Efficacy Evaluation of Brexucabtagene Autoleucel in Relapsed/Refractory Mantle Cell Lymphoma: A Phase 2 Multicenter Study

The primary objective of this Phase 2 multicenter study is to evaluate the **efficacy** of KTE-X19, as measured by the objective response rate (ORR), in subjects with relapsed/refractory Mantle Cell Lymphoma (MCL). This is clinically relevant as it aims to determine the therapeutic potential of KTE-X19 in a population with limited treatment options, potentially improving patient outcomes in this challenging condition.

Secondary objectives include:

• Assessing the **safety** and tolerability of KTE-X19, which is crucial for understanding the risk-benefit profile of the treatment.
• Evaluating patient-reported outcomes (PROs) in Cohort 1 and Cohort 2, focusing on changes in the European Quality of Life-5 Dimensions (EQ-5D) scores from baseline to Month 6, providing insights into the impact of treatment on patients' quality of life.
• Assessing PROs in Cohort 3, including changes in EQ-5D and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) scores from baseline over time, further elucidating the treatment's effect on quality of life.

The clinical trial involves a total of **115 participants** diagnosed with **Relapsed/Refractory Mantle Cell Lymphoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having undergone up to five prior regimens for Mantle Cell Lymphoma, which must have included anthracycline- or bendamustine-containing chemotherapy and anti-CD20 monoclonal antibody therapy, while excluding those who have received prior therapy with a BTKi. The trial population is characterized by a general health status that requires a platelet count of at least 75,000/uL, a creatinine clearance of at least 60 cc/min, a cardiac ejection fraction of at least 50%, no evidence of pericardial effusion, and baseline oxygen saturation greater than 92% on room air. The study also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed to evaluate the efficacy of **brexucabtagene autoleucel** in subjects with relapsed/refractory mantle cell lymphoma. This is a Phase 2, multicenter study employing a randomized, double-blind, controlled trial design. The trial is expected to run from July 17, 2018, to March 30, 2025, with the primary objective of assessing the objective response rate (ORR) in participants. The study includes several key phases, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as prior treatment regimens, measurable lesions, and specific health parameters like platelet count and cardiac function. Participants will then undergo treatment and be monitored through a series of follow-up visits to assess primary and secondary endpoints, including progression-free survival and incidence of adverse events. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 25 months, depending on individual treatment response and adherence to protocol. Conditions that may lead to early termination from the study include significant adverse events or failure to comply with study requirements. The trial's methodology ensures rigorous data collection and analysis, contributing to the understanding of treatment efficacy and safety in this patient population.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Dexamethasone** is provided in the form of 4 mg tablets, manufactured by Mercury Pharmaceuticals Ltd. It is administered orally or intravenously, with a maximum daily dose of 40 mg and a total dose not exceeding 960 mg over a 12-day period. This corticosteroid is used to manage inflammation and immune responses.

**Cytarabine** is available as a 20 mg/ml solution for injection or infusion, produced by Pfizer Healthcare Ireland. It is administered via intravenous infusion, with a maximum daily dose of 2 gm/m² and a total dose of 4 gm/m² over a 2-day period. Cytarabine acts as an anti-neoplastic agent, targeting rapidly dividing cancer cells.

**Acalabrutinib**, marketed as Calquence 100 mg hard capsules by AstraZeneca AB, is administered orally. The maximum daily dose is 200 mg, with a total dose of 5000 mg over a 25-day period. It functions as a Bruton's tyrosine kinase inhibitor, interfering with cancer cell growth and survival.

**Cyclophosphamide** is provided as a 500 mg powder for solution for injection or infusion by Sandoz Ltd. It is administered intravenously, with a maximum daily dose of 2 gm/m² and a total dose of 4 gm/m² over a 3-day period. This anti-neoplastic agent is used to disrupt cancer cell replication.

**Fludarabine phosphate** is available as a 25 mg/ml concentrate for solution for injection or infusion, manufactured by Accord Healthcare Limited. It is administered via intravenous infusion, with a maximum daily dose of 30 mg/m² and a total dose of 90 mg/m² over a 3-day period. It serves as an antineoplastic agent, inhibiting DNA synthesis in cancer cells.

**Diphenhydramine hydrochloride**, marketed as Histergan Tablets by Norma Chemicals Ltd, is administered orally or intravenously. The maximum daily dose is 25 mg, with a total dose of 25 mg over a 1-day period. It functions as an antihistamine, alleviating allergic reactions.

**Brexucabtagene autoleucel**, marketed as Tecartus, is a dispersion for infusion provided by Kite Pharma EU B.V. It is administered via intravenous infusion, with a single dose containing 0.4 - 2 x 10^8 cells. This genetically modified autologous cell-based product targets CD19-positive cancer cells.

**Mesna** is available as an injection solution, produced by Baxter Healthcare Ltd. It is administered intravenously, with a maximum daily dose of 540 mg and a total dose of 1620 mg over a 3-day period. Mesna acts as a detoxifying agent, protecting against the harmful effects of certain chemotherapy drugs.

**Methylprednisolone** is provided as a 1000 mg powder and solvent for solution for injection or infusion by Kent Pharma UK Limited. It is administered intravenously, with a maximum daily dose of 3000 mg and a total dose of 36000 mg over a 12-day period. This corticosteroid is used to reduce inflammation and modulate immune responses.

**Tocilizumab**, marketed as RoActemra 20 mg/mL concentrate for solution for infusion by Roche Registration GmbH, is administered via intravenous infusion. The maximum daily dose is 2400 mg, with a total dose of 3200 mg over a 2-day period. It is used to modulate immune responses in inflammatory conditions.

**Paracetamol**, marketed as Panadol 500 mg Film Coated Tablets by Haleon Ireland Limited, is administered orally. The maximum daily dose is 650 mg, with a total dose of 650 mg over a 1-day period. It functions as an analgesic and antipyretic, providing pain relief and reducing fever.

**Ibrutinib**, marketed as IMBRUVICA 140 mg hard capsules by Janssen-Cilag International NV, is administered orally. The maximum daily dose is 560 mg, with a total dose of 14000 mg over a 25-day period. It acts as a Bruton's tyrosine kinase inhibitor, targeting cancer cell growth and survival.

The efficacy of KTE-X19 in subjects with relapsed/refractory Mantle Cell Lymphoma (MCL) will be assessed primarily through the **Objective Response Rate (ORR)**, which includes complete response (CR) and partial response (PR) as per the Lugano Classification. This primary endpoint will be evaluated by an Independent Radiology Review Committee (IRRC). Secondary endpoints include Duration of Response (DOR), Best Objective Response (BOR), ORR as determined by study investigators, Progression-Free Survival, Overall Survival, and the incidence of adverse events (AEs) and clinically significant changes in laboratory values. Additionally, the study will monitor the incidence of anti-CD19 CAR antibodies, levels of anti-CD19 CAR T cells in blood, and levels of cytokines in serum. Patient-reported outcomes will be measured using changes over time in the EQ-5D scale score and visual analogue scale score, as well as the EORTC-QLQ-C30 score for Cohort 3.