Phase I/II Study on Safety and Efficacy of AZD5492 as Monotherapy and in Combination for Relapsed/Refractory B-Cell Malignancies

The primary objective of this study is to assess the **safety** and tolerability of AZD5492, a T cell-engaging antibody targeting CD20, as monotherapy or in combination with other anticancer agents in participants with relapsed or refractory (R/R) **B-cell malignancies**. This is clinically relevant as it aims to determine the potential of AZD5492 to be a safe treatment option for patients with these challenging hematological cancers, where current therapeutic options may be limited or ineffective.

Secondary objectives include:

• To evaluate the preliminary antitumor activity of AZD5492 as monotherapy or in combination with other anticancer agents in participants with R/R B-cell malignancies.
• To characterize the pharmacokinetics (PK) of AZD5492 as monotherapy or in combination with other anticancer agents in participants with R/R B-cell malignancies.
• To determine the immunogenicity of AZD5492 as monotherapy or in combination with other anticancer agents in participants with R/R B-cell malignancies.

The clinical trial involves a total of **110 participants** diagnosed with **B-cell malignancies**, including conditions such as large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. The study population comprises both male and female subjects aged 18 years and older, with a focus on individuals who have relapsed, progressive, and/or refractory disease following at least two prior lines of therapy. Participants are required to have a histologically documented CD20+ mature B-cell neoplasm and an ECOG performance status of less than 2. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. The selection process for participants is based on specific inclusion criteria, ensuring that the study population is representative of the target demographic for assessing the safety and tolerability of AZD5492 as monotherapy or in combination with other anticancer agents.

The clinical trial is designed to evaluate the **safety** and tolerability of AZD5492, a T cell-engaging antibody targeting CD20, in subjects with relapsed or refractory **B-cell malignancies**. This study is a modular Phase I/II open-label dose escalation and dose expansion trial. The trial will assess AZD5492 both as a monotherapy and in combination with other anticancer agents. The study is expected to commence recruitment on August 29, 2024, and conclude by February 14, 2028, with an estimated duration of participant involvement of up to 10 days for the treatment period.

Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being 18 years or older, having a histologically documented CD20+ mature B-cell neoplasm, and an ECOG performance status of less than 2. The trial will include follow-up visits to monitor the occurrence of dose-limiting toxicities, adverse events, and any clinically significant changes in vital signs or laboratory parameters. The end-of-study visit will evaluate the overall response rate, duration of response, progression-free survival, and overall survival according to established criteria.

Participants may be withdrawn from the study if they experience severe adverse events or if there are significant alterations in their health status that warrant discontinuation of AZD5492. The trial will also investigate the pharmacokinetics and immunogenicity of AZD5492, including the development of anti-drug antibodies. The study is not categorized as low intervention and is conducted under the sponsorship of AstraZeneca AB, with AZD5492 administered subcutaneously as a solution for injection.

The clinical trial involves the administration of **AZD5492**, an experimental medication developed by AstraZeneca AB. AZD5492 is a T cell-engaging antibody targeting CD20, designed for the treatment of relapsed or refractory B-cell malignancies. The pharmaceutical form of AZD5492 is a **solution for injection**, and it is administered via the **subcutaneous** route. The dosing schedule for AZD5492 is determined by the study protocol, with a maximum treatment period of 10 days. The specific dosage in milligrams is not predefined, as the study is a dose escalation and dose expansion trial, allowing for adjustments based on safety and tolerability assessments. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In this study, AZD5492 is evaluated as a monotherapy or in combination with other anticancer agents. However, no specific non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial data. The focus of the trial is to assess the safety, pharmacokinetics, pharmacodynamics, and efficacy of AZD5492 in the target patient population. The trial does not include a pediatric formulation, and AZD5492 is not classified as an orphan drug. The study is conducted under an open-label design, allowing for the observation of direct effects and side effects of the treatment in participants with relapsed or refractory B-cell malignancies.

The efficacy of AZD5492 in the clinical trial will be assessed through several secondary endpoints. These include evaluating the preliminary antitumor activity in participants with relapsed or refractory B-cell malignancies. The parameters for this evaluation are the **Overall Response Rate (ORR)**, **Complete Response (CR) Rate**, **Duration of Response (DoR)**, and **Progression-Free Survival (PFS)**, which will be measured according to the Lugano criteria and iwCLL 2018 criteria. Additionally, **Overall Survival (OS)** will be assessed.

The pharmacokinetics profile of AZD5492 will also be characterized by determining pharmacokinetic parameters such as **Cmax** (maximum observed concentration), **AUC** (Area under the curve), clearance, and **t½** (half-life). Antibody serum concentration will be measured to support this analysis. Furthermore, the immunogenicity of AZD5492 will be determined by assessing the number and percentage of participants who develop **Anti-Drug Antibodies (ADA)**.