the end of induction therapy	All visible tumor lesions have completely disappeared, no new lesions have appeared, and this has been maintained for at least 4 weeks at the end of induction therapy.	From enrollment to the end of induction treatment at 8 weeks
24-month progression-free survival rate	PFS defined as the time from RD initiation to first documented disease progression, relapse after RD, death from any cause, or last follow-up at 24-month..	From enrollment to 24 months
24-Month Overall Survival Rate	OS was measured from RD start to death or last follow-up at 24-month.	From enrollment to 24 months

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Collaborators: InnoCare Pharma Inc.; BioRay Pharmaceutical Co., Ltd.
• Investigators: Study Chair: Xinxin Cao, doctor, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2025
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 2, 2029

Study Registration Dates

• First Submitted: March 14, 2026
• First Submitted That Met QC Criteria: March 14, 2026
• First Posted (Actual): March 18, 2026

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 29, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• 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; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Hydrocarbons, Cyclic; Alkaloids; Hydrocarbons, Aromatic; Indoles; Benzene Derivatives; Sulfonic Acids; Sulfur Acids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Benzenesulfonates; Arylsulfonates; Arylsulfonic Acids; Cyclophosphamide; Vincristine; Calcium Dobesilate; orelabrutinib
• Other Study ID Numbers: NCCH0037

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