Evaluation of Safety and Efficacy of AUTO1 CAR T Cells Targeting CD19 in Adults with Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia

The primary objective of this study is to evaluate the **safety** and clinical efficacy of AUTO1, a CAR T cell treatment targeting CD19, in adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia. This is clinically relevant as it addresses the need for effective treatment options in a population with limited therapeutic alternatives.

Secondary objectives include:

• Evaluating the clinical efficacy of AUTO1.
• Assessing the safety and tolerability of AUTO1.
• Evaluating the feasibility of manufacturing and administering AUTO1.
• Evaluating the expansion and persistence of AUTO1.
• Evaluating the duration of B cell aplasia.

The clinical trial involves a total of **136 participants** diagnosed with **relapsed or refractory B cell acute lymphoblastic leukaemia**. The study population includes both male and female subjects aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate renal, hepatic, pulmonary, and cardiac function. The trial population was selected based on specific inclusion criteria, including the presence of relapsed or refractory CD19-positive B-ALL. Patients with Philadelphia chromosome-positive ALL are eligible if they meet certain conditions related to tyrosine kinase inhibitor therapy. The study also considers vulnerable populations, ensuring comprehensive safety and efficacy evaluations of the investigational treatment, AUTO1. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed to evaluate the **safety** and clinical efficacy of AUTO1, a CAR T cell treatment targeting CD19, in adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia. This is an open-label, multi-centre, Phase Ib/II study. The trial employs a non-randomized design, focusing on the administration of AUTO1 through **intravenous infusion**. The study is expected to conclude by May 25, 2028, with recruitment having commenced on December 1, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older), ECOG performance status of 0 or 1, and adequate organ function. The primary endpoints include the frequency and severity of adverse events and the overall complete remission rate. Secondary endpoints encompass complete remission rate within three months post-infusion, duration of remission, and overall survival, among others.

Following the screening, participants will receive the investigational product, AUTO1, and will be monitored through follow-up visits to assess safety and efficacy outcomes. These visits will include evaluations of adverse events, remission status, and the presence of CAR T cells in the peripheral blood. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last until the study's conclusion unless early termination criteria are met.

Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial aims to provide comprehensive data on the therapeutic potential of AUTO1 in this patient population, contributing to the understanding of its role in treating relapsed or refractory B cell acute lymphoblastic leukaemia.

The clinical trial involves the administration of **AUTO1**, an experimental medication consisting of **autologous enriched T cells** retrovirally transduced to express two chimeric antigen receptors targeting CD19 and CD22. This investigational product is provided in the form of an infusion and is administered via **intravenous infusion**. The frequency and specific dosing schedule for AUTO1 are determined based on the study protocol, with careful monitoring of participant compliance to ensure adherence to the treatment regimen.

In addition to AUTO1, the study utilizes **Genoxal 200 mg**, a non-experimental treatment containing **cyclophosphamide monohydrate**. This medication is available as a solution for injection or infusion and is administered accordingly. Cyclophosphamide is a chemical substance used as a standard-of-care therapy in certain oncological settings, and its administration is guided by established dosing protocols.

Another auxiliary treatment in the study is **Fludarabina Teva 25 mg/ml**, which contains **fludarabine phosphate**. This product is provided as a concentrate for solution for infusion or injection. Fludarabine is classified as an antimetabolite and is administered as per the dosing guidelines relevant to its use in the clinical setting. The administration route is either injection or infusion, depending on the specific requirements of the treatment protocol.

Additionally, **Paracetamol MABO 500 mg** tablets are included as a supportive care measure. The active substance, **paracetamol**, is a chemical compound used for its analgesic and antipyretic properties. It is administered orally, with the dosage and frequency tailored to manage symptoms such as pain or fever that may arise during the trial. Compliance with paracetamol administration is monitored to ensure effective symptom management.

The clinical trial aims to assess the efficacy of **AUTO1**, a CAR T cell treatment targeting CD19, in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL). Efficacy will be evaluated through several primary and secondary endpoints. The primary endpoints include the overall complete remission rate (ORR) for Cohort IIA, defined as the proportion of patients achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as assessed by an Independent Response Review Committee (IRRC). For Cohort IIB, the primary endpoint is the proportion of patients achieving minimal residual disease (MRD)-negative remission, determined by central ClonoSEQ next-generation sequencing (NGS) testing, with a threshold of less than 10^-4 leukemic cells.

Secondary endpoints encompass a range of efficacy measures, including the complete remission rate (CRR) within three months post-AUTO1 infusion, the proportion of patients achieving MRD-negative remission by central ClonoSEQ NGS testing, polymerase chain reaction (PCR), and/or flow cytometry. Additional secondary endpoints include the duration of remission (DOR), duration of complete remission (DOCR), event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). The ORR, defined as CR plus CRi, will also be assessed by the investigator. Furthermore, the trial will measure the detection of CAR T cells in the peripheral blood and bone marrow (BM) using PCR following AUTO1 infusion, as well as the depletion of circulating B cells assessed by flow cytometry in the peripheral blood.