Long-term Follow-up of Gene-Modified Cell Therapy with Brexucabtagene Autoleucel and Axicabtagene Ciloleucel in Solid and Hematological Malignancies

The primary objective of this study is to evaluate the incidence and severity of late-onset targeted **adverse events** (AEs) and serious adverse events (SAEs) that are suspected to be possibly related to the administration of gene-modified cells. This includes the assessment of neurological disorders, autoimmune disorders, hematological disorders, serious infections, and new malignancies. Additionally, the study aims to evaluate the growth, development, and sexual maturity of pediatric and adolescent subjects who have been treated with gene-modified cells. These objectives are clinically relevant as they address the long-term safety and developmental impact of gene-modified cell therapies in patients with solid and hematological malignancies.

Secondary objectives include:

• Determining the time to next treatment after administration of gene-modified cells in the completed parent study.
• Determining survival status.
• Determining the cause of death.
• Determining the status of the primary malignant disease.
• Evaluating the incidence of overall replication-competent retrovirus (RCR) and replication-competent lentivirus (RCL).

The clinical trial involves a total of **408 participants** who have previously received an infusion of gene-modified cells in a completed Kite-sponsored parent study. The study population includes both **male and female subjects** across a broad age range, encompassing pediatric, adolescent, and adult individuals. Participants are selected based on their completion of the minimum duration of follow-up assessments in the parent study and their ability to comply with the study requirements. The trial focuses on individuals with **solid and hematological malignancies**. The population includes vulnerable groups, and participants must have provided informed consent or assent. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study, focusing on the long-term follow-up of participants who have previously received gene-modified cells in Kite-sponsored interventional studies. The primary objective is to evaluate the incidence and severity of late-onset adverse events (AEs) and serious adverse events (SAEs) potentially related to the gene-modified cells, including neurological, autoimmune, and hematological disorders, as well as serious infections and new malignancies. The trial will also assess the growth, development, and sexual maturity of pediatric and adolescent subjects treated with these cells. The study is set to run until September 2038, with recruitment having commenced in December 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as prior infusion of gene-modified cells in a completed parent study and the ability to comply with follow-up schedules. Follow-up visits will be conducted to monitor the occurrence of late-onset AEs/SAEs, assess subsequent anti-cancer therapies, and evaluate survival status and the status of the primary malignant disease. The end-of-study visit will conclude the participant's involvement, summarizing all findings and outcomes. The expected length of participant involvement is contingent upon the completion of the follow-up assessments, with early termination possible if the participant withdraws consent or fails to comply with study requirements.

Key elements of the research methodology include the use of **brexucabtagene autoleucel** and **axicabtagene ciloleucel**, both administered as a dispersion for infusion via **intravenous infusion**. The study will monitor the occurrence of specific late-onset AEs/SAEs, such as neurologic and autoimmune disorders, and new malignancies, with detailed documentation of their type, onset, severity, treatment, and resolution. Secondary endpoints include the evaluation of subsequent anti-cancer therapies, survival status, and the overall rates of replication-competent retrovirus (RCR) or replication-competent lentivirus (RCL). The trial is categorized as a Phase 4 study, not classified as low intervention, and is conducted under the regulatory framework of the European Union.

The clinical trial involves the administration of **Tecartus**, a dispersion for infusion containing **brexucabtagene autoleucel** as the active substance. This product is a genetically modified autologous cell-based therapy, specifically designed to target CD19. The pharmaceutical form is a dispersion for infusion, and it is administered via **intravenous infusion**. The dosage consists of 0.4 - 2 x 10⁸ cells, with a maximum daily and total dose of 200,000,000 cells. The treatment period is limited to a single day. **Brexucabtagene autoleucel** is a structurally diverse substance used in cell therapy, transduced ex vivo using a retroviral vector to express an anti-CD19 chimeric antigen receptor (CAR). This CAR comprises a murine anti-CD19 single chain variable fragment (scFv) linked to CD28 co-stimulatory domain and CD3-zeta signaling domain. The product is not formulated for pediatric use and is classified as an orphan drug.

Another treatment used in the trial is **Yescarta**, which also comes in the form of a dispersion for infusion. The active substance in Yescarta is **axicabtagene ciloleucel**, another genetically modified autologous cell-based product. Similar to Tecartus, Yescarta is administered via intravenous infusion, with a dosage of 0.4 - 2 x 10⁸ cells and a maximum daily and total dose of 200,000,000 cells. The treatment period is also restricted to one day. **Axicabtagene ciloleucel** is a structurally diverse substance used in cell therapy, involving T cells transduced ex vivo with a retroviral vector to express an anti-CD19 CAR. This CAR includes a murine anti-CD19 single chain variable fragment (ScFv) linked to CD28 co-stimulatory domain and CD3-zeta signaling domain. Yescarta is not intended for pediatric use and is designated as an orphan drug.

Both treatments are provided by Kite Pharma EU B.V. and are authorized for use in the European Union. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance is monitored through adherence to the dosing schedule and administration route. The trial aims to evaluate the incidence and severity of late-onset adverse events related to the gene-modified cells, including neurological, autoimmune, hematological disorders, serious infections, and new malignancies.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on evaluating the occurrence of late-onset targeted adverse events (AEs) and serious adverse events (SAEs) that are suspected to be possibly related to the administration of gene-modified cells. These include **neurologic disorders**, autoimmune disorders, hematologic disorders, serious infections, and new malignancies. Specific parameters such as the type, date of onset, severity, treatment, and date of resolution for each disorder will be recorded. Additionally, the trial will monitor the height, weight, and sexual maturation of pediatric and adolescent subjects.

Secondary endpoints will include the assessment of subsequent anti-cancer therapies, survival status, cause of death, overall rates of replication-competent retrovirus (RCR) or replication-competent lentivirus (RCL), and the status of the primary malignant disease. The data collection will be conducted in accordance with the trial's follow-up schedule, ensuring comprehensive monitoring of the participants' health outcomes over the course of the study. The trial is designed to provide a long-term follow-up for participants who have previously received gene-modified cells in Kite-sponsored interventional studies, with an estimated end date in 2038.