Evaluation of Anti-CD19 CAR-T Cell Therapy with KYV-101, Fludarabine Phosphate, and Cyclophosphamide Monohydrate in Refractory ANCA-IgG-Positive Vasculitis

The primary objective of this study is to assess the **safety** of anti-CD19 CAR T cell therapy in subjects with active, treatment-refractory, ANCA-IgG-positive ANCA-associated vasculitis (AAV). This is crucial as it evaluates the potential risks associated with the therapy, ensuring that it can be administered safely to patients who have not responded to conventional treatments. Additionally, in phase II, the study aims to assess the ANCA seroconversion rate, which is clinically relevant as it may indicate a change in the disease state or response to the therapy.

The secondary objectives include:

• Assessing the clinical efficacy and the cellular and humoral response after anti-CD19 CAR T cell therapy.
• Analyzing changes in the B cell receptor repertoire.
• Evaluating therapy-induced changes in B cell subsets.
• Characterizing B cell and plasma cell niches in tissues.
• Evaluating therapy-induced alterations in T cell compartments.
• Evaluating changes in lymphocyte numbers and composition in various biopsies and bronchoalveolar lavage.

These secondary objectives are significant as they provide insights into the immunological changes and potential mechanisms of action of the therapy, which could inform future therapeutic strategies and improve patient outcomes.

The clinical trial involves participants diagnosed with **ANCA-IgG-positive ANCA associated vasculitis**. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have active disease, defined by a clinical activity score (BVAS ≥ 3) at screening, and must have shown insufficient response or intolerance to standard treatments such as glucocorticoids, rituximab, or other specified medications. The trial population was selected based on their ability to adhere to study visits and protocols, and they must fulfill specific classification criteria for granulomatosis with polyangiitis or microscopic polyangiitis. Participants are expected to maintain an updated vaccination record according to recommendations for immunocompromised patients. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and lifestyle considerations such as contraception use are required for both male and female participants to prevent pregnancy during and after the trial period. The selection criteria ensure that participants do not have clinically significant active infections or acute central neurological toxicity before various stages of the trial.

The clinical trial is designed as a **two-stage interventional, prospective, open-label, phase I/II trial** to evaluate the safety and efficacy of anti-CD19 CAR T cell therapy in patients with active, treatment-refractory **ANCA-IgG-positive ANCA-associated vasculitis**. The trial will commence with a screening visit to assess eligibility based on specific inclusion criteria, such as age, disease activity, and previous treatment responses. Participants will be required to sign an informed consent form and undergo various assessments, including a negative urine pregnancy test for females and the absence of significant active infections or neurological toxicity.

The trial will be conducted over several years, with an estimated recruitment start date in 2025 and an expected end date in 2030. Participants will be involved in the study for a duration that includes initial treatment and follow-up phases. The primary objectives in phase I focus on assessing the safety of the therapy, while phase II aims to evaluate both safety and the ANCA seroconversion rate. The trial will involve multiple study visits, including follow-up visits at weeks 12, 24, and 52, to monitor safety and efficacy endpoints such as the incidence of **Cytokine Release Syndrome (CRS)** and **Immune Cell Associated Neurotoxicity Syndrome (ICANS)**, as well as changes in antibody levels and disease activity scores.

Participants will receive the investigational medicinal product, KYV-101, administered intravenously as a suspension. The trial also involves the use of auxiliary cytostatic drugs, including Fludarabinphosphat-GRY® and ENDOXAN, both administered intravenously. The study will include a long-term safety follow-up phase lasting 15 years, with data registered in the EBMT registry. Conditions that may lead to early termination from the study include the development of significant adverse events or failure to adhere to the study protocol. The trial's design ensures rigorous monitoring and evaluation to achieve its primary and secondary endpoints, contributing valuable data to the understanding of CAR T cell therapy in this patient population.

The clinical trial involves the administration of **KYV-101**, an experimental medication developed by Kyverna Therapeutics Inc. **KYV-101** is a **suspension** formulated for **intravenous** administration. It is a structurally diverse substance categorized under cell therapy, specifically utilizing T-cells. The dosing schedule and frequency of administration are determined based on the trial protocol, with careful monitoring of participant compliance to ensure adherence to the treatment regimen.

In addition to the experimental treatment, the study includes the use of **Fludarabinphosphat-GRY® 25 mg/ml**, a concentrate for the preparation of an **injection** or **infusion** solution. This auxiliary medication, produced by Teva GmbH, contains the active substance **fludarabine phosphate**, a chemical compound classified under the ATC code L01BB05. It is administered via the **intravenous** route, serving as a cytostatic drug to support the trial's therapeutic objectives.

Another auxiliary treatment used in the trial is **ENDOXAN Lyophilisat 2 g**, a powder for the preparation of a **solution for injection**. Manufactured by Baxter Oncology GmbH, this medication contains **cyclophosphamide monohydrate**, a chemical substance with the ATC code L01AA01. It is administered through **intravenous infusion** and functions as a cytostatic drug, complementing the primary investigational therapy. The administration and dosing schedules for both auxiliary treatments are aligned with the trial's protocol to ensure optimal therapeutic outcomes and participant safety.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint for Phase II is the percentage of patients with **ANCA-associated vasculitis (AAV)** who achieve normalization of specific antibodies: anti-PR3 antibodies for granulomatosis with polyangiitis (GPA) and anti-MPO antibodies for microscopic polyangiitis (MPA) at week 24. Secondary efficacy endpoints include the percentage of patients achieving a ≥50% reduction in the Birmingham Vasculitis Activity Score (BVAS) at weeks 12, 24, and 52, as well as the percentage of patients reaching sustained remission criteria through week 52. Additional secondary endpoints involve changes in the Vasculitis Damage Index (VDI) and BVAS over time, the number of disease flares, and the duration of CAR T cell persistence and B cell depletion in peripheral blood.

Patient-reported outcomes and quality of life measures will also be evaluated using tools such as the European Quality of Life 5 Dimensions (EQ-5D) and the Short Form 36 (SF-36) questionnaire. The ANCA-associated vasculitis patient-reported outcome (AAV-PRO) will be utilized to capture patient perspectives on disease activity. Efficacy assessments will be conducted at specified timepoints, including weeks 12, 24, and 52, to monitor changes in disease activity and treatment response. The trial will also analyze changes in B cell receptor repertoire and therapy-induced alterations in B cell and T cell compartments, providing a comprehensive evaluation of the treatment's impact on the immune system.