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 B – Relapsed/Refractory Richter Transformation (RT)

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 assess the potential of brexucabtagene autoleucel in providing therapeutic benefits to patients with these challenging conditions. In substudy B, the focus is on evaluating the efficacy of brexucabtagene autoleucel on diffuse large B cell lymphoma (DLBCL)-Richter Transformation (RT) in subjects with RT, by determining the objective response rate (ORR) through central assessment.

The secondary objectives of ZUMA-25 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 on DLBCL-RT in subjects with RT, by determining the ORR by investigator assessment.
• Evaluating the efficacy of brexucabtagene autoleucel on DLBCL-RT based on clonal relationship to the underlying chronic lymphocytic leukemia (CLL) by central assessment.
• Evaluating the efficacy of brexucabtagene autoleucel on the underlying CLL by investigator assessment.

The clinical trial involves a total of **25 participants** diagnosed with **relapsed/refractory Richter Transformation (RT)**, a rare B-cell malignancy. The study population includes both male and female subjects who are **18 years of age or older**. Participants were selected based on specific inclusion criteria, including having at least one measurable lesion according to the Lugano Classification and a confirmed diagnosis of chronic lymphocytic leukemia (CLL) with histologically confirmed RT to a diffuse large B-cell lymphoma (DLBCL) subtype. The trial population is characterized by an **ECOG performance status score of 0 or 1**, indicating a relatively stable general health status. Participants must have adequate hematologic and end-organ function, and any toxicities from prior therapies must be stable and recovered to Grade 1 or lower. Lifestyle considerations such as diet and physical activity are not specified, but participants of childbearing potential are required to use specified methods of contraception. The trial does not specify any particular lifestyle habits or restrictions beyond these criteria.

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 **Richter Transformation (RT)**. The trial employs a non-randomized, controlled methodology, with the primary objective being the assessment of the objective response rate (ORR) by central assessment. The trial is expected to run from March 2023 to November 2026, with participant involvement anticipated to last up to 25 weeks, depending on individual response and treatment tolerance.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, measurable lesions, and adequate organ function. Following successful screening, participants will receive the investigational product, **brexucabtagene autoleucel**, via intravenous infusion. Subsequent follow-up visits will be scheduled to monitor response and manage any adverse events. The end-of-study visit will conclude the participant's involvement, assessing the final response and overall health status.

Participant involvement may be terminated early if significant adverse events occur, if the participant withdraws consent, or if the investigator deems it necessary for the participant's safety. The trial's primary endpoint is the ORR, defined as the proportion of subjects achieving a complete or partial response. Secondary endpoints include the duration of response, overall survival, and progression-free survival, among others. The trial aims to provide valuable insights into the efficacy of brexucabtagene autoleucel for patients with relapsed/refractory Richter Transformation, contributing to the broader understanding of treatment options for this rare condition.

The clinical trial involves the administration of **brexucabtagene autoleucel**, marketed as Tecartus, which is a genetically modified autologous cell-based product. It is provided as a dispersion for infusion, with a dosage range of 0.4 to 2 × 10^8 cells. The route of administration is **intravenous infusion**, and the maximum treatment period is one day. This product is specifically designed to target CD19, a protein found on the surface of B cells, and is used in the treatment of rare B-cell malignancies.

**Ibrutinib**, marketed as IMBRUVICA, is administered in the form of 140 mg hard capsules. The route of administration is **oral**, with a maximum daily dose of 420 mg and a total dose of 10,500 mg over a treatment period of 25 days. Ibrutinib functions as a Bruton's tyrosine kinase inhibitor, playing a role in the treatment of B-cell malignancies.

**Vinblastine sulfate** is administered via **intravenous infusion**. The pharmaceutical form is coded as PHF675, with a maximum daily dose of 2 mg and a total dose of 4 mg over a 4-day treatment period. It is classified as an antineoplastic agent, used in chemotherapy regimens.

**Fludarabine** is also administered through **intravenous infusion**, with a pharmaceutical form coded as PHF675. The dosing is based on body surface area, with a maximum daily dose of 30 mg/m² and a total dose of 90 mg/m² over a 3-day treatment period. It is an antineoplastic agent used in the treatment of hematological malignancies.

**Betamethasone sodium phosphate** is administered orally, with a pharmaceutical form coded as PHF00059MIG. The maximum daily dose is 120 mg/m², with a total dose of 600 mg/m² over a 5-day treatment period. It is classified as a corticosteroid, used to manage inflammation and immune responses.

**Ifosfamide** is administered via **intravenous infusion**, with a pharmaceutical form coded as PHF00231MIG. The dosing is based on body surface area, with a maximum daily dose of 5000 mg/m² and a total dose of 150,000 mg/m² over a 3-day treatment period. It is an antineoplastic agent used in chemotherapy.

**Methylprednisolone** is administered through **intravenous use**, with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 3000 mg, with a total dose of 36,000 mg over a 12-day treatment period. It is a corticosteroid used to reduce inflammation and modulate immune responses.

**Etoposide** is administered via **intravenous infusion**, with a pharmaceutical form coded as PHF675. The dosing is based on body surface area, with a maximum daily dose of 100 mg/m² and a total dose of 300 mg/m² over a 4-day treatment period. It is used in chemotherapy regimens.

**Doxorubicin** is administered through **intravenous infusion**, with a pharmaceutical form coded as PHF00231MIG. The dosing is based on body surface area, with a maximum daily dose of 50 mg/m² and a total dose of 50 mg/m² over a 4-day treatment period. It is an antimitotic and cytotoxic agent used in cancer treatment.

**Mesna** is administered via **intravenous injection**, with a pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 540 mg, with a total dose of 1620 mg over a 3-day treatment period. It is used as a detoxifying agent to protect against the harmful effects of certain chemotherapy drugs.

**Cyclophosphamide** is administered through **intravenous infusion**, with a pharmaceutical form coded as PHF00231MIG. The dosing is based on body surface area, with a maximum daily dose of 750 mg/m² and a total dose of 1500 mg/m² over a 3-day treatment period. It is an antineoplastic agent used in chemotherapy.

**Dexamethasone** is administered both orally and intravenously, with a pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 40 mg, with a total dose of 480 mg over a 12-day treatment period. It is a corticosteroid used to manage inflammation and immune responses.

**Alpelisib** is administered orally, with a pharmaceutical form coded as PHF00082MIG. The maximum daily dose is 400 mg, with a total dose of 8800 mg over a 22-day treatment period. It is classified as an antineoplastic agent.

**Oxaliplatin** is administered via **intravenous infusion**, with a pharmaceutical form coded as PHF00230MIG. The dosing is based on body surface area, with a maximum daily dose of 100 mg/m² and a total dose of 100 mg/m² over a 1-day treatment period. It is a platinum-containing antineoplastic agent used in chemotherapy.

**Gemcitabine** is administered through **intravenous infusion**, with a pharmaceutical form coded as PHF00230MIG. The dosing is based on body surface area, with a maximum daily dose of 1000 mg/m² and a total dose of 1000 mg/m² over a 1-day treatment period. It is a pyrimidine nucleoside antimetabolite used in cancer treatment.

**Carboplatin** is administered via **intravenous infusion**, with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 800 mg, with a total dose of 800 mg over a 1-day treatment period. It is an antineoplastic agent used in chemotherapy.

**Rituximab** is administered through **intravenous use**, with a pharmaceutical form coded as PHF00230MIG. The dosing is based on body surface area, with a maximum daily dose of 375 mg/m² and a total dose of 375 mg/m² over a 1-day treatment period. It is used in the treatment of certain types of cancer and autoimmune diseases.

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 (Cheson et al 2014). The primary endpoint for Substudy B (RT) specifically focuses on ORR in subjects with diffuse large B cell lymphoma (DLBCL)-Richter Transformation (RT).

Secondary endpoints include several measures: 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 evaluated. Substudy B (RT) will also assess ORR in subgroups based on clonal relationship to the underlying chronic lymphocytic leukemia (CLL), with clonality determined by central assessment. Furthermore, ORR will be evaluated using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria, including CR with incomplete marrow recovery (CRi).