Study of AZD5863 in Adult Participants With Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This research is designed to determine if experimental treatment with AZD5863, a T cell-engaging bispecific antibody that targets Claudin 18.2 (CLDN18.2) and CD3, is safe, tolerable and has anti-cancer activity in patients with advanced solid tumors.

Detailed Description
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This is a first-time in human, modular Phase I/II, open-label multicentre study of AZD5863 monotherapy administered intravenously (Module 1), or AZD5863 monotherapy administered subcutaneously (Module 2) in patients with advanced or metastatic solid tumors. Each module contains dose-escalation (Part A) and dose-expansion (Part B).

Official Title
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A Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD5863, a T Cell-engaging Bispecific Antibody That Targets Claudin 18.2 (CLDN18.2) and CD3 in Adult Participants With Advanced or Metastatic Solid Tumors

Conditions
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Gastric Cancer, Gastro-esophageal Junction Cancer, Pancreatic Ductal Adenocarcinoma, Esophageal Adenocarcinoma

Intervention / Treatment
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* Drug: AZD5863


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 at the time of signing the informed consent Histologically confirmed diagnosis of adenocarcinoma of the stomach, gastro-esophageal junction, esophagus, or pancreas Must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Must show positive CLDN18.2 expression in tumor cells as determined by central immunohistochemistry (IHC) Eastern Cooperative Oncology Group Performance status (ECOG PS): 0-1 at screening Predicted life expectancy of ≥ 12 weeks Adequate organ and bone marrow function measured within 28 days prior to first dose as defined by the protocol Contraceptive use by men or women should be consistent with local regulations, as defined by the protocol Must have received at least one prior line of systemic therapy in the advanced/metastatic setting Key Exclusion Criteria: Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 except for those defined by the protocol Participant experienced unacceptable cytokine release syndrome (CRS) or Immune Effector Cell Associated Neurotoxicity (ICANS) following prior T cell engagers (TCE) or chimeric antigen receptor T (CAR-T) cell therapy Previous history of hemophagocytic lymphohistiocytosis (HLH) / macrophage activation syndrome (MAS) Active or prior documented autoimmune or inflammatory disorders within 3 years of start of treatment central nervous system (CNS) metastases or CNS pathology, as defined by the protocol, within 3 months prior to consent Infectious disease including active human immunodeficiency virus (HIV), active hepatitis B/C, uncontrolled infection with EBV, uncontrolled active systemic fungal, bacterial or other infection Cardiac conditions as defined by the protocol History of thromboembolic event within the past 3 months prior to the scheduled first dose of study intervention Participant requires chronic immunosuppressive therapy Participants on anticoagulation therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study consists of individual modules each evaluating the safety and tolerability of AZD5863 dosed as monotherapy: Module 1: AZD5863 intravenous administration Module 2: AZD5863 subcutaneous administration Modules 1 and 2 each consist of two parts: Part A, Dose Escalation and Part B, Dose Expansion.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1: AZD5863 Monotherapy Intravenous (IV)<br>Module 1: AZD5863 Intravenous (IV) Monotherapy | Drug: AZD5863<br>* T cell-engaging bi-specific antibody that targets CLDN18.2 (Claudin18.2) on tumor cells and CD3 on T cells<br>|
| Experimental: Module 2: AZD5863 Monotherapy Subcutaneous (SC)<br>Module 2: AZD5863 Subcutaneous (SC) Monotherapy | Drug: AZD5863<br>* T cell-engaging bi-specific antibody that targets CLDN18.2 (Claudin18.2) on tumor cells and CD3 on T cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients with adverse events | Number of patients with adverse events by system organ class and preferred term | From first dose of study drug up to 90 days post last dose and prior to start of subsequent anticancer therapy | 
| The number of patients with adverse events of special interest | Number of patients with adverse events of special interest by system organ class and preferred term | From first dose of study drug up to 90 days post last dose and prior to start of subsequent anticancer therapy | 
| The number of patients with dose-limiting toxicity (DLT), as defined in the protocol. | A DLT is a toxicity as defined in the protocol that occurs from the first dose of study drug up to and including the planned end of Cycle 1 (the DLT assessment period) that is assessed as unrelated to the disease or disease-related processes under investigation. | From first dose of study drug until the end of Cycle 1 | 
| The number of patients with serious adverse events | Number of patients with serious adverse events by system organ class and preferred term | From first dose of study drug up to 90 days post last dose and prior to start of subsequent anticancer therapy | 
| Objective Response Rate (ORR) | The percentage of patients with a confirmed investigator assessed complete or partial response according to response criteria in solid tumours (RECIST 1.1). Dose expansion only. | From first dose of study drug to progressive disease or death in the absence of disease progression (approx. 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The percentage of patients with a confirmed investigator assessed complete or partial response according to response criteria in solid tumours (RECIST 1.1). Dose escalation only. | From first dose of study drug to progressive disease or death in the absence of disease progression (approx. 2 years) | 
| Disease Control Rate (DCR) | Percentage of patients with confirmed complete or partial response or having stable disease maintained for >= 11 weeks from first dose, according to response criteria in solid tumours (RECIST 1.1). | From first dose of study drug to progressive disease or death in the absence of disease progression (approx. 2 years) | 
| Duration of response (DoR) | The time from the date of first response until date of disease progression or death in the absence of disease progression, according to response criteria in solid tumours (RECIST 1.1). | From the first documented response to progressive disease or death in the absence of disease progression (approx. 2 years) | 
| Progression free Survival (PFS) | The time from the start of study treatment/date of randomization until RECIST 1.1 defined disease progression or death in the absence of disease progression. | From the start of study treatment/date of randomization to progressive disease or death in the absence of disease progression (approx. 2 years) | 
| Overall Survival (OS) | The time from the start of study treatment/date of randomization until death due to any cause. | From the start of study treatment/date of randomization to death (to be followed-up for approx. 2 years) | 
| Pharmacokinetics of AZD5863: Maximum plasma concentration of the study drug (Cmax) | Maximum observed plasma concentration of the study drug | From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years) | 
| Pharmacokinetics of AZD5863: Area Under the concentration-time curve (AUC) | Area under the plasma concentration-time curve | From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years) | 
| Pharmacokinetics of AZD5863: Clearance | A pharmacokinetic measurement of the volume of plasma from which the study drug is completely removed per unit time. | From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years) | 
| Pharmacokinetics of AZD5863: Terminal elimination half-life (t 1/2) | Terminal elimination half life. | From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years) | 
| Immunogenicity of AZD5863 | The number and percentage of participants who develop anti-drug antibodies (ADAs) measured in serum | From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years) | 
| Preliminary antitumor activity with target expression pre- and post-delivery of AZD5863 | Measure CLDN18.2 expression (IHC) in baseline and/or on-treatment tumor biopsies and correlate with clinical outcome | From time of Informed consent, at predefined intervals (including screening, on-treatment or end of treatment) throughout the study (over approx. 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLDN18.2 / Claudin 18.2, CD3, T cell-engaging bi-specific antibody, Gastric cancer, Solid tumors, Gastro-esophageal junction cancer, Pancreatic ductal adenocarcinoma, AZD5863