Long-Term Follow-Up Study of Idecabtagene Vicleucel and Lisocabtagene Maraleucel in Patients Previously Treated with Gene-Modified T Cells

The primary objective of this study is to assess the risk of delayed **adverse events** following exposure to gene-modified (GM) T cells. This is clinically relevant as it helps in understanding the long-term safety profile of GM T-cell therapies, which are increasingly used in treating various conditions. Additionally, the study aims to monitor the long-term persistence of GM T cells, including the analysis of vector integration sites, which is crucial for evaluating the potential for long-term efficacy and safety. Monitoring for the generation of replication-competent lentiviruses is also a key focus, as it addresses concerns about viral vector safety. Furthermore, the study seeks to assess the long-term efficacy following treatment with GM T cells, providing insights into the sustained therapeutic benefits of these treatments. For subjects who were aged less than 18 years at the time of GM T-cell treatment, the study will describe growth and sexual maturity status, which is important for understanding the developmental impact of such therapies.

Secondary objectives include monitoring B-cell levels in subjects who received CD19-directed GM T-cell therapy. This is important for evaluating the immunological impact and potential side effects related to B-cell depletion or recovery, which can influence patient management and therapeutic strategies.

The clinical trial involves a total of **425 participants**, comprising both adult and pediatric subjects who have previously received at least one infusion of genetically modified T cells in a prior Celgene-sponsored study. The study population includes both **male and female** participants, with an age range that encompasses children, adolescents, and adults. Participants were selected based on their prior involvement in a Celgene-sponsored or Celgene alliance partner-sponsored study, having either completed or discontinued the post-treatment follow-up period in the parent protocol. The trial includes a vulnerable population, indicating that special considerations are in place for the protection of these subjects. The study does not specify particular lifestyle considerations such as diet or physical activity. The primary focus is on assessing the risk of delayed adverse events and monitoring the long-term persistence and efficacy of the genetically modified T cells.

The clinical trial is designed to assess the long-term safety and efficacy of **gene-modified T cells** in subjects who have previously received at least one infusion of these cells in a prior Celgene-sponsored study. This trial is a **phase II/III** study, employing a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The trial commenced on June 24, 2021, and is expected to conclude by January 9, 2025, with recruitment having started on October 28, 2021. The study will enroll both adult and pediatric subjects who have completed the post-treatment follow-up period in the parent treatment protocol.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. These criteria include having received at least one genetically modified T cell infusion in a previous study and the ability to adhere to the study visit schedule. The trial will involve multiple follow-up visits to monitor for delayed adverse events, the persistence of gene-modified T cells, and the generation of replication-competent lentiviruses. The primary endpoints focus on the incidence of delayed adverse events related to prior gene-modified T-cell therapy, including new neurologic, rheumatologic, or hematologic disorders, as well as new infections or other clinical conditions. Secondary endpoints include lymphocyte count monitoring in subjects who received CD19-directed gene-modified T-cell therapy.

The expected length of participant involvement in the study is until the estimated end date of April 2, 2033. However, conditions that may lead to early termination from the study include the occurrence of severe adverse events or the participant's inability to comply with the study protocol. The end-of-study visit will assess the overall health status of the participants, including disease status, progression, relapse, and survival status, where applicable. The trial aims to provide comprehensive data on the long-term effects of gene-modified T-cell therapy, contributing valuable insights into its safety and efficacy for future therapeutic applications.

The clinical trial involves the use of two experimental medications, **idecabtagene vicleucel** and **lisocabtagene maraleucel**, both of which are cell suspensions for injection. **Idecabtagene vicleucel** is a gene-modified T cell therapy, specifically a CAR+ T cell product, with a dosage range of 300 - 460 x 10^6 CAR+ T cells. The pharmaceutical form is a cell suspension for injection, and the route of administration is categorized as "other use." The treatment does not specify a maximum daily or total dose amount, and the maximum treatment period is set at 9999 days, indicating long-term follow-up. The active substance, idecabtagene vicleucel, is a structurally diverse substance used in cell therapy, and the product is developed by Celgene Corporation.

**Lisocabtagene maraleucel** is another gene-modified T cell therapy used in this trial. It is also presented as a cell suspension for injection, with the administration route similarly classified as "other use." Like idecabtagene vicleucel, lisocabtagene maraleucel does not have a specified maximum daily or total dose amount, and the maximum treatment period is 9999 days. The active substance, lisocabtagene maraleucel, is derived from nucleic acid, and the product is also developed by Celgene Corporation. Both medications are part of a long-term follow-up study, GC-LTFU-001, which does not involve any investigational medicinal product (IMP) usage. Participant compliance and monitoring are integral to the study, ensuring the assessment of long-term efficacy and safety of these gene-modified T cell therapies.

The efficacy of the clinical trial will be assessed through several key parameters. The primary efficacy endpoints include the evaluation of **disease status**, the date of disease progression, the date of relapse, and survival status. These parameters will be measured to determine the long-term efficacy following treatment with gene-modified (GM) T cells. The assessment will involve monitoring the persistence of GM T cells and analyzing vector integration sites, as appropriate. Additionally, the incidence of replication-competent lentiviruses will be evaluated. For pediatric subjects, physical growth and sexual maturity will be assessed through physical examinations.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial. The trial is designed to monitor subjects over an extended period, with the estimated end date set for April 2, 2033. The trial will include both adult and pediatric subjects who have previously received at least one GM T cell infusion in a prior Celgene-sponsored study. The efficacy assessments will be conducted in accordance with the trial protocol, ensuring that all data collected is accurate and reliable for evaluating the long-term outcomes of the treatment.