Evaluation of AZD5863 and Tocilizumab in Advanced or Metastatic Solid Tumors: A Phase I/II Dose Escalation and Expansion Study

The primary objective of this study is to investigate the **safety** and tolerability of AZD5863, a T cell-engaging bispecific antibody targeting Claudin 18.2 (CLDN18.2) and CD3, in adult participants with advanced or metastatic solid tumors. This includes characterizing dose-limiting toxicities (DLTs) and determining the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of AZD5863 as a monotherapy or in combination. The clinical relevance of this objective lies in establishing a safe and effective dosing regimen for AZD5863, which could potentially offer a new therapeutic option for patients with these challenging malignancies.

Secondary objectives include: - Evaluating the preliminary antitumor activity of AZD5863 monotherapy or in combination in participants with advanced or metastatic solid tumors expressing CLDN18.2. - Characterizing the pharmacokinetics (PK) of AZD5863 monotherapy or in combination in the same patient population. - Determining the immunogenicity of AZD5863 monotherapy or in combination. - Assessing the preliminary antitumor activity of AZD5863 with target expression pre- and post-delivery of AZD5863 monotherapy or in combination.

The clinical trial involves a total of **192 participants** diagnosed with **advanced or metastatic solid tumors**. The study population includes both male and female subjects, aged 18 years and older, who have a histologically confirmed diagnosis of adenocarcinoma of the stomach, gastro-esophageal junction, esophagus, or pancreas. Participants must exhibit positive CLDN18.2 expression in tumor cells and have at least one measurable lesion according to RECIST v1.1. The trial population was selected based on specific criteria, including an Eastern Cooperative Oncology Group Performance status of 0-1 at screening and a predicted life expectancy of at least 12 weeks. Participants are required to have adequate organ and bone marrow function and must have received at least one prior line of systemic therapy in the advanced or metastatic setting. The study includes individuals from a vulnerable population, and lifestyle considerations such as contraceptive use are consistent with local regulations. The trial aims to investigate the safety, tolerability, and preliminary antitumor activity of AZD5863, either as a monotherapy or in combination, in this specific patient group.

The clinical trial is designed as a **Phase I/II open-label** study to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of **AZD5863**, a T cell-engaging bispecific antibody targeting Claudin 18.2 and CD3, in adult participants with advanced or metastatic solid tumors. The trial will follow a dose escalation and dose expansion approach. The primary objective during the dose escalation phase is to investigate the safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of AZD5863. The dose expansion phase aims to further assess the safety and tolerability, as well as evaluate the preliminary antitumor activity of AZD5863.

The trial is expected to commence recruitment on October 15, 2023, and conclude by December 30, 2026. Participants will be involved in the study for an estimated duration that aligns with the trial's end date, subject to individual response and tolerability. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, histologically confirmed diagnosis, and positive CLDN18.2 expression; regular follow-up visits to monitor safety, efficacy, and pharmacokinetic parameters; and an end-of-study visit to assess overall outcomes and gather final data.

Participants may be withdrawn from the study early if they experience adverse events (AEs) leading to discontinuation, fail to comply with study procedures, or if the investigator deems it in the participant's best interest. The primary endpoints include the incidence of AEs, adverse events of special interest (AESIs), DLTs, and serious adverse events (SAEs), as well as clinically significant alterations in vital signs and laboratory parameters. Secondary endpoints focus on overall response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival, and serum concentrations of AZD5863, among others.

The clinical trial involves the administration of **AZD5863**, a T cell-engaging bispecific antibody targeting Claudin 18.2 (CLDN18.2) and CD3, in adult participants with advanced or metastatic solid tumors. AZD5863 is provided as a **powder for solution for injection/infusion**. The administration routes for AZD5863 include both **subcutaneous and intravenous** methods. The dosing schedule for AZD5863 will be determined based on the dose escalation phase to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Participant compliance will be monitored through regular assessments and documentation of dosing adherence.

In addition to AZD5863, the trial utilizes **RoActemra** (tocilizumab), a **20 mg/mL concentrate for solution for infusion**. RoActemra is administered via **intravenous use**. This medication is used as an auxiliary treatment to manage potential cytokine release syndrome (CRS) associated with the administration of AZD5863. The frequency and dosage of RoActemra will be adjusted based on the clinical presentation of CRS symptoms in participants. Monitoring of participant compliance with RoActemra administration will be conducted through scheduled infusion sessions and documentation of any adverse reactions.

No placebo or standard-of-care therapy is employed in this study. The trial focuses on evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of AZD5863, both as a monotherapy and in combination with RoActemra, in the specified patient population. The study protocol includes detailed guidelines for drug administration, dosing schedules, and participant monitoring to ensure adherence to the trial's objectives and safety standards.

The efficacy of AZD5863 in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for the dose escalation phase include the incidence of adverse events (AEs), adverse events of special interest (AESIs), dose-limiting toxicities (DLTs), and serious adverse events (SAEs). Additionally, the trial will monitor AEs leading to the discontinuation of AZD5863, as well as clinically significant alterations in vital signs and laboratory parameters. For the dose expansion phase, the primary endpoints are similar, with the addition of evaluating the objective response rate (ORR) according to RECIST v1.1.

Secondary endpoints for both the dose escalation and dose expansion phases include the ORR, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival. The trial will also measure serum concentrations of AZD5863 and its pharmacokinetic (PK) parameters, such as maximum concentration (Cmax), area under the curve (AUC), clearance, and half-life (t1/2). Furthermore, the development of anti-drug antibodies (ADAs) in participants will be assessed, and the expression of **CLDN18.2** in tumor cells will be investigated in relation to the response to AZD5863.