Eureka Therapeutics is currently evaluating ECT204, an investigational autologous glypican 3 (GPC3)-directed T-cell therapy, for the treatment of advanced GPC3-positive hepatocellular carcinoma (HCC) in the phase 1/2 ARYA-3 clinical trial (NCT04864054). The ARYA-3 trial is designed as a dose escalation and expansion study to assess the safety, tolerability, and efficacy of ECT204 in patients with advanced HCC who have failed prior systemic therapies.
ARTEMIS Technology
ECT204 is based on Eureka Therapeutics’ ARTEMIS platform, which differs from traditional chimeric antigen receptor T-cell (CAR-T) technology. ARTEMIS T-cells are activated via a pathway more similar to that seen in endogenous T-cell receptors and are able to target intracellular cancer-specific antigens in addition to surface antigens typically targeted by CAR-T therapies.
According to Cheng Liu, PhD, the president and chief executive officer at Eureka Therapeutics’ subsidiary Estrella, the goal is to develop ARTEMIS T-cell therapies that not only match but also surpass the efficacy of commercially available CAR-T therapies, while also addressing their safety shortcomings. By improving safety, the hope is to reach a broader patient population and make T-cell therapy accessible in community hospitals, not just specialized cancer centers.
ARYA-3 Trial Design and Patient Population
The open-label, multicenter ARYA-3 trial initiated on March 11, 2024, includes a phase 1 dose escalation portion, which has been completed, and a phase 2 dose expansion portion, which is currently underway. In phase 2, patients are assigned to one of two treatment arms. Arm A includes 10 to 15 patients receiving ECT204 as a monotherapy at the recommended phase 2 dose (RP2D). Arm B involves patients receiving ECT204 at the RP2D following pretreatment with regorafenib (Stivarga). All participants in both arms receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine before ECT204 treatment.
The trial's primary endpoints include determining the RP2D and assessing safety and tolerability, measured by the incidence rates of dose-limiting toxicities and the type, frequency, and severity of adverse events (AEs) and laboratory abnormalities within 28 days post-infusion. Secondary endpoints include overall response rate, disease control rate, duration of response, progression-free survival, overall survival, and pharmacokinetics.
ARYA-3 is enrolling patients aged 18 years or older with histologically confirmed unresectable, recurrent, and/or metastatic HCC with GPC3 expression. Phase 2 participants must exhibit at least 3+ GPC3 expression intensity in over 50% of tumor cells in a biopsy and must have experienced unsuccessful treatment with two or more systemic anti-HCC agents. Additional requirements include a life expectancy of at least 4 months, a Karnofsky Performance Scale of at least 70, adequate organ function, a Child-Pugh score of A6 or better, and measurable disease per RECIST v1.1.
Regulatory Designations
ECT204 has been granted orphan drug designation (ODD) by the FDA for the treatment of HCC in February 2022. At the same time, the agency also granted ODD to ET140203, another of Eureka’s investigational cell therapy products based on the ARTEMIS platform, which is being evaluated in the phase 1/2 ARYA-2 clinical trial (NCT04634357) in children with relapsed/refractory hepatoblastoma (HB), hepatocellular neoplasm not otherwise specified (HCN-NOS), and HCC.
