A Phase I/II Study to Evaluate AZD5851 in GPC3+ Advanced/Recurrent Hepatocellular Carcinoma

Study Overview
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Brief Summary
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A Phase I/II study to evaluate AZD5851 in patients with GPC3+ advanced/recurrent hepatocellular carcinoma.

Detailed Description
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This first-time in human, single-arm, open-label multicentre Phase I/II study will evaluate the safety, tolerability, antitumour activity, cellular kinetics, pharmacodynamics, and immunogenicity of AZD5851 in adult participants with GPC3+ advanced/recurrent HCC, where at least one line of prior therapy has failed/or was intolerable, or participant/investigator decision.

Official Title
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A Phase I/II Open-Label Study to Evaluate the Safety, Cellular Kinetics and Efficacy of AZD5851, a Chimeric Antigen Receptor T-Cell (CAR-T) Therapy Directed Against GPC3 in Adult Participants With Advanced/Recurrent Hepatocellular Carcinoma: ATHENA

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: AZD5851


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 years or older and has voluntarily agreed to participate by giving written informed consent. Participants with confirmed advanced/recurrent or metastatic and/or unresectable HCC based on histopathological findings Completed or were unable to tolerate at least one prior line of standard systemic therapy for HCC and/or participant/investigator decision. GPC3-positive tumour as determined by a central laboratory using an analytically validated IHC assay Barcelona Clinic Liver Cancer Stage B (if not amenable to local treatment/surgery) or C prior to apheresis Child-Pugh score: Grade A Participants with HBV and HCV undergoing management of these infections per institutional practice. Exclusion Criteria: Active or prior documented gastrointestinal (GI) variceal bleed or history of upper GI bleeding, ulcers, or esophageal varices with bleeding within 12 months History of liver transplantation or on waiting list Current clinically significant ascites Main portal vein thrombus, or tumor thrombus invasion of mesenteric vein / inferior vena cava Uncontrolled intercurrent illness Active Infections Positive serology for HIV History of hepatic encephalopathy within 12 months prior to treatment allocation History of chronic or recurrent (within the last year) severe autoimmune or immune mediated disease requiring steroids or other immune-suppressive treatments. Prior treatment with any CAR-T therapy directed at any target or any therapy that is targeted to GPC3. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, or monoclonal antibodies, investigational product) within 5 half-lives or ≤ 21 days (whichever is shortest).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD5851<br>Subjects will receive AZD5851 following 3 consecutive doses of lymphodepleting chemotherapy (fludarabine and cyclophosphamide). | Biological: AZD5851<br>* Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to produce AZD5851. During AZD5851 production, subjects may receive bridging therapy for disease control. Upon successful generation of AZD5851 product, subjects will receive treatment with AZD5851 therapy. Study treatment will include lymphodepleting chemotherapy followed by one dose of AZD5851 administered by intravenous (IV) infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Incidence of participants with dose-limiting toxicities (DLTs), adverse events (AEs), including adverse events of special interest (AESI) and serious adverse events (SAEs). Determination of the recommended dose of AZD5851 for expansion phase | Determine if treatment with AZD5851 is safe and tolerable through assessment of DLTs, AEs, SAEs and changes from baseline in vital signs, ECGs, and laboratory parameters | Through study completion, an average of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Proportion of participants with a confirmed Complete Response (CR) or Partial Response (PR) | Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to RECIST v1.1 (ORR) | Through study completion, an average of 2 years | 
| 2. Interval between the date of AZD5851 infusion dose and first documented evidence of CR or PR | Evaluation of the efficacy of the treatment by assessment of time to first response (TTR) | Through study completion, an average of 2 years | 
| 3. Proportion of participants who have a confirmed CR, PR, or who have stable disease (SD) for at least 5 weeks after the date of AZD5851 infusion | Evaluation of the efficacy of the treatment by assessment of disease control rate according to RECIST v1.1 (DCR) | Through study completion, an average of 2 years | 
| 4. The proportion of participants who have a confirmed response (CR/PR) with a duration of at least a specific number of months | Evaluation of the efficacy of the treatment by assessment of durable response rate according to RECIST v1.1 (DRR) | Through study completion, an average of 2 years | 
| 5. The best response the participant achieved according to RECIST v1.1 | Evaluation of the efficacy of the treatment by assessment of best overall response according to RECIST v1.1 (BoR) | Through study completion, an average of 2 years | 
| 6. Interval between the date of first documented objective response date of first documented disease progression or the last evaluable assessment in the absence of progression | Evaluation of the efficacy of the treatment by assessment of duration of response according to RECIST v1.1 (DoR) | Through study completion, an average of 2 years | 
| 7. Interval between the date of first T cell infusion and the earliest date of disease progression or death due to any cause | Evaluation of the efficacy of the treatment by assessment of progression-free survival (PFS) | Through study completion, an average of 2 years | 
| 8. Interval between the date of first T cell infusion and date of death due to any cause | Evaluation of the efficacy of the treatment by assessment of overall survival (OS) | Through study completion, an average of 2 years | 
| 9. Pharmacokinetics - maximum serum concentration of AZD5851 | Maximum blood concentration (Cmax) | Through study completion, an average of 2 years | 
| 10. Pharmacokinetics -time to peak serum concentration of AZD5851 | Time to peak (maximum) blood concentration (Tmax) | Through study completion, an average of 2 years | 
| 11. Pharmacokinetics -time to last measurable serum concentration of AZD5851 | Time to last detectable blood concentration (Tlast) | Through study completion, an average of 2 years | 
| 12. Pharmacokinetics - Exposure of AZD5851 | Area under the curve (AUC) | Through study completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma, Liver Cancer, Liver Neoplasm, advanced HCC, HCC, Metastatic Liver Cancer, CAR-T, CART, AZD5851, T-cell, Cell Therapy