Orelabrutinib Combined With Rituximab ± Lenalidomide in Response-Adapted Stratified Therapy for Untreated MZL

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

This is a prospective, single-arm, phase II study aimed at evaluating the safety and efficacy of orelabrutinib combined with rituximab ± lenalidomide in response-adapted stratified therapy for untreated marginal zone lymphoma. The primary endpoint is the complete response rate (CRR).

Study Overview

• Status: Recruiting
• Conditions: Marginal Zone Lymphoma(MZL)
• Intervention / Treatment: Drug: Orelabrutinib; Drug: Rituximab; Drug: Lenalidomide

Detailed Description

Marginal zone lymphoma (MZL) is a type of lymphoma that comprises three main subtypes: extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, nodal MZL, and splenic MZL. Accounting for approximately 7.8% of all non-Hodgkin lymphomas (NHL), MZL is the third most common subtype, following diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Although generally considered an indolent lymphoma with a favorable overall survival prognosis, some patients still face challenges such as disease relapse or transformation into aggressive large cell lymphoma, which leads to a poor prognosis.

This is a prospective, single-arm, phase II study designed to evaluate the safety and efficacy of orelabrutinib combined with rituximab ± lenalidomide in response-adapted stratified therapy for untreated marginal zone lymphoma. Eligible patients who meet the screening criteria will enter the treatment phase and receive orelabrutinib in combination with rituximab. After 6 cycles, patients who achieve complete response (CR) will continue with orelabrutinib and rituximab for an additional 6 cycles; patients with partial response (PR) or stable disease (SD) will receive orelabrutinib combined with rituximab and lenalidomide for an additional 6 cycles; patients with progressive disease (PD) will be withdrawn from the study.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lei Fan, PhD, MD; Phone Number: +86 13813976136; Email: fanlei3014@126.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • The First Affiliated Hospital with Nanjing Medical University
      • Contact: Lei Fan, PhD, MD; Phone Number: +86 13813976136; Email: fanlei3014@126.com

Participation Criteria

Eligibility Criteria

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

Description

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.

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: Orelabrutinib Combined with Rituximab ± Lenalidomide	Drug: Orelabrutinib; Orelabrutinib: 150mg qd C1-C6; Drug: Rituximab; Rituximab: C1-C6; Drug: Lenalidomide; After 6 cycles of orelabrutinib + rituximab CR: Continue orelabrutinib + rituximab for 6 cycles. PR/SD: Switch to orelabrutinib + rituximab + lenalidomide for 6 cycles. PD: Discontinue study treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate (CRR)	CRR is defined as the proportion of patients with complete response	At the end of cycle 12 (each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	ORR is the proportion of patients who achieve either a complete or partial response	At the end of cycle 12(each cycle is 21 days)
2 years Progression free survival (PFS)	PFS is defined as the time from registration to the first occurrence of progression or relapse as assessed by the investigator, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment.	From date of signing the informed consent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
2 years overall survival (OS)	Overall survival is defined as the period from the induction registration to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date	From date of signing the informed consent until the date of death from any cause, whichever came first, assessed up to 2 years

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: January 28, 2026
• First Submitted That Met QC Criteria: March 2, 2026
• First Posted (Actual): March 4, 2026

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: April 1, 2025

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; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carboxylic Acids; Piperidines; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Isoindoles; Lenalidomide; Rituximab; orelabrutinib
• Other Study ID Numbers: 2025-SR-258

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No