A Phase 2, Open-Label, Multicenter, Basket Study Evaluating the Safety and Efficacy of Brexucabtagene Autoleucel in Adults with Rare B-cell Malignancies (ZUMA-25) – Substudy A – Relapsed/Refractory Waldenstrom Macroglobulinemia

The primary objective of the ZUMA-25 study is to evaluate the **efficacy** of brexucabtagene autoleucel in subjects with rare B-cell malignancies, specifically by determining the Response Rates as defined within the substudies through central assessment. In substudy A, the focus is on assessing the efficacy of brexucabtagene autoleucel in patients with Relapsed/Refractory Waldenstrom Macroglobulinemia (WM) by determining the combined rate of complete response (CR) and very good partial response (VGPR) according to the criteria set by the Sixth International Workshop in WM.

The secondary objectives of the ZUMA-25 study include:

• Evaluating the Complete Response (CR) by central assessment as defined within each substudy.
• Determining response durability.
• Assessing survival status.
• Evaluating survival status without progression.
• Determining the time to next treatment (TTNT) after administration of brexucabtagene autoleucel.
• Assessing the time to first response.
• For Substudy A (WM), determining the efficacy of brexucabtagene autoleucel by assessing the Objective Response Rate (ORR) through central assessment.
• Determining the combined rate of CR and VGPR by investigator assessment.
• Evaluating the rates of individual responses by central assessment.

The clinical trial involves a total of **25 participants** diagnosed with **Relapsed/Refractory Waldenstrom Macroglobulinemia (WM)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a confirmed clinicopathological diagnosis of WM, measurable disease, and relapsed or refractory disease after two or more lines of therapy. The trial population is characterized by an **ECOG performance status** score of 0 or 1, indicating that participants are fully active or restricted in physically strenuous activity but ambulatory. Adequate hematologic and end-organ function is required, and participants must have stable and recovered toxicities from prior therapies. The trial includes individuals who are part of a vulnerable population, and lifestyle considerations such as the continuation of certain medications like ibrutinib through leukapheresis are noted. The study does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is designed to evaluate the **efficacy** and safety of **brexucabtagene autoleucel** in adults with relapsed or refractory Waldenstrom Macroglobulinemia (WM). This is a Phase 2, open-label, multicenter, basket study. The trial employs a randomized, controlled design, with a primary focus on determining the response rates by central assessment. The trial is expected to run until November 2029, with recruitment having commenced in March 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, measurable disease, and prior treatment history. Following successful screening, participants will receive the investigational product, **brexucabtagene autoleucel**, via intravenous infusion. The treatment period varies, with a maximum duration of 21 days for certain products like **ibrutinib**. Follow-up visits will be scheduled to monitor response rates, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, assessing the final response and any long-term effects.

Participant involvement is expected to last up to the end of the trial, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study protocols. The primary endpoint is the combined rate of complete response (CR) and very good partial response (VGPR) by central assessment. Secondary endpoints include overall survival, progression-free survival, and time to next treatment. The trial aims to provide comprehensive data on the therapeutic potential of **brexucabtagene autoleucel** in treating rare B-cell malignancies, specifically focusing on WM.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Brexucabtagene autoleucel**, marketed as Tecartus, is the primary experimental treatment. It is a genetically modified autologous cell-based product containing T cells transduced ex vivo using a retroviral vector expressing an anti-CD19 chimeric antigen receptor (CAR). The pharmaceutical form is a dispersion for infusion, administered via **intravenous infusion**. The maximum daily and total dose is 200,000,000 cells, with a treatment period of up to 1 day. This product is designated as an orphan drug for the treatment of rare B-cell malignancies.

**Mesna** is used as an auxiliary treatment in the trial. It is a chemical substance known as sodium 2-mercaptoethanesulphonate, serving as a detoxifying agent for antineoplastic treatment. Mesna is administered as an **intravenous injection** with a maximum daily dose of 540 mg and a total dose of 1620 mg over a treatment period of 3 days.

**Ibrutinib**, marketed as IMBRUVICA, is another auxiliary treatment. It is a Bruton's tyrosine kinase inhibitor provided in the form of 140 mg hard capsules. The route of administration is **oral**, with a maximum daily dose of 40 mg and a total dose of 8820 mg over a 21-day treatment period.

**Anhydrous cyclophosphamide** is included as a chemotherapy agent, specifically a nitrogen mustard analogue. It is administered via **intravenous infusion** with a maximum daily dose of 500 mg/m² and a total dose of 1500 mg/m² over 3 days.

**Methylprednisolone** is used as a corticosteroid in the trial. It is administered via **intravenous use** with a maximum daily dose of 3000 mg and a total dose of 36000 mg over a 12-day treatment period.

**Betamethasone sodium phosphate**, also known as dexamethasone, is another corticosteroid used in the trial. It is administered via **intravenous infusion** with a maximum daily dose of 40 µg and a total dose of 960 mg over a 12-day treatment period.

**Fludarabine** is an antineoplastic agent administered via **intravenous infusion**. The maximum daily dose is 30 mg/m², with a total dose of 90 mg/m² over a 3-day treatment period.

Additional non-experimental treatments include immunosuppressive agents, analgesics, antipyretics, and antihistamines, which are administered as needed to manage symptoms and side effects. These treatments are provided in various pharmaceutical forms and routes, including **oral use** and **intravenous infusion**. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols.

The efficacy of brexucabtagene autoleucel in the clinical trial will be assessed primarily by determining the **Response Rates** as defined within the substudies by central assessment. Specifically, for Substudy A, which focuses on relapsed/refractory Waldenstrom Macroglobulinemia (WM), the primary endpoint is the combined rate of complete response (CR) and very good partial response (VGPR) by central assessment, as per the criteria established by the Sixth International Workshop in WM.

Secondary endpoints for the trial include the CR rate by central assessment, duration of response, overall survival, progression-free survival, and time to next treatment. Additionally, the time to first response from brexucabtagene autoleucel infusion to the first response is evaluated. Substudy A-specific secondary endpoints include the overall response rate (ORR), defined as the proportion of subjects achieving a best response of CR, VGPR, or partial response (PR), and the rate of VGPR and PR separately. These efficacy parameters will be measured and analyzed according to the predefined schedule and criteria outlined in the trial protocol.