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

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 C, which focuses on relapsed/refractory Burkitt Lymphoma (BL), the primary objective is to assess the efficacy of brexucabtagene autoleucel by determining the objective response rate (ORR) through central assessment. This is clinically relevant as it aims to provide insights into the potential therapeutic benefits of brexucabtagene autoleucel for patients with these challenging conditions.

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.
• Determining the time to first response.
• For Substudy C (BL), specifically evaluating the efficacy of brexucabtagene autoleucel in subjects with BL by determining the ORR by investigator assessment.

The clinical trial involves a total of **15 participants** diagnosed with **Relapsed/Refractory Burkitt Lymphoma (BL)**. The study population includes both male and female subjects who are 18 years of age or older. Participants were selected based on specific criteria, including having at least one measurable lesion according to the Lugano Classification and a stable recovery from prior therapy toxicities to Grade 1 or lower. The trial includes individuals with an **ECOG performance status** score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate hematologic and end-organ function. The study population is characterized by a history of relapsed or refractory disease following first-line chemoimmunotherapy. Lifestyle considerations such as diet and physical activity are not specified, but participants of childbearing potential must agree to use specified contraception methods. The trial does not exclude vulnerable populations, indicating a broad inclusion of eligible subjects.

The clinical trial is designed to evaluate the efficacy of **brexucabtagene autoleucel** in adults with relapsed or refractory Burkitt lymphoma. This is a Phase 2, open-label, multicenter, basket study. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from March 2023 to February 2027, with participant involvement expected to last up to 22 months, depending on individual response and treatment cycles.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, measurable lesions, and performance status. Following successful screening, participants will receive the investigational product via **intravenous infusion**. The primary endpoint is the objective response rate, determined by central assessment using the Lugano Classification. Secondary endpoints include complete response rate, duration of response, overall survival, and progression-free survival.

Study visits will include regular follow-up assessments to monitor response to treatment and any adverse events. These visits are crucial for evaluating the safety and efficacy of the treatment. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment's impact.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. The trial is conducted in accordance with regulatory guidelines to ensure participant safety and data integrity. The study aims to provide valuable insights into the treatment of rare B-cell malignancies, specifically focusing on Burkitt lymphoma.

The clinical trial involves the administration of several **experimental medications** and auxiliary treatments. **Brexucabtagene autoleucel**, marketed as Tecartus, 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. It is administered as a dispersion for infusion with a dosage form of 0.4 – 2 × 10^8 cells, delivered via **intravenous infusion**. The maximum daily and total dose is 200,000,000 cells, with a treatment period of 1 day.

**Gemcitabine** is a pyrimidine nucleoside antimetabolite administered as an intravenous infusion. The pharmaceutical form is PHF00230MIG, with a maximum daily and total dose of 1000 mg/m². The treatment period is limited to 1 day.

**Vinblastine sulfate**, also known as **vincristine**, is an antineoplastic agent administered via intravenous infusion. The pharmaceutical form is PHF675, with a maximum daily dose of 2 mg and a total dose of 4 mg/kg over a treatment period of 4 days.

**Doxorubicin** is an antimitotic and cytotoxic agent administered as an intravenous infusion. The pharmaceutical form is PHF00231MIG, with a maximum daily and total dose of 50 mg/m², over a treatment period of 4 days.

**Fludarabine** is an antineoplastic agent administered via intravenous infusion. The pharmaceutical form is PHF675, with a maximum daily dose of 30 mg/m² and a total dose of 90 mg/m² over a treatment period of 3 days.

**Anhydrous cyclophosphamide** is an antineoplastic agent administered as an intravenous infusion. The pharmaceutical form is PHF00231MIG, with a maximum daily dose of 750 mg/m² and a total dose of 1500 mg/m² over a treatment period of 3 days.

**Mesna** is a detoxifying agent for antineoplastic treatment, administered via intravenous injection. The pharmaceutical form is PHF00231MIG, with a maximum daily dose of 540 mg/m² and a total dose of 1620 mg/m² over a treatment period of 3 days.

**Carboplatin** is an antineoplastic agent administered as an intravenous infusion. The pharmaceutical form is PHF00230MIG, with a maximum daily and total dose of 800 mg, over a treatment period of 1 day.

**Dexamethasone**, a corticosteroid, is administered both orally and intravenously. The pharmaceutical form is PHF00231MIG, with a maximum daily dose of 40 mg and a total dose of 480 mg over a treatment period of 12 days.

**Ifosfamide** is an antineoplastic agent administered via intravenous infusion. The pharmaceutical form is PHF00231MIG, with a maximum daily dose of 5000 mg/m² and a total dose of 15000 mg/m² over a treatment period of 3 days.

**Oxaliplatin** is a platinum-containing antineoplastic agent administered as an intravenous infusion. The pharmaceutical form is PHF00230MIG, with a maximum daily and total dose of 100 mg/m², over a treatment period of 1 day.

**Methylprednisolone**, a corticosteroid, is administered via intravenous use. The pharmaceutical form is PHF00230MIG, with a maximum daily dose of 3000 mg and a total dose of 36000 mg over a treatment period of 12 days.

**Etoposide** is a chemotherapy agent administered as an intravenous infusion. The pharmaceutical form is PHF675, with a maximum daily dose of 100 mg/m² and a total dose of 300 mg/m² over a treatment period of 4 days.

**Prednisolone**, a corticosteroid, is administered orally. The pharmaceutical form is PHF00059MIG, with a maximum daily dose of 120 mg/m² and a total dose of 600 mg/m² over a treatment period of 5 days.

**Alpelisib** is an antineoplastic agent administered orally. The pharmaceutical form is PHF00082MIG, with a maximum daily dose of 400 mg and a total dose of 8800 mg over a treatment period of 22 days.

**Rituximab** is administered via intravenous use. The pharmaceutical form is PHF00230MIG, with a maximum daily dose of 375 mg/m² and a total dose of 750 mg/m² over a treatment period of 2 days.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. The administration of these medications is conducted under strict clinical supervision to ensure participant safety and data integrity.

The efficacy of brexucabtagene autoleucel in the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which is defined as the proportion of subjects achieving a best response of either complete response (CR) or partial response (PR). This assessment will be conducted by central evaluation according to the Lugano Classification. The primary endpoint for Substudy C, focusing on relapsed/refractory Burkitt Lymphoma, is the ORR as determined by central assessment.

Secondary endpoints 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 will be measured. These secondary endpoints will be evaluated by investigator assessment per the Lugano Classification. The schedule for these assessments will align with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration.