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)

Overview

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).

Interventions

• Drug AZD9793 Intravenous (IV) monotherapy
  T cell-engaging antibody that targets GPC3 on tumour cells
• Drug AZD9793 Subcutaneous (SC) monotherapy
  T cell-engaging antibody that targets GPC3 on tumour cells

Primary outcome measures

• The number of patients with adverse events [Time frame: From first dose of study drug up to 30 days post last dose and prior to start of subsequent anticancer therapy]
• The number of patients with serious adverse events [Time frame: From first dose of study drug up to 30 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 30 days post last dose and prior to start of subsequent anticancer therapy]
• The number of AEs leading to discontinuation of AZD9793 [Time frame: From first dose of study drug up to 30 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 [Part A Dose Escalation only] [Time frame: From date of first dose of study drug until the end of DLT evaluation period (up to 21, 28 or 35 days depending on dose regimen)]
• Objective Response Rate (ORR) [Part B Dose Expansion only] [Time frame: 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 outcome measures (12)

• Objective Response Rate (ORR) [Part A Dose Escalation only] [Time frame: 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)]
• Best overall response (BOR) [Time frame: From first dose until disease progression or the last evaluable assessment in the absence of progression (up to approximately 2 years)]
• Duration of response (DoR) [Time frame: From the first documented objective response (subsequently confirmed) to progressive disease or death in absence of progression (up to approximately 2 years)]
• Disease Control Rate (DCR) at 12 weeks [Time frame: 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]]
• Durable response rate (DRR) [Time frame: 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)]
• Time To Response (TTR) [Time frame: 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)]
• Percentage change in tumour size [Time frame: From first dose of study drug to the last evaluable assessment]
• Progression free Survival (PFS) [Time frame: From the start of study treatment to progressive disease or death due to any cause (up to approximately 2 years)]
• Overall Survival (OS) [Dose expansion only] [Time frame: From the start of study treatment to death (up to approximately 2 years)]
• Pharmacokinetics of AZD9793: Maximum serum concentration of the study drug (Cmax) [Time frame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)]
• Pharmacokinetics of AZD9793: Area Under the concentration-time curve (AUC) [Time frame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)]
• Pharmacokinetics of AZD9793: Clearance [Time frame: From the first dose of study intervention, at predefined intervals throughout the study (up to approximately 2 years)]

Eligibility criteria

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. Patients who previously received any therapy targeting GPC3 must undergo central laboratory GPC3 testing on tumour tissue collected after completion of the prior GPC3-targeted therapy.
• 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 National Comprehensive Cancer Network 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 one prior line of systemic therapy in the advanced recurrent and/or metastatic setting.

Exclusion criteria

• Unresolved toxicity from prior anticancer therapy, including imAEs, 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).
• Received radiation within 14 days prior to first dose of study treatment; 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 prior to first dose of study treatment 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.
• Known fibrolamellar HCC, sarcomatoid HCC, or combined hepatocellular malignant cholangiocarcinoma.

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

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 6 centers

• Research Site — La Jolla
• Research Site — Los Angeles
• Research Site — Baltimore
• Research Site — St Louis
• Research Site — Hackensack
• Research Site — Houston

China · 4 centers

• Research Site — Chengdu
• Research Site — Guangzhou
• Research Site — Harbin
• Research Site — Shanghai

Hong Kong · 2 centers

• Research Site — Pokfulam
• Research Site — Shatin

Japan · 2 centers

• Research Site — Kashiwa
• Research Site — Yokohama

South Korea · 2 centers

• Research Site — Seoul
• Research Site — Seoul

Spain · 2 centers

• Research Site — Barcelona
• Research Site — Pamplona

Taiwan · 2 centers

• Research Site — Taipei
• Research Site — Taoyuan

Identifiers

NCT: NCT06795022 · D7040C00001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗