Long-Term Follow-up of Patients Treated with Miltenyi Cell and Gene Therapies

The primary objective of this study is to evaluate the **long-term safety** following treatment with Miltenyi CAR T cell therapy. This is clinically relevant as it aims to ensure the sustained safety of patients who have undergone this advanced therapy, which is crucial for its continued use in treating conditions such as unresectable stage III or IV melanoma, and various relapsed or refractory CD19 and CD20 positive B cell malignancies.

Secondary objectives include:

• Further assessment of safety concerning blood count, growth, and development in pediatric patients, as well as the occurrence of replication-competent lentivirus post-therapy.
• Evaluation of long-term treatment efficacy in surviving patients, measured by disease progression status and survival status over time, and the persistence of the transgene.

The clinical trial involves participants with **unresectable stage III or IV melanoma** and various **relapsed or refractory CD19 and CD20 positive B cell malignancies**, including adult and pediatric acute lymphatic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The study population includes both male and female subjects, spanning age categories 2, 3, and 4, which typically correspond to children, adolescents, and adults. The trial population was selected based on prior treatment with Miltenyi CAR T cell therapy, with participants having undergone this treatment at least 12 months before enrollment in the long-term follow-up study. Informed consent was obtained from all participants. The sponsor has not provided the total number of participants involved in the study. The trial includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of these individuals. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the long-term safety of **Miltenyi CAR T cell therapy** in patients who have previously undergone treatment for specific conditions, including unresectable stage III or IV melanoma and relapsed or refractory CD19 and CD20 positive B cell malignancies. The trial follows a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The estimated duration of the trial extends until December 31, 2040, with recruitment anticipated to commence on April 30, 2024.

Participants will be involved in a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as prior treatment with Miltenyi CAR T cell therapy at least 12 months before enrollment and provision of informed consent. Follow-up visits will be scheduled to monitor the primary endpoint, which includes the percentage of patients experiencing late-onset adverse reactions, serious adverse events, and other significant health outcomes. Secondary endpoints will assess parameters such as B- and T-lymphocyte counts, and the presence of replication-competent lentivirus and transgene levels. The end-of-study visit will conclude the participant's involvement, summarizing the collected data and ensuring the participant's health status is stable.

The expected length of participant involvement is contingent upon the trial's duration and the individual's health status. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or the participant's decision to withdraw consent. The trial's methodology and design are structured to maintain scientific rigor and participant safety throughout the study period.

The clinical trial involves the administration of three experimental medications, each designed as an **infusion** for the treatment of patients. The first experimental medication, **MB-CART19.1**, consists of **autologous T cells** transduced with a **lentiviral vector** expressing a **chimeric antigen receptor** (CAR) directed against **CD19**. This product is administered via **intravenous infusion**. The T cells are enriched for **CD4/CD8** and derived from a **leukapheresis** procedure. The medication is not a pediatric formulation and is classified as a **structurally diverse substance** under **cell therapy**. The administration schedule and dosage are determined based on the trial protocol, and participant compliance is monitored throughout the study.

The second experimental medication, **MB-CART20.1**, is similar in its formulation, consisting of **autologous T cells** transduced with a **chimeric antigen receptor** targeting **CD20**. Like MB-CART19.1, it is administered through **intravenous infusion** and involves **CD4/CD8** enriched T cells derived from **leukapheresis**. This medication is also not intended for pediatric use and is categorized as a **structurally diverse substance** in the context of **cell therapy**. The administration and monitoring procedures are consistent with those outlined for MB-CART19.1.

The third experimental medication, **MB-CART2019.1**, contains **zamtocabtagene autoleucel**, which is also administered as an **intravenous infusion**. This product is designated as an **orphan drug** and follows the same cell therapy principles as the other two medications, being a **structurally diverse substance**. The administration protocol and compliance monitoring are aligned with the trial's requirements to ensure the safety and efficacy of the treatment.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. The focus remains on evaluating the long-term safety of these **CAR T cell therapies**. The trial is conducted under the sponsorship of **Miltenyi Biomedicine GmbH**, and all medications are produced by this organization. The trial's objective is to assess the long-term safety of these therapies in patients, with compliance and safety monitoring being integral components of the study protocol.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the percentage of patients experiencing late-onset adverse reactions, serious adverse events, serious adverse reactions, and adverse events of special interest, including relapse or progression of the underlying disease, life-threatening infections, death due to any cause, and new and secondary malignancies. These parameters will provide a comprehensive overview of the long-term safety and potential efficacy of the Miltenyi CAR T cell therapy.

Secondary endpoints include the evaluation of B- and T-lymphocyte counts, as well as specific assessments for pediatric patients such as height, weight, Tanner staging, and menstruation status. Additionally, the trial will monitor the percentage of patients with detectable replication-competent lentivirus (RCL) and transgene levels. If results are negative for two consecutive years for an individual patient, further sampling will be discontinued. The trial will also track the percentage of patients who relapse or progress since enrollment and the rate of surviving patients. These endpoints will be measured and analyzed over the course of the trial, providing valuable data on the efficacy of the treatment.