Long-Term Follow-Up of Patients with Myxoid/Round Cell Liposarcoma, Multiple Myeloma, NSCLC, and Synovial Sarcoma Treated with Letetresgene Autoleucel

The primary objective of this study is to monitor participants for delayed **adverse events** (AEs) associated with the administration of autologous cells that have been genetically modified by lentiviral vectors. This is clinically relevant as it aims to ensure the long-term safety of adoptive cell therapies, which are used in treating conditions such as myxoid/round cell liposarcoma, multiple myeloma, non-small cell lung cancer, and synovial sarcoma.

Secondary objectives include:

• Monitoring replication competent lentivirus (RCL) to ensure the genetic modification process does not result in unintended viral replication.
• Measuring the persistence of genetically modified cells in the body, which is crucial for understanding the longevity and potential efficacy of the treatment.
• Assessing the pattern of vector integration sites if at least 1% of cells in the surrogate sample are positive for vector sequences by polymerase chain reaction (PCR), to evaluate the integration and stability of the genetic modification.
• Monitoring survival status to gather data on the long-term outcomes of the therapy.

The clinical trial involves a total of **66 participants** who have been previously involved in an Adaptimmune sponsored or supported interventional study. The study population includes both **male and female** participants, with an age range that encompasses children, adolescents, and adults. Participants are individuals who have received at least one infusion of an Adaptimmune adoptive cell therapy agent. The trial focuses on monitoring delayed adverse events associated with the administration of autologous cells genetically modified by lentiviral vectors. Participants are required to adhere to specific contraceptive guidelines, reflecting the study's consideration of reproductive health and safety. The trial includes individuals with medical conditions such as **non-small cell lung cancer (NSCLC)**, myxoid/round cell liposarcoma, multiple myeloma, and synovial sarcoma. The selection process ensures that participants have completed or withdrawn from a prior interventional study, and informed consent is a prerequisite for participation. The trial also includes a vulnerable population, indicating a careful approach to ethical considerations in clinical research.

The clinical trial is designed to monitor participants for delayed adverse events (AEs) associated with the administration of **autologous cells** genetically modified by lentiviral vectors. This trial is a Phase 3, non-low intervention study, involving participants who have previously received at least one infusion of an Adaptimmune adoptive cell therapy agent. The trial is structured as a long-term follow-up (LTFU) study, with an estimated duration extending until April 2032. Participants will be monitored for new malignancies, neurologic disorders, rheumatologic or autoimmune disorders, hematologic disorders, infections potentially related to gene-modified cell therapy, and any unanticipated illness or hospitalization deemed related to the therapy.

The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. These criteria include having completed an Adaptimmune-sponsored or supported interventional study or having withdrawn from it, as defined by the interventional protocol. Follow-up visits will be scheduled periodically to assess the persistence of gene-modified cells and monitor for any AEs or serious adverse events (SAEs). The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of their health status and any long-term effects of the therapy.

The expected length of participant involvement in the study is approximately 14 years, with conditions for early termination including the participant's withdrawal of consent, non-compliance with study procedures, or the investigator's decision based on safety concerns. Participants are required to adhere to specific contraceptive guidelines to prevent pregnancy during the study period, with male participants refraining from sperm donation and female participants agreeing not to donate eggs. The trial will also collect data on secondary endpoints, such as the presence of Vesicular Stomatitis Virus G protein (VSV-G) DNA copies, Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) or Psi DNA copies, and vector integration patterns in peripheral blood samples, as well as the incidence of death and time to death.

The clinical trial involves the administration of the experimental medication **GSK3377794**, which is an advanced therapy investigational medicinal product (ATIMP) classified as a gene therapy medicinal product. The active substance in GSK3377794 is **letetresgene autoleucel**, a structurally diverse substance used in cell therapy. This medication is composed of autologous CD4+ and CD8+ T cells that have been transduced with a non-replicating human immunodeficiency virus-derived self-inactivating vector. This vector encodes an affinity-enhanced T cell receptor specific to the NY-ESO-1 antigen, a cancer/testis antigen. The pharmaceutical form of GSK3377794 is an infusion, and it is administered via the **intravenous route**. The maximum daily and total dose is 15 billion organisms, with a treatment period limited to one day.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on monitoring participants for delayed adverse events associated with the administration of the genetically modified autologous cells. Participant compliance with the dosing schedule is critical, and adherence will be monitored throughout the trial. The trial aims to ensure the safety and efficacy of the gene therapy product, with a particular emphasis on long-term follow-up of participants treated with adoptive cell therapies.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the reporting of adverse events (AEs) and serious adverse events (SAEs), specifically targeting new malignancies, new or exacerbated neurologic disorders, rheumatologic or other autoimmune disorders, hematologic disorders, infections potentially related to gene-modified cell therapy, and any unanticipated illness or hospitalization deemed related to the therapy. These endpoints are crucial for evaluating the safety and potential adverse effects associated with the administration of **letetresgene autoleucel**.

Secondary endpoints include the measurement of Vesicular Stomatitis Virus G protein (VSV-G) DNA copies, Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) or Psi DNA copies, and the analysis of integrated vector sequences and vector integration patterns (e.g., polyclonal, oligoclonal, or monoclonal) in peripheral blood samples. Additionally, the incidence of death and time to death will be recorded. These secondary endpoints are designed to provide insights into the biological activity and long-term effects of the gene therapy product. The collection and analysis of these parameters will be conducted at specified intervals throughout the trial to ensure comprehensive monitoring of the therapy's efficacy and safety profile.