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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 65
- 试验地点
- 1
- 主要终点
- 24-month complete remission rate
研究概览
简要总结
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.
详细描述
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 .
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. 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; 9.Subjects voluntarily agree to participate in this study, sign the informed consent form, have good compliance, and cooperate with follow-up.
排除标准
- •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;
- •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);
- •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.
研究组 & 干预措施
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.
干预措施: Orelabrutinib (Drug)
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.
干预措施: Zuberitamab (Drug)
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.
干预措施: Cyclophosphamide (Drug)
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.
干预措施: Vincristine (Drug)
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.
干预措施: Prednisoneacetatetablets (Drug)
结局指标
主要结局
24-month complete remission rate
时间窗: From enrollment to 24 months
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.
次要结局
- Objective response rate (ORR) 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(From enrollment to the end of induction treatment at 8 weeks)
- 24-month progression-free survival rate(From enrollment to 24 months)
- 24-Month Overall Survival Rate(From enrollment to 24 months)