Orelabrutinib plus zebetuzumab and lenalidomide vs bendamustine‑rituximab for newly diagnosed marginal zone lymphoma

A Prospective Multicenter Study of Orelabrutinib Combined With Zebetuzumab and Lenalidomide or Bendamustine Combined With Rituximab for the Treatment of Newly Diagnosed MZL

This study will test whether a combination of orelabrutinib, zebetuzumab, and lenalidomide helps people with newly diagnosed marginal zone lymphoma compared with a standard bendamustine plus rituximab regimen.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 169 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: The First Affiliated Hospital with Nanjing Medical University (Academic / other)
• Drugs / interventions: radiation, zebetuzumab, rituximab, orelabrutinib
• Locations: 1 site (Nanjing, Jiangsu)
• Trial ID: NCT07208981 on ClinicalTrials.gov

What this trial studies

This is an open‑label, multicenter phase 2, non‑randomized study enrolling adults with newly diagnosed CD20‑positive marginal zone lymphoma. Participants meeting treatment indications receive either the experimental oral BTK inhibitor orelabrutinib combined with zebetuzumab and lenalidomide or a comparator arm of bendamustine plus rituximab. Investigators will monitor tumor response and side effects through scheduled visits and imaging over the planned follow‑up period. The goal is to characterize response rates and the safety profile of the experimental combination in the frontline setting.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18–75 with histologically confirmed CD20‑positive MZL (MALT, SMZL, or NMZL), at least one measurable lesion, and a clinical indication for systemic treatment.

Not a fit: Patients unlikely to benefit include those outside the 18–75 age range, those without measurable disease or without indications for immediate treatment, and patients with prior therapy for MZL or significant comorbidities that preclude study drugs.

Why it matters

Potential benefit: If successful, the experimental combination could produce higher remission rates or a tolerable chemo‑sparing option compared with standard chemoimmunotherapy.

How similar studies have performed: Elements of this approach—BTK inhibitors and lenalidomide‑based or rituximab‑based regimens—have shown activity in MZL, but this specific three‑drug combination is novel and not yet proven in prior trials.

Eligibility criteria

Inclusion Criteria:

* 1\. Age 18-75 years, gender not restricted;
* 2\. Histopathologically confirmed CD20-positive marginal zone lymphoma includes MALT, SMZL, and NMZL; at least one measurable lesion;
* 3\. Indication for treatment

  * 3.1. Initial diagnosis II 2 or IIE or IV stage gastric MALT treatment indications. Including: ① Meeting the inclusion criteria for clinical trials; ② Presence of lymphoma-related clinical symptoms; ③ Gastrointestinal bleeding (bleeding condition controlled or assessed by the investigator for suitability of inclusion); ④ End-organ damage; ⑤ Large mass; ⑥ Persistent or rapid disease progression; ⑦ Patient's willingness;
  * 3.2. Recommendations for treatment indications of newly diagnosed stage III-IV non-gastric MALT and NMZL. The GELF criteria, similar to those used for follicular lymphoma, include: ① The presence of ≥3 distinct regions of involved lymph nodes, with each involved lymph node having a diameter of ≥3 cm; ② The presence of any lymph node or extranodal lesion with a diameter \>7 cm; ③ The presence of B symptoms; ④ Splenomegaly; ⑤ Symptoms of organ compression, pleural or peritoneal effusion; ⑥ Cytopenia caused by the disease; ⑦ Persistent or rapid disease progression, with tumor size increasing by 20%-30% within 2-3 months or approximately 50% within 6 months; ⑧ Meeting the inclusion criteria for clinical trials;
  * 3.3. Recommended indications for the treatment of newly diagnosed SMZL. Including: ① Progressive or painful splenomegaly; ② Symptomatic or progressive cytopenia such as HB\<100g/L, PLT\<80×10\^9/L, absolute neutrophil count (ANC)\<1.0×10\^9/L (note to differentiate from cytopenia caused by autoimmune factors);
* 4\. Without prior systemic treatment, may include MZL (marginal zone lymphoma) that has progressed, relapsed, or is unsuitable for local treatment after previous local therapy (local treatment includes surgery, radiotherapy, anti-Helicobacter pylori therapy for at least 12 months, or anti-hepatitis C therapy);
* 5\. ECOG performance status score 0-2 points
* 6\. The main organ functions meet the following criteria (except for SMZL, which is judged separately by the investigator to meet treatment requirements): Complete blood count: Absolute neutrophil count ≥1.5×10\^9/L, platelets ≥75×10\^9/L, hemoglobin ≥75g/L; if accompanied by bone marrow involvement, absolute neutrophil count ≥1.0×10\^9/L, platelets ≥50×10\^9/L, hemoglobin ≥50g/L; Blood biochemistry: Total bilirubin ≤ 1.5 times ULN, AST or ALT ≤ 2 times ULN; serum creatinine ≤ 1.5 times ULN; serum amylase ≤ ULN; creatinine clearance rate ≥ 60 mL/min;
* 7\. Coagulation function: International Normalized Ratio (INR) ≤1.5 times ULN;
* 8\. Expected survival time ≥ 12 months;
* 9\. Voluntarily sign a written informed consent before trial screening.

Exclusion Criteria:

* 1\. Currently or previously diagnosed with other malignancies, unless radical treatment has been performed and there is evidence of no recurrence or metastasis within the past 5 years, excluding cured cervical carcinoma in situ, basal cell carcinoma of the skin, and localized squamous cell carcinoma of the skin;
* 2\. Lymphoma involving the central nervous system or transforming to a higher grade;
* 3\. Uncontrolled or significant cardiovascular diseases, including: a) Occurrence of New York Heart Association (NYHA) Class III-IV congestive heart failure, unstable angina, myocardial infarction within 6 months prior to the first administration of the investigational drug, or the presence of treatable arrhythmias at screening, with left ventricular ejection fraction (LVEF) \<50%; b) Primary cardiomyopathies (such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy); c) A clinically significant history of QTc interval prolongation, or QTc interval during the screening period \>470ms for females and \>450ms for males; d) Subjects with symptomatic or medication-requiring coronary heart disease; e) Suffering from uncontrolled hypertension (blood pressure remains uncontrolled after more than one month of using a reasonable and tolerable dosage of three or more antihypertensive drugs (including diuretics) based on lifestyle improvements, or blood pressure can only be effectively controlled by taking four or more antihypertensive drugs);
* 4\. Active bleeding within 2 months prior to screening, or currently taking anticoagulants, or deemed by the investigator to have a clear bleeding tendency;
* 5\. History of deep vein thrombosis or pulmonary embolism in the past six months;
* 6\. Underwent major surgery within 6 weeks prior to screening or minor surgery within 2 weeks prior to screening. Major surgery refers to procedures performed under general anesthesia, but endoscopic examinations for diagnostic purposes are not considered major surgery. The insertion of vascular access devices is exempt from this exclusion criterion;
* 7\. Active infection or uncontrolled HBV (HBsAg positive and/or HBcAb positive with HBV DNA titer positive), HCV RNA positive, HIV/AIDS, or other severe infectious diseases;
* 8\. Currently, there are subjects with severe pulmonary function impairment due to conditions such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, and drug-related pneumonia: FEV1% or DLCO (or DLCO/VA) %pred \< 40% (with severe pulmonary ventilation and gas exchange dysfunction);
* 9\. Pregnant, lactating women and childbearing age subjects unwilling to use contraception;
* 10\. Need to continuously take medications with moderate to strong inhibitory or strong inducing effects on cytochrome P450 CYP3A;
* 11\. The investigator considers other conditions unsuitable for participating in this trial.

Where this trial is running

Nanjing, Jiangsu

• The First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital — Nanjing, Jiangsu, China (Recruiting)

Study contacts

• Study coordinator: Jianyong Li, PhD, MD

Conditions Marginal Zone Lymphoma