Evaluation of Safety and Efficacy of ARI0002h CAR-T Cells Targeting BCMA in Initial Treatment of Primary Plasma Cell Leukemia

The primary objective of this Phase II, multicenter, open-label, prospective, non-randomized study is to assess the **safety** and **efficacy** of CARTBCMA ARI0002h (Cesnicabtagene autoleucel) following initial treatment to induce a response in patients with newly diagnosed primary **plasma cell leukaemia**. This is clinically relevant as it aims to establish a novel therapeutic approach for a condition with limited treatment options, potentially improving patient outcomes.

Secondary objectives include:

• Evaluating the efficacy of ARI0002h.
• Assessing the duration of response after administration of ARI0002h.
• Evaluating the overall survival after the administration of ARI0002h.
• Evaluating the persistence of ARI0002h cells in peripheral blood after their administration.
• Evaluating the effect of treatment with ARI0002h on the quality of life of patients during the first year.
• Assessing adverse events occurring at 3 months and 1 year.

The clinical trial involves participants diagnosed with **plasma cell leukemia**, specifically targeting individuals with newly diagnosed primary cases. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are required to have a measurable disease at diagnosis, as defined by the presence of a monoclonal component in serum or urine, or by free light chains in serum. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 and a life expectancy greater than three months. Participants must have adequate venous access and no contraindications for lymphoapheresis. The trial population was selected based on these criteria, and all participants provided informed consent. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, as indicated by the selection criteria.

The clinical trial is a **Phase II**, multicenter, open-label, prospective, non-randomized study designed to evaluate the safety and efficacy of ARI0002h, a CAR-T cell therapy targeting BCMA, for the initial treatment of patients with newly diagnosed primary **plasma cell leukemia**. The trial aims to assess the overall response rate (ORR) and safety profile, including the incidence of cytokine release syndrome and neurological toxicity, within the first 30 days post-administration. The study is expected to commence recruitment on March 10, 2025, and conclude by March 31, 2027.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, disease measurability, and performance status. Following the screening, eligible participants will receive the investigational product, Cesnicabtagene autoleucel, administered intravenously. The primary efficacy endpoint will be evaluated over the first three months, with follow-up visits scheduled at 3, 6, and 12 months post-infusion to monitor response rates, progression-free survival, and overall survival. The end-of-study visit will occur at 24 months, assessing long-term outcomes and quality of life.

Participant involvement is anticipated to last up to 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will employ a comprehensive monitoring strategy to ensure participant safety and data integrity throughout the study duration.

The clinical trial involves the administration of **Cesnicabtagene autoleucel**, an experimental medication formulated as a dispersion for infusion. This investigational product consists of **autologous genetically modified T lymphocytes** transduced with lentivirus expressing a chimeric antigen receptor (CAR) protein directed against B-cell maturation antigen (BCMA). The medication is administered intravenously with a maximum daily dose of 3 units and a total dose of 6 units over a treatment period of 21 days. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Lenalidomide** is utilized as a non-experimental treatment in the study. It is provided in the form of hard capsules and administered orally. The maximum daily dose is 15 mg, with a total dose of 10,800 mg over a 24-week period. This medication is used as part of the standard-of-care therapy for the participants.

**Cyclophosphamide** is another non-experimental treatment included in the trial. It is supplied as a powder for solution for injection and administered intravenously. The maximum daily dose is 300 mg/m², with a total dose of 900 mg/m² over a 3-day period. This medication is part of the chemotherapy regimen for the participants.

**Paracetamol** is provided as an auxiliary treatment in the form of tablets, administered orally. The maximum daily dose is 1 g, with a total dose of 3 g over a 3-day period. It serves as an analgesic and antipyretic to manage symptoms associated with the treatment.

**RoActemra** (tocilizumab) is included as an auxiliary treatment in the form of a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 12 mg/kg and a total dose of 800 mg over a 1-day period. This medication is used to manage potential inflammatory responses during the trial.

**Fludarabine** is also part of the auxiliary treatments, provided as a powder for solution for injection and administered intravenously. The maximum daily dose is 30 mg/m², with a total dose of 90 mg/m² over a 3-day period. It is used as part of the chemotherapy regimen for the participants.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary efficacy endpoint is the **Overall Response Rate (ORR)** during the first 3 months following the initial infusion, defined as achieving at least a partial response according to the International Myeloma Working Group criteria. Secondary efficacy endpoints include the duration of response, response rates during the first year, complete response rate at 3, 6, and 12 months, overall response rate at 6 and 12 months, time to complete response, and time to best response. Additionally, the **Minimal Residual Disease (MRD)** negative rate in bone marrow will be evaluated by flow cytometry at 3, 6, 12, and 24 months. The response rate of extramedullary disease will be assessed by PET-CT at 3 and 12 months.

Progression-free survival will be measured as the time between the administration of ARI0002h and disease progression or death, with patients who are alive and in complete remission being censored at the last follow-up. Progression-free survival at 12 months post-administration will also be evaluated. Overall survival (OS) is defined as the time from infusion of ARI0002h to death from any cause, with living patients censored at the last follow-up. The presence of infusion reactions, tumor lysis syndrome, cytokine release syndrome, neurological toxicity, and prolonged cytopenias will be monitored as part of the safety assessments. Quality of life will be evaluated during the first two years post-infusion using the 2008 EuroQol Group EQ-5D questionnaire.