Clinical trial NCT06795022: First in Human Study to Evaluate AZD9793 in Participants With Advanced or Metastatic Solid Tumours
Official title: A Modular Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD9793, a T Cell-engaging Antibody Targeting Glypican-3 (GPC3) in Adult Participants With Advanced or Metastatic Solid Tumours (RHEA-1)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma
Keywords: Glypican-3
GPC3
GPC3+ tumours
T cell-engaging antibody
TCE
AZD9793
Solid tumours
HCC
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2025-01-27
Enrollment: 304
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The study consists of individual modules each evaluating the safety and tolerability of AZD9793 dosed as monotherapy:

Module 1: AZD9793 intravenous administration Module 2: AZD9793 subcutaneous administration

Modules 1 and 2 each consist of two parts: Part A, Dose Escalation and Part B, Dose Expansion.
Primary purpose: TREATMENT

Brief summary: This research is designed to determine if experimental treatment with AZD9793, a T cell-engaging antibody that targets GPC3, is safe, tolerable and has anti-cancer activity in patients with advanced or metastatic solid tumours which are GPC3+.

Detailed description: This is a first-time in human, modular Phase I/II, open-label multicentre study of AZD9793 monotherapy administered intravenously (Module 1), or AZD9793 monotherapy administered subcutaneously (Module 2) in patients with advanced or metastatic solid tumours. Each module contains dose-escalation (Part A) and dose-expansion (Part B).

Eligibility criteria: Key Inclusion Criteria:

* Age ≥ 18 at the time of signing the informed consent.
* GPC3 positive tumour as determined by a central laboratory using an analytically validated IHC assay.
* Must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
* 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.
* Confirmed advanced recurrent and/or metastatic and/or unresectable HCC, which is histopathologically proven based on the criteria established by the World Health Organization.
* Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C.
* Child-Pugh Score class A.
* Previous therapy:

Part A: Patients who have received at least one prior line of standard systemic therapy for HCC as per NCCN or other local scientific guidelines and for which a clinical study is the best option for next treatment based on prior response and/or tolerability and/or patient/investigator decision.

Part B: Patients must not have received more than 1 prior line of systemic therapy in the advanced recurrent and/or metastatic setting.

Key Exclusion Criteria:

* Unresolved toxicity from prior anticancer therapy, including irAEs, of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 except for vitiligo, peripheral neuropathy related to prior anti-cancer therapy, alopecia, endocrine disorders that are controlled with replacement hormone therapy and asymptomatic laboratory abnormalities.
* Prior to enrolment, participation in another clinical study with an investigational product administered in the last 21 days or 5 half-lives whichever is shorter.
* CAR-T cell therapy within the last 6 months prior to enrolment on this study.
* Known allergy or hypersensitivity to AZD9793 or any of the excipients of the product as outlined in the IB.
* Requires chronic immunosuppressive therapy (including steroids \> 10 mg prednisone/day or equivalent).
* Prior treatment with any therapy that is targeted to GPC3.
* Received any therapy to treat cancer (including chemotherapy, biologics, cellular therapies) within 5 half-lives of an anticancer drug prior to the first dose of study treatment.
* Received radiation within 14 days; palliative radiation to reduce the risk of tumour lysis syndrome (TLS) or CRS/neurotoxicity in participants with bulky disease is permitted.
* Undergone a major surgical procedure within 14 days to allow adequate healing
* 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.
* 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.
* 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), and uncontrolled active systemic fungal, bacterial or other infection.

Primary outcomes:
measure: The number of patients with adverse events
timeFrame: From first dose of study drug up to 30 days post last dose and prior to start of subsequent anticancer therapy
measure: The number of patients with serious adverse events
timeFrame: From first dose of study drug up to 30 days post last dose and prior to start of subsequent anticancer therapy
measure: The number of patients with adverse events of special interest
timeFrame: From first dose of study drug up to 30 days post last dose and prior to start of subsequent anticancer therapy
measure: The number of patients with dose-limiting toxicity (DLT), as defined in the protocol.
timeFrame: From date of first dose of study drug until the end of Cycle 1 (up to 28 days)
measure: Objective Response Rate (ORR) [Dose expansion only]
timeFrame: From first dose of study drug to progressive disease or the last evaluable assessment in the absence of disease progression whichever comes first (up to approximately 2 years)
Secondary outcomes:
measure: Objective Response Rate (ORR) [Dose escalation only]
timeFrame: From first dose of study drug to progressive disease or the last evaluable assessment in the absence of disease progression whichever comes first (up to approximately 2 years)
measure: Best overall response (BOR)
timeFrame: From first dose until disease progression or the last evaluable assessment in the absence of progression (up to approximately 2 years)
measure: Disease Control Rate (DCR) at 12 weeks
timeFrame: From first dose of study drug to progressive disease or last evaluable assessment in the absence of disease progression. [Expected to be measured for each patient at 12 weeks]
measure: Durable response rate (DRR)
timeFrame: From first documented objective response (subsequently confirmed) to the date of disease progression or the last evaluable assessment in the absence of progression (up to approximately 2 years)
measure: Duration of response (DoR)
timeFrame: From the first documented objective response (subsequently confirmed) to progressive disease or death in absence of progression (up to approximately 2 years)
measure: Time To Response (TTR)
timeFrame: From start of study treatment until the date of first documented objective response, which is subsequently confirmed as assessed by the Investigator per RECIST 1.1 (up to approximately 2 years)
measure: Progression free Survival (PFS)
timeFrame: From the start of study treatment to progressive disease or death due to any cause (up to approximately 2 years)
measure: Overall Survival (OS) [Dose expansion only]
timeFrame: From the start of study treatment to death (up to approximately 2 years)
measure: Pharmacokinetics of AZD9793: Maximum serum concentration of the study drug (Cmax)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)
measure: Pharmacokinetics of AZD9793: Area Under the concentration-time curve (AUC)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)
measure: Pharmacokinetics of AZD9793: Clearance
timeFrame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)
measure: Pharmacokinetics of AZD9793: Terminal elimination half-life (t 1/2)
timeFrame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)
measure: Immunogenicity of AZD9793
timeFrame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)
measure: Change in CD8+ Levels
timeFrame: From time of Informed consent, at predefined intervals (including screening, on-treatment or end of treatment) throughout the study (up to approximately 2 years)
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Houston
country: United States
facility: Research Site
state: Texas
city: Shatin
country: Hong Kong
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
Study officials:
References: