Exploratory Study of Orelabrutinib in the Treatment of Early-stage Untreated MZL

Orelabrutinib for the Treatment of Marginal Zone Lymphoma: A Phase II, Multicenter, Open-label Study

This is a single-arm, multicenter, prospective, phase II study. The primary objective is to assess the efficacy and safety of orelabrutinib in treatment-naïve patients with marginal zone lymphoma.

Marginal zone lymphoma (MZL) is a group of indolent B-cell malignancies originating from B lymphocytes, primarily occurring in the marginal zones of the spleen, lymph nodes, and mucosa-associated lymphoid tissues. Its histological features are characterized by abnormal proliferation of marginal zone cells surrounding lymphoid follicles. The Bruton tyrosine kinase (BTK) signaling pathway plays a critical role in B-cell receptor-mediated signal transduction and is significant in the development and progression of various B-cell malignancies. Ibrutinib, as the first BTK inhibitor, has demonstrated remarkable efficacy in the treatment of B-cell lymphomas. However, its poor kinase selectivity leads to a high incidence of off-target toxicities, including thrombocytopenia, neutropenia, bleeding, fatigue, rash, and atrial fibrillation in clinical settings, which limits its long-term use. Orelabrutinib is a highly selective oral small-molecule BTK inhibitor belonging to the nicotinamide class of compounds. It covalently binds to BTK and represents a new generation of selective irreversible BTK inhibitors. Due to its higher selectivity for BTK and favorable safety profile observed in previous human studies, orelabrutinib holds promise as a superior therapeutic option for B-cell malignancies. To further improve clinical outcomes for MZL patients, there is an urgent need to explore treatment strategies with better efficacy and lower toxicity. This study aims to evaluate the efficacy and safety of orelabrutinib in previously untreated localized-stage MZL patients, providing new therapeutic evidence for this population.

This study is a multicenter, prospective trial involving previously untreated patients with MZL. During the induction phase (cycles 1-6), patients will receive orelabrutinib 150 mg, administered in 28-day treatment cycles. Following completion of the induction phase, patients will be followed during a post-treatment follow-up period.

Inclusion Criteria:

1. Age ≥18 years, regardless of gender;

2. Patients with histopathologically confirmed stage I/II marginal zone lymphoma;

3. ECOG performance status score of 0-2;

4. Major organ functions meeting the following criteria:

   1. Blood tests: Absolute neutrophil count (ANC) ≥1.5×10^9/L, platelets ≥75×10^9/L, hemoglobin ≥75g/L; if accompanied by bone marrow involvement, ANC ≥1.0×10^9/L, platelets ≥50×10^9/L, hemoglobin ≥50g/L;
   2. Blood biochemistry: Total bilirubin ≤1.5×ULN, AST or ALT ≤2×ULN; serum creatinine ≤1.5×ULN;

5. Coagulation function: International normalized ratio (INR) ≤1.5×ULN;

6. Expected survival time ≥12 months;

7. Voluntary written informed consent signed before trial screening.

Exclusion Criteria:

1. Lymphoma involving the central nervous system or transformation to high-grade;

2. 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 dose of the study drug, or arrhythmia requiring treatment at screening, with left ventricular ejection fraction (LVEF) <50%;
   2. Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, or unclassified cardiomyopathy);
   3. History of clinically significant QTc interval prolongation, or QTc interval >470 ms for females or >450 ms for males at screening;
   4. Subjects with symptomatic coronary artery disease requiring medication;
   5. Poorly controlled hypertension (failure to achieve target blood pressure after at least one month of lifestyle modification and treatment with three or more antihypertensive drugs, including diuretics, at maximally tolerated doses, or requiring four or more antihypertensive drugs for effective control).

3. Active bleeding within 2 months prior to screening, or current use of anticoagulants, or investigator-determined clear bleeding tendency;

4. History of deep vein thrombosis or pulmonary embolism within the past six months;

5. Urine protein ≥2+ and 24-hour urine protein quantification ≥2 g/24 hours;

6. Clinically significant gastrointestinal abnormalities that may affect drug intake, transport, or absorption (e.g., inability to swallow, chronic diarrhea, intestinal obstruction), or subjects with total gastrectomy;

7. Current pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, or other conditions affecting lung function;

8. Pregnant or breastfeeding women, or subjects of childbearing potential unwilling to use contraception;

9. Continuous use of drugs with moderate to strong cytochrome P450 CYP3A inhibition or strong induction effects;

10. Other conditions deemed by the investigator as unsuitable for participation in this trial.