Orelabrutinib plus rituximab with optional lenalidomide for untreated marginal zone lymphoma using a response-adapted plan

Orelabrutinib Combined With Rituximab ± Lenalidomide in Response-Adapted Stratified Therapy for Untreated MZL#a Prospective Single Arm Trial

This will test whether giving orelabrutinib with rituximab, and adding lenalidomide for those who don't fully respond, helps people with newly diagnosed marginal zone lymphoma achieve complete remissions.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: The First Affiliated Hospital with Nanjing Medical University (Academic / other)
• Drugs / interventions: radiation, rituximab, orelabrutinib
• Locations: 1 site (Nanjing, Jiangsu)
• Trial ID: NCT07448324 on ClinicalTrials.gov

What this trial studies

This is a prospective, single-arm phase II trial that gives all eligible, untreated CD20-positive MZL patients orelabrutinib combined with rituximab. After six treatment cycles, patients who reach a complete response continue orelabrutinib plus rituximab for six more cycles, while those with a partial response or stable disease receive lenalidomide added for the next six cycles; patients with progressive disease are withdrawn. The study's primary endpoint is complete response rate, with safety and tolerability also monitored. The design aims to personalize therapy intensity based on early response while avoiding upfront multiagent systemic therapy for all patients.

Who should consider this trial

Good fit: Adults aged 18 or older with histologically confirmed CD20-positive stage III or IV marginal zone lymphoma, at least one measurable lesion, ECOG 0–2, adequate organ function, and no prior systemic therapy are eligible.

Not a fit: Patients who have received prior systemic lymphoma therapy, who have inadequate organ function, who cannot travel to the study site, or who progress during initial therapy are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could raise complete remission rates and offer a more targeted frontline option that tailors additional therapy only to those who need it.

How similar studies have performed: Other BTK inhibitors and combinations of rituximab with lenalidomide have shown activity in MZL, but this specific orelabrutinib-plus-rituximab with response-adapted lenalidomide approach is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Aged ≥18 years, either sex.
2. Histopathologically confirmed CD20-positive marginal zone lymphoma (including MALT, SMZL, and NMZL) with at least 1 measurable lesion.
3. Stage III or IV disease with an indication for treatment.
4. No prior systemic therapy. Patients may have received prior local treatment (including surgery, radiotherapy, anti-Helicobacter pylori therapy, or anti-hepatitis C therapy) if they subsequently progressed, relapsed, or were unsuitable for local therapy.
5. ECOG performance status of 0-2.
6. Adequate organ function meeting the following criteria:

   1. Blood count: Absolute neutrophil count ≥1.5×10⁹/L, platelets ≥75×10⁹/L, hemoglobin ≥75 g/L. If bone marrow involvement is present: absolute neutrophil count ≥1.0×10⁹/L, platelets ≥50×10⁹/L, hemoglobin ≥50 g/L.
   2. Blood chemistry: Total bilirubin ≤1.5×ULN, AST or ALT ≤2×ULN; serum creatinine ≤1.5×ULN; serum amylase ≤ULN.
7. Coagulation: International normalized ratio (INR) ≤1.5×ULN.
8. Expected survival ≥12 months.
9. Voluntary provision of written informed consent before trial screening.

Exclusion Criteria:

1. Current or history of other malignancies, unless treated with curative intent and without evidence of recurrence or metastasis within the past 5 years.
2. Central nervous system involvement or transformation to high-grade lymphoma.
3. Uncontrolled or significant cardiovascular diseases, including:

   1. New York Heart Association (NYHA) Class II or higher congestive heart failure, unstable angina, myocardial infarction within 6 months prior to the first study drug dose, or arrhythmia requiring treatment at screening; left ventricular ejection fraction (LVEF) \<50%.
   2. Primary cardiomyopathy (e.g., dilated, hypertrophic, arrhythmogenic right ventricular, restrictive, or unclassified cardiomyopathy).
   3. History of clinically significant QTc interval prolongation, or QTc interval \>470 ms (female) or \>450 ms (male) at screening.
   4. Symptomatic coronary artery disease or subjects requiring medication for it.
   5. Poorly controlled hypertension (defined as failure to achieve target blood pressure after ≥1 month of lifestyle modification combined with an adequate, tolerable regimen of ≥3 antihypertensive drugs including a diuretic, or requiring ≥4 antihypertensive drugs for control).
4. Active bleeding within 2 months prior to screening, current use of anticoagulants, or any condition deemed by the investigator to indicate a clear bleeding tendency.
5. History of deep vein thrombosis or pulmonary embolism within the past 6 months.
6. History of organ transplantation or allogeneic bone marrow transplantation.
7. Major surgery within 6 weeks or minor surgery within 2 weeks prior to screening. Major surgery requires general anesthesia (diagnostic endoscopy excluded). Insertion of vascular access devices is exempt.
8. Active infection or uncontrolled HBV (HBsAg positive and/or HBcAb positive with positive HBV DNA), HCV Ab positive, HIV/AIDS, or other serious infectious diseases. (Active infection is defined as requiring systemic antimicrobial therapy or associated with systemic signs/symptoms of inflammation.)
9. Current conditions severely impairing pulmonary function, such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or drug-related pneumonia.
10. Prior treatment with BTK inhibitors, BCR pathway inhibitors (e.g., PI3K, Syk inhibitors), or BCL-2 inhibitors.
11. Pregnancy, lactation, or unwillingness to use effective contraception in subjects of childbearing potential.
12. Concomitant use of moderate/strong cytochrome P450 CYP3A inhibitors or strong inducers.
13. Any other condition considered by the investigator to make the subject unsuitable for trial participation.

Where this trial is running

Nanjing, Jiangsu

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

Study contacts

• Study coordinator: Lei Fan, PhD, MD

Conditions Marginal Zone Lymphoma