Phase 3 Multicenter Randomized Study of Rituximab Plus Zanubrutinib Versus Rituximab Monotherapy in Untreated Symptomatic Splenic Marginal Zone Lymphoma

The primary objective of this Phase 3, interventional, multicentre, open-label, randomized study is to evaluate the **efficacy** of the addition of zanubrutinib to rituximab versus rituximab monotherapy in subjects with previously untreated, symptomatic **splenic marginal zone lymphoma** (SMZL) in terms of **Progression-Free Survival** (PFS). This is clinically relevant as PFS is a critical endpoint in assessing the effectiveness of cancer therapies, indicating the length of time during and after treatment that a patient lives with the disease without it worsening.

Secondary objectives include:

• Evaluating the activity of the addition of zanubrutinib to rituximab versus rituximab monotherapy in terms of **Overall Response Rate** (ORR), **Duration of Response** (DoR), and **Overall Survival** (OS).
• Assessing the safety profile of the addition of zanubrutinib to rituximab compared to rituximab monotherapy in the same patient population.

The clinical trial involves a total of **30 participants** diagnosed with **splenic marginal zone lymphoma** (SMZL). The study population includes both male and female subjects, aged 18 years and older, with an **ECOG performance status** of 0, 1, or 2. Participants were selected based on their ability to provide informed consent and meet specific health criteria, such as adequate hepatic and renal function, and specific blood count thresholds. The trial excludes vulnerable populations and focuses on individuals with previously untreated SMZL. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Key inclusion criteria include the ability to swallow trial drugs and agreement to use effective birth control methods during and after the trial. Participants must have measurable lesions and meet treatment needs according to ESMO guidelines. The trial does not include individuals with reproductive potential unless they have a negative serum pregnancy test upon study entry.

The clinical trial is a **Phase 3**, interventional, multicentre, open-label, randomized study designed to compare the efficacy of **rituximab** plus **zanubrutinib** versus rituximab monotherapy in patients with previously untreated, symptomatic **splenic marginal zone lymphoma** (SMZL). The primary objective is to evaluate the efficacy of adding zanubrutinib to rituximab in terms of progression-free survival (PFS). The trial is expected to commence recruitment on May 15, 2024, and conclude by May 15, 2029, with an estimated duration of 5 years.

Participants will be randomly assigned to receive either the combination therapy or rituximab alone. The study will involve several key visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as adequate hepatic and renal function, confirmed diagnosis of SMZL, and measurable lesions. Participants must be at least 18 years old and have an ECOG performance status of 0, 1, or 2. Follow-up visits will occur at regular intervals to monitor treatment response and adverse events, with assessments conducted according to the Lugano 2014 criteria. The primary endpoint is the investigator-assessed PFS rate at 3 years, while secondary endpoints include complete remission rates at 12 and 24 months, time to next anti-lymphoma treatment, and overall survival.

The expected length of participant involvement is up to 24 months of treatment, with additional follow-up as necessary. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants will be required to adhere to the study protocol, including the use of highly effective birth control methods during and after the treatment period. The trial will ensure compliance with ICH/GCP regulations, and all participants must provide informed consent prior to any trial-specific procedures.

The clinical trial involves the administration of **Zanubrutinib**, an experimental medication, in the form of a **capsule**. Zanubrutinib is a chemically synthesized active substance, identified by the sponsor product code BGB-3111, and is manufactured by BEIGENE. The medication is administered **orally** with a maximum daily dose of 320 mg. The total maximum dose over the treatment period is 215,040 mg, with a treatment duration of up to 24 months. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to Zanubrutinib, the trial also includes the administration of **Truxima**, a 500 mg concentrate for solution for infusion, which contains the active substance **Rituximab**. Rituximab is a protein-based therapeutic agent, produced by CELLTRION HEALTHCARE HUNGARY KFT. The pharmaceutical form of Truxima is a solution for infusion, administered **intravenously**. The maximum daily dose is 375 mg/m², with a total maximum dose of 1,500 mg/m² over the course of the treatment, which also spans up to 24 months. The administration of Truxima will be conducted under controlled conditions to ensure proper infusion and participant safety.

The trial is designed to compare the efficacy of the combination of Rituximab and Zanubrutinib against Rituximab monotherapy in patients with previously untreated, symptomatic splenic marginal zone lymphoma. The primary objective is to assess the progression-free survival of participants receiving the combination therapy versus those receiving only Rituximab. Compliance with the treatment protocol will be closely monitored to ensure the integrity of the trial data.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression Free Survival (PFS)** in subjects with previously untreated splenic marginal zone lymphoma (SMZL). The primary endpoint is the investigator-assessed PFS rate at 3 years, measured according to the Lugano 2014 criteria. Secondary endpoints include investigator-assessed complete remission rates at 12 and 24 months, best response achieved at any time during the 24-month treatment period, time to next anti-lymphoma treatment (TTNT), duration of response, and overall survival, all assessed according to the Lugano 2014 criteria. Additionally, complete remission rates and best response will also be evaluated using the Matutes criteria.

The trial will involve the administration of rituximab plus zanubrutinib compared to rituximab monotherapy. Efficacy assessments will be conducted at specified intervals throughout the treatment period, with key timepoints at 12 and 24 months. The analysis of type and severity of adverse events will be conducted according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. These assessments will provide comprehensive data on the efficacy of the treatment regimens in achieving disease control and improving patient outcomes.