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 D - Relapsed/Refractory Hairy Cell Leukemia (HCL)

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. This is clinically relevant as it aims to establish the therapeutic potential of brexucabtagene autoleucel in treating these malignancies, which include Relapsed/Refractory Hairy Cell Leukemia (HCL). In substudy D, the focus is on evaluating the efficacy in subjects with HCL by determining the objective response rate (ORR) through central assessment.

The secondary objectives of the study include:

• Evaluating the Complete Response (CR) by central assessment as defined within each substudy.
• Determining response durability.
• Determining survival status.
• Determining survival status without progression.
• Determining the time to next treatment (TTNT) after administration of brexucabtagene autoleucel.
• Determining the time to first response.
• Evaluating the efficacy of brexucabtagene autoleucel in subjects with HCL by ORR by investigator assessment in Substudy D.

The clinical trial involves a total of **8 participants** diagnosed with **Relapsed/Refractory Hairy Cell Leukemia**. The study population includes both male and female subjects aged 18 years or older. Participants were selected based on specific criteria, including a stable recovery from prior therapy toxicities to Grade 1 or lower, an ECOG performance status score of 0 or 1, and adequate hematologic and end-organ function. The trial population is characterized by individuals who have received at least two prior therapies, including a purine nucleoside analog and moxetumomab pasudotox if eligible and available. Participants must have a histologically confirmed need for therapy due to conditions such as neutrophils < 1.0 x 10^9/L, platelets < 100 x 10^9/L, hemoglobin < 11 g/dL, symptomatic splenomegaly, or symptomatic lymphadenopathy. The study includes individuals of childbearing potential who agree to use specified contraception methods. The trial does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across a diverse group of subjects.

The clinical trial is designed as a **Phase 2, open-label, multicenter, basket study** to evaluate the safety and efficacy of **brexucabtagene autoleucel** in adults with rare B-cell malignancies, specifically focusing on **relapsed/refractory hairy cell leukemia (HCL)**. The trial employs a **randomized, controlled** methodology to ensure robust data collection and analysis. The primary objective is to determine the objective response rate (ORR) by central assessment, while secondary endpoints include complete response (CR) rate, duration of response, overall survival, progression-free survival, and time to next treatment.

The trial is expected to run from March 2023 to November 2029, with participant involvement lasting up to 12 months, depending on individual response and treatment schedules. The study includes several key visits: an initial **screening visit** to confirm eligibility based on criteria such as age, ECOG performance status, and hematologic function; **treatment visits** where participants receive the investigational product; and **follow-up visits** to monitor response and safety. The **end-of-study visit** will assess the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest. The trial is not a low-intervention study, and all procedures are conducted in accordance with regulatory standards to ensure participant safety and data integrity. The investigational product, brexucabtagene autoleucel, is administered via **intravenous infusion**, and the trial includes auxiliary medications such as **methylprednisolone** and **cyclophosphamide** to support the treatment regimen. The study aims to provide valuable insights into the treatment of rare B-cell malignancies, contributing to the advancement of therapeutic options for these conditions.

The clinical trial involves the administration of **brexucabtagene autoleucel**, marketed as Tecartus, which is a genetically modified autologous cell-based product. This experimental medication is provided as a dispersion for infusion, with a dosage form of 0.4 – 2 × 10^8 cells. The route of administration is **intravenous infusion**, and the maximum daily and total dose is 200,000,000 cells. The treatment period is limited to one day. This product is specifically designed for the treatment of rare B-cell malignancies, including relapsed/refractory hairy cell leukemia.

**Methylprednisolone** is used as a non-experimental treatment in this study. It is a corticosteroid administered via **intravenous use**. The pharmaceutical form is coded as PHF00230MIG, with a maximum daily dose of 3000 mg and a total dose of 36,000 mg over a treatment period of up to 12 days. This medication is utilized to manage inflammation and immune responses.

**Fludarabine**, an antineoplastic agent, is administered as an **intravenous infusion**. The pharmaceutical form is PHF675, with a dosing unit of mg/m². The maximum daily dose is 30 mg/m², and the total dose is 90 mg/m² over a treatment period of three days. This agent is used in the chemotherapy regimen for its cytotoxic effects on cancer cells.

**Mesna** is employed as a detoxifying agent for antineoplastic treatment. It is administered via **intravenous injection** with a pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 540 mg, and the total dose is 1620 mg over a three-day treatment period. Mesna is used to mitigate the toxic effects of certain chemotherapy drugs.

**Anhydrous cyclophosphamide** is a chemotherapy agent administered as an **intravenous infusion**. The pharmaceutical form is PHF00231MIG, with a dosing unit of mg/m². The maximum daily dose is 500 mg/m², and the total dose is 1500 mg/m² over a three-day treatment period. It is a nitrogen mustard analogue used for its antineoplastic properties.

**Dexamethasone**, a corticosteroid, is administered via **intravenous infusion**. The pharmaceutical form is PHF00231MIG, with a maximum daily dose of 40 mg and a total dose of 960 mg over a 12-day treatment period. It is used to reduce inflammation and suppress immune responses.

Additional non-experimental treatments include an **analgesic and antipyretic** administered orally, with a maximum daily and total dose of 1000 mg over one day, and an **antihistamine** administered both orally and intravenously, with a maximum daily and total dose of 25 mg over one day. These treatments are used to manage symptoms and side effects associated with the primary therapy.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy and safety of the experimental and non-experimental treatments in the context of rare B-cell malignancies.

The efficacy of brexucabtagene autoleucel in the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)** by central assessment. This primary endpoint is defined as the proportion of subjects who achieve either a complete response (CR) or partial response (PR) in the context of the study. The secondary endpoints include the CR rate by central assessment, duration of response, overall survival, progression-free survival, time to next treatment, and time to first response from brexucabtagene autoleucel infusion to the first response as defined in the substudy. Additionally, the substudy D specific secondary endpoint is ORR by investigator assessment, also defined as the proportion of subjects achieving CR or PR.