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

Official title

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

Overview

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).

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combined with rituximab and lenalidomide for an additional 6 cycles; patients with progressive disease (PD) will be withdrawn from the study.

Interventions

• 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.

Primary outcome measures

• Complete response rate (CRR) [Time frame: At the end of cycle 12 (each cycle is 21 days)]

Secondary outcome measures (3)

• Overall response rate (ORR) [Time frame: At the end of cycle 12(each cycle is 21 days)]
• 2 years Progression free survival (PFS) [Time frame: 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) [Time frame: From date of signing the informed consent until the date of death from any cause, whichever came first, assessed up to 2 years]

Eligibility criteria

Inclusion criteria

• Aged ≥18 years, either sex.
• Histopathologically confirmed CD20-positive marginal zone lymphoma (including MALT, SMZL, and NMZL) with at least 1 measurable lesion.
• Stage III or IV disease with an indication for treatment.
• 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.
• ECOG performance status of 0-2.
• Adequate organ function meeting the following criteria:

• 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.
• Blood chemistry: Total bilirubin ≤1.5×ULN, AST or ALT ≤2×ULN; serum creatinine ≤1.5×ULN; serum amylase ≤ULN.
• Coagulation: International normalized ratio (INR) ≤1.5×ULN.
• Expected survival ≥12 months.
• Voluntary provision of written informed consent before trial screening.

Exclusion criteria

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

• 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%.
• Primary cardiomyopathy (e.g., dilated, hypertrophic, arrhythmogenic right ventricular, restrictive, or unclassified cardiomyopathy).
• History of clinically significant QTc interval prolongation, or QTc interval >470 ms (female) or >450 ms (male) at screening.
• Symptomatic coronary artery disease or subjects requiring medication for it.
• 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).
• 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.
• History of deep vein thrombosis or pulmonary embolism within the past 6 months.
• History of organ transplantation or allogeneic bone marrow transplantation.
• 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.
• 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.)
• Current conditions severely impairing pulmonary function, such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or drug-related pneumonia.
• Prior treatment with BTK inhibitors, BCR pathway inhibitors (e.g., PI3K, Syk inhibitors), or BCL-2 inhibitors.
• Pregnancy, lactation, or unwillingness to use effective contraception in subjects of childbearing potential.
• Concomitant use of moderate/strong cytochrome P450 CYP3A inhibitors or strong inducers.
• Any other condition considered by the investigator to make the subject unsuitable for trial participation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital with Nanjing Medical University — Nanjing

Identifiers

NCT: NCT07448324 · 2025-SR-258

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗