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
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 392
- Locations
- 27
- Primary Endpoint
- Objective Response Rate (ORR)
Study Overview
Brief Summary
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
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, or AZD5863 in combination with Rilvegostomig (Module 3). Each module contains dose-escalation (Part A) and dose-expansion (Part B).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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 with long-acting anticoagulants or other class of anticoagulants at therapeutic doses Module 3 - Active or ongoing interstitial lung disease / pneumonitis, serious chronic gastrointestinal conditions Module 3 - Any of the following cardiac conditions as determined by investigator: Complex ventricular arrhythmia, symptomatic heart failure, Cardiomyopathy, myocardial infarction or unstable angina (within past 6 months) and uncontrolled hypertension.
- •Module 3 - Known allergy or hypersensitivity to rilvegostomig or its excipients Module 3 - Prior exposure to an anti-TIGIT therapy
Arms & Interventions
Module 1: AZD5863 Monotherapy Intravenous (IV)
Module 1: AZD5863 Intravenous (IV) Monotherapy
Intervention: AZD5863 (Drug)
Module 2: AZD5863 Monotherapy Subcutaneous (SC)
Module 2: AZD5863 Subcutaneous (SC) Monotherapy
Intervention: AZD5863 (Drug)
Module 3: AZD5863 Combination and Rilvegostomig
Module 3: AZD5863 Combination and Rilvegostomig
Intervention: AZD5863 (Drug)
Module 3: AZD5863 Combination and Rilvegostomig
Module 3: AZD5863 Combination and Rilvegostomig
Intervention: AZD2936 (Drug)
Outcomes
Primary Outcomes
Objective Response Rate (ORR)
Time Frame: From first dose of study drug to progressive disease or death in the absence of disease progression (approx. 2 years)
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.
The number of patients with adverse events
Time Frame: From first dose of study drug up to 90 days post last dose and prior to start of subsequent anticancer therapy
Number of patients with adverse events by system organ class and preferred term
The number of patients with dose-limiting toxicity (DLT), as defined in the protocol.
Time Frame: From first dose of study drug until the end of Cycle 1
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.
The number of patients with adverse events of special interest
Time Frame: From first dose of study drug up to 90 days post last dose and prior to start of subsequent anticancer therapy
Number of patients with adverse events of special interest by system organ class and preferred term
The number of patients with serious adverse events
Time Frame: From first dose of study drug up to 90 days post last dose and prior to start of subsequent anticancer therapy
Number of patients with serious adverse events by system organ class and preferred term
Secondary Outcomes
- Immunogenicity of AZD5863(From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years))
- Objective Response Rate (ORR)(From first dose of study drug to progressive disease or death in the absence of disease progression (approx. 2 years))
- Pharmacokinetics of AZD5863: Maximum plasma concentration of the study drug (Cmax)(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)(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)(From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years))
- Disease Control Rate (DCR)(From first dose of study drug to progressive disease or death in the absence of disease progression (approx. 2 years))
- Duration of response (DoR)(From the first documented response to progressive disease or death in the absence of disease progression (approx. 2 years))
- Pharmacokinetics of AZD5863: Clearance(From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years))
- Progression free Survival (PFS)(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)(From the start of study treatment/date of randomization to death (to be followed-up for approx. 2 years))
- Preliminary antitumor activity with target expression pre- and post-delivery of AZD5863(From time of Informed consent, at predefined intervals (including screening, on-treatment or end of treatment) throughout the study (over approx. 2 years))