Evaluation of AZD0486 Monotherapy and Combination Therapy in Mature B-Cell Malignancies: A Phase I/II Study in Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, and Large B-Cell Lymphoma

The primary objective of this study is to evaluate the **safety** and **tolerability** of AZD0486, administered either as a monotherapy or in combination with other anticancer agents, in participants with mature B-cell malignancies. This includes determining the recommended Phase II dose (RP2D) of AZD0486 when administered intravenously (IV) or subcutaneously (SC). The clinical relevance of this objective lies in establishing a safe and effective dosage regimen for AZD0486, which could potentially improve treatment outcomes for patients with mature B-cell malignancies, such as Chronic Lymphocytic Leukaemia, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, and Large B-Cell Lymphoma.

The clinical trial involves a total of **229 participants** diagnosed with various mature B-cell malignancies, including **Large B-Cell Lymphoma**, **Chronic Lymphocytic Leukaemia**, **Small Lymphocytic Lymphoma**, and **Mantle Cell Lymphoma**. The study population comprises both male and female subjects, all over the age of 18, with no vulnerable populations included. Participants were selected based on specific inclusion criteria, such as having a confirmed diagnosis according to WHO classifications and meeting certain clinical parameters like ECOG performance status of 0 to 2. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The trial aims to assess the safety and tolerability of AZD0486, administered either intravenously or subcutaneously, as a monotherapy and in combination with other anticancer agents. Key inclusion criteria include having at least one measurable site of disease and, for certain sub-studies, a history of relapse after specific lines of therapy. The trial does not focus on any particular lifestyle habits or conditions beyond the medical criteria outlined.

The clinical trial is designed to evaluate the **safety** and efficacy of AZD0486, a **human IgG4 kappa monoclonal antibody against CD3 and CD19**, as monotherapy or in combination with other anticancer agents in participants with mature B-cell malignancies, including **Chronic Lymphocytic Leukaemia**, **Small Lymphocytic Lymphoma**, **Mantle Cell Lymphoma**, and **Large B-Cell Lymphoma**. This trial is structured as a Phase I/II open-label, multi-centre master protocol. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from March 2025 to August 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria such as age, diagnosis, and prior treatment history. Following successful screening, participants will be enrolled in the trial and will attend regular follow-up visits to monitor the incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs) as per NCI CTCAE v5.0/ASTCT criteria. These visits will also evaluate changes in laboratory data and vital signs compared to baseline. The primary endpoint includes the incidence of dose-limiting toxicity (DLTs) and the nature of study drug discontinuation, dose reduction, and dose delay due to AEs. The end-of-study visit will conclude the participant's involvement, summarizing the overall safety and efficacy outcomes.

The expected length of participant involvement varies depending on individual response and tolerance to the treatment, with the possibility of early termination if significant adverse effects occur or if the participant withdraws consent. Participants are required to adhere to contraception guidelines during treatment and for a specified period after the final dose to prevent potential drug-related risks. The trial aims to determine the recommended Phase II dose (RP2D) of AZD0486, administered intravenously or subcutaneously, either alone or in combination with other agents, across the specified B-cell malignancies.

The clinical trial involves the administration of **AZD0486**, a **human IgG4 kappa monoclonal antibody** targeting CD3 and CD19. This experimental medication is provided in two pharmaceutical forms: a **solution for infusion** and a **solution for injection**. The solution for infusion is administered **intravenously**, while the solution for injection is administered **subcutaneously**. The dosing schedule and frequency are determined based on the study protocol, with the primary objective being to assess the safety and tolerability of AZD0486 as monotherapy and in combination with other anticancer agents in participants with mature B-cell malignancies.

In addition to AZD0486, the trial includes several non-experimental treatments. **Doxorubicin hydrochloride** is administered as a comparator treatment in the form of **PHF00231MIG**, delivered **intravenously**. **Rituximab**, another comparator, is provided in the form of **PHF00230MIG** and is also administered **intravenously**. **Prednisolone** is included as a comparator treatment, available in the form of **PHF00245MIG** and administered **orally**. **Betamethasone sodium phosphate** is another comparator, provided in the form of **PHF00059MIG** and administered **orally**.

Additional comparator treatments include **Acalabrutinib**, marketed as Calquence 100 mg film-coated tablets, administered **orally**. **Cyclophosphamide** is provided in the form of **PHF00231MIG** and administered **intravenously**. Lastly, **Vinorelbine** is included as a comparator, provided in the form of **PHF00007MIG** and administered **intravenously**. The dosing schedules for these non-experimental treatments are aligned with standard-of-care practices and are detailed in the study protocol.

Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the protocol. The trial aims to determine the recommended Phase II dose of AZD0486, both as a standalone treatment and in combination with the aforementioned anticancer agents, across various mature B-cell malignancies, including chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, and large B-cell lymphoma.

The efficacy of the investigational product AZD0486, a **human IgG4 kappa monoclonal antibody against CD3 and CD19**, will be assessed in a Phase I/II clinical trial involving participants with mature B-cell malignancies. The primary endpoints for evaluating efficacy include the incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs) based on NCI CTCAE v5.0/ASTCT criteria, as well as changes in laboratory data and vital signs compared with baseline. Additionally, the incidence of dose-limiting toxicity (DLTs), the incidence and severity of adverse events of special interest (AESIs), and the incidence and nature of study drug discontinuation, dose reduction, and dose delay due to AEs will be monitored.