Summary
This is an open-label, multi-center, Phase 1/2 clinical trial evaluating the safety, tolerability, and efficacy of ECT204, an investigational ARTEMIS® T-cell therapy, in adult subjects with GPC3-positive hepatocellular carcinoma (HCC) who have experienced disease progression on, or intolerance to, prior systemic therapy.
Detailed Description
ECT204 is an autologous T-cell product built on the ARTEMIS® Cell Receptor platform, incorporating two GPC3-targeting surface components: an antibody-T-cell receptor (AbTCR) and a chimeric stimulating receptor (CSR). Each subject's T cells are collected and genetically modified ex vivo to co-express these receptors, then re-administered to selectively recognize and eliminate GPC3-expressing HCC tumor cells.
The study consists of a completed Phase 1 and a Phase 2 expansion cohort. Phase 1 used a traditional 3+3 dose-escalation design to determine the recommended Phase 2 dose (RP2D), followed by an RP2D confirmatory cohort to further characterize safety. Phase 2 evaluates a multi-infusion strategy of up to four ECT204 infusions administered across two treatment cycles, with the second cycle administered to subjects who achieve stable disease or better at the Month 2 assessment.
The active assessment period extends for 2 years (24 months) after the first ECT204 infusion (Day 0). Subjects then enter long-term follow-up (LTFU) for ongoing safety and overall survival assessments through Year 15.
Eligibility Criteria
Age Range: 18 years to No maximum
Inclusion Criteria:
* Histologically confirmed HCC, that is unresectable, recurrent, and/or metastatic.
* GPC3-positive tumor expression confirmed by immunohistochemistry (IHC).
* For the dose-escalation cohort: ≥10-20% tumor cells, ≥2+ IHC.
* Beginning with the RP2D confirmatory cohort: ≥ 50% tumor cells, 2+/3+ IHC.
* Must have received at least first-line systemic therapy for HCC and have experienced disease progression on, or intolerance to, that therapy.
* Life expectancy of at least 4 months per the Investigator's opinion.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* Measurable disease by RECIST v1.1.
* Child-Pugh score of A6 or better.
* Adequate organ function.
Exclusion Criteria:
* Pre-existing illness (e.g., symptomatic congestive heart failure) that would limit compliance with study requirements.
* Active, uncontrolled systemic bacterial, fungal, or viral infection. Subjects with Human Immunodeficiency Virus (HIV), hepatitis B, or hepatitis C are eligible provided their infection is being treated and the viral load is controlled.
* History of malignancy other than HCC within 5 years before screening, except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other malignancies with low risk of recurrence.
* Known brain metastases or other active central nervous system (CNS) involvement, including leptomeningeal disease. Subjects with brain metastases that have been adequately treated (no evident neurological deficit and no steroid or anti-epileptic therapy for brain metastases) are eligible.
* Pregnant or lactating women.
* Currently receiving or ending (\< 14 days from date of consent) liver tumor-directed therapy (e.g., radiation, ablation, embolization), or hepatic surgery.
* Concurrently receiving other investigational agents, biological, chemical, or radiation therapies, while participating in the study.
* Active autoimmune disease requiring systemic immunosuppressive therapy.
* Presence of portal vein tumor thrombus (PVTT) classified as grade Vp4, or any invasion into the inferior vena cava (IVC), except for subjects with IVC invasion who have been treated and radiographically stable for at least 6 months prior to screening.
* Ascites requiring active treatment, such as a requirement for paracentesis or escalation of diuretic doses. Exception: Subjects maintained on a stable dose of diuretics with controlled, asymptomatic ascites are eligible.
* Active gastrointestinal (GI) bleeding event ≥ Grade 3 per National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE), version 5.0, within 6 months prior to screening.
* Coagulation abnormality defined as international normalized ratio (INR) \> 1.7, unless the elevation is due to therapeutic anticoagulation that, in the Investigator's judgment, can be safely managed in the context of study procedures.
* History of organ transplant.
* HCC involving greater than 50% of the liver volume.
* Experienced allergies to any component of the study drug (ECT204), mouse immunoglobulin, or iron-dextran, or have a history of severe hypersensitivity, including anaphylaxis.
* Previously received other gene therapy (e.g., chimeric antigen receptor T-cell \[CAR-T\] therapy); exception: prior oncolytic virus therapy is permitted.).
* Contraindication for undergoing leukapheresis procedure or receipt of conditioning agents