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

Official title

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

Overview

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. Each module contains dose-escalation (Part A) and dose-expansion (Part B).

Interventions

• Drug AZD5863
  T cell-engaging bi-specific antibody that targets CLDN18.2 (Claudin18.2) on tumor cells and CD3 on T cells

Primary outcome measures

• 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]
• 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]
• 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]
• 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]
• 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)]

Secondary outcome measures (11)

• 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)]
• Disease Control Rate (DCR) [Time frame: From first dose of study drug to progressive disease or death in the absence of disease progression (approx. 2 years)]
• Duration of response (DoR) [Time frame: From the first documented response to progressive disease or death in the absence of disease progression (approx. 2 years)]
• Progression free Survival (PFS) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years)]
• Pharmacokinetics of AZD5863: Clearance [Time frame: 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) [Time frame: From the first dose of study intervention, at predefined intervals throughout the study (approx. 2 years)]
• Immunogenicity of AZD5863 [Time frame: 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 [Time frame: From time of Informed consent, at predefined intervals (including screening, on-treatment or end of treatment) throughout the study (over approx. 2 years)]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 4 centers

• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul

United Kingdom · 4 centers

• Research Site — Dundee
• Research Site — London
• Research Site — Metropolitan Borough of Wirral
• Research Site — Oxford

United States · 3 centers

• Research Site — Jacksonville
• Research Site — Rochester
• Research Site — New York

China · 3 centers

• Research Site — Beijing
• Research Site — Beijing
• Research Site — Shandong

Japan · 3 centers

• Research Site — Chūōku
• Research Site — Kashiwa
• Research Site — Kōtoku

Netherlands · 3 centers

• Research Site — Amsterdam
• Research Site — Groningen
• Research Site — Rotterdam

Taiwan · 3 centers

• Research Site — Kaohsiung City
• Research Site — Tainan
• Research Site — Taoyuan

France · 2 centers

• Research Site — Toulouse
• Research Site — Villejuif

Publications

• Gaspar M, Natoli M, Castan L, Rahmy S, Korade M 3rd, Kelton C, Mulgrew K, Huhn O, Rees DG, Sigurdardottir A, Lloyd C, Taylor JJ, Brailey PM, Dallaway L, Toloczko A, Giraldo N, Broggi MAS, Kunihiro A, Abhishek S, He Y, Rong Y, Eyles J, Ball K, Fitzgerald J, Hammond SA, Cemerski S, Dovedi SJ, Cobbold M. An affinity-modulated T cell engager targeting Claudin 18.2 shows potent anti-tumor activity with PMID 40759445

Identifiers

NCT: NCT06005493 · D9750C00001 · 2023-504139-42-00 · 2023-000154-20

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗