Eureka Therapeutics Tackling Advanced Hepatocellular Carcinoma With T-Cell Therapy ECT204 in Phase 1/2 ARYA-3 Clinical Trial
Following up on Liver Cancer Awareness Month, which is observed annually in October by the patient and clinician communities, CGTLive has decided to take a closer look at this ongoing study.
Eureka Therapeutics’ ECT204, an investigational autologous glypican 3 (GPC3)-directed T-cell therapy based on the company’s ARTEMIS platform, is currently being evaluated for the treatment of advanced GPC3-positive hepatocellular carcinoma (HCC) in the phase 1/2 ARYA-3 clinical trial (NCT04864054).1 Following up on Liver Cancer Awareness Month, which is observed annually in October by the patient and clinician communities, CGTLive® has decided to take a closer look at this ongoing study.
ARTEMIS differs from traditional chimeric antigen receptor T-cell (CAR-T) technology in that it allows the T-cells to be activated via a pathway more similar to that seen in endogenous T-cell receptors.2,3 Notably, ARTEMIS T-cells are able to target intracellular cancer-specific antigens in addition to the surface-antigens typically used as targets for CAR-T.4
“Our 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,” Cheng Liu, PhD, the president and chief executive officer at Eureka Therapeutics’ subsidiary Estrella, said in a September 2024 statement.5 “By improving safety, we hope to reach a broader patient population and make T-cell therapy accessible in community hospitals, not just specialized cancer centers.”
The open-label, multicenter ARYA-3 trial was initiated on March 11, 2024 and takes the form of a dose escalation and expansion study. Pei Wang, PhD, the vice president of clinical development and technical operations at Eureka Therapeutics, is serving as the study director. At this time, the phase 1 dose escalation portion of the study has been completed and the phase 2 dose expansion portion is underway. In the phase 2 portion, patients will be assigned to 1 of 2 treatment arms. In arm A, 10 to 15 patients will receive ECT204 as a monotherapy at the recommended phase 2 dose (RP2D). In arm B, patients will received ECT204 at the RP2D following pretreatment with regorafenib (Stivarga). Participants in both arm A and arm B will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine before treatment with the cell therapy. According to the clinicaltrials.gov page for ARYA-3, which was most recently updated on May 6, 2024, the study is currently recruiting at City of Hope in Duarte, California; Kansas University Medical Center in Westwood, Kansas; and Roswell Park Comprehensive Cancer Center in Buffalo, New York.
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In addition to determining the RP2D, the trial’s other primary end point is safety and tolerability as assessed by incidence rates of dose limiting toxicities and the type, frequency, and severity of adverse events (AEs) and laboratory abnormalities in the 28 days following infusion of the cell therapy product. The study’s secondary end points include the overall response rate, disease control rate, duration of response, progression-free survival, overall survival, and pharmacokinetics as measured by peak exposure, time to reach peak exposure, partial area under the curve, and other parameters in the peripheral blood.
ARYA-3 is open to patients aged 18 years or older who have histologically confirmed unresectable, recurrent, and/or metastatic HCC with GPC3 expression determined via immunohistochemistry. For the phase 2 portion of the study, participants are required to show at least 3+ GPC3 expression intensity in more than 50% of tumor cells in a biopsy. Participants in ARYA-3 must additionally have had previous unsuccessful treatment with 2 or more different systemic antiHCC agents; 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 according to RECIST v1.1.
Patients with preexisting illness limiting ability to comply with ARYA-3's requirements and those with advanced HCC that involves more than half of the liver will be excluded from participation. Additional exclusion criteria include active uncontrolled systemic infections; active malignancies besides HCC, excepting cholangiocarcinoma and some malignancies without any organ involvement and with an expected survival of 3 years or more without any treatment; treatment with liver tumor-directed therapy or liver surgery within less than 14 days of study consent; concomitant treatment with other investigational products; active autoimmune disease that necessitates therapy; a history of organ transplant; or compromised circulation in the main portal vein, hepatic vein, or vena cava because of obstruction.
ECT204 has previously been granted orphan drug designation (ODD) by the FDA for the treatment of HCC, in February 2022.1 At the same time, the agency also granted ODD to ET140203, another of Eureka’s investigational cell therapy products based on the ARTEMIS platform. ET140203 is currently 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.
“We are pleased to have received ODD for ET140203 and ECT204 just months after receiving FDA fast track designation for the treatment of HB and HCC in pediatric patients, and rare pediatric disease designation for the treatment of HB,” Liu said at the time.1 “These designations for Eureka’s clinical candidates underscore the significant unmet medical need for more effective liver cancer treatment options. We are committed to working closely with regulators, clinical investigators, patients and their families to advance these programs in the clinics.”
