987TiP - First-in-human dose escalation trial of fourth generation chimeric antigen receptor (CAR) T cell therapy (EU307) in patients with glypican-3 (GPC3) positive hepatocellular carcinoma (HCC)

Background

EU307 is an innovative anti-GPC3 CAR-T cell therapy developed specifically for treating GPC3-positive advanced hepatocellular carcinoma. GPC3, which is prominently expressed in HCC, represents a promising target for CAR-T cell therapy. However, the efficacy of CAR-T cell therapy in solid tumors like HCC is hindered by challenges such as identifying targetable antigens and overcoming the immunosuppressive tumor microenvironment. To address these challenges, EU307, as a fourth-generation CAR-T therapy, incorporates genetic engineering to secrete Interleukin-18 (IL-18), thereby enhancing CAR-T cell persistence and function within the solid tumor environment while specifically targeting the HCC-specific tumor antigen GPC3. This dual action stimulates autocrine co-stimulation of CAR-T cells and leads to the reprogramming of the tumor microenvironment into an environment conducive to tumor eradication.

Trial design

This is the first-in-human, open-label, multicenter Phase 1 dose-escalation trial to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of EU307. Eligibility criteria include patients with GPC3-positive advanced hepatocellular carcinoma who have failed standard therapy. Patients undergo lymphodepletion with cyclophosphamide and fludarabine before receiving EU307 CAR-T cell infusion. The starting dose of 1.0 x 10ˆ8 cells was determined based on the minimally anticipated biological effect level and pharmacologically active dose evaluation in non-clinical conditions. The primary objective is to assess safety through the evaluation of dose-limiting toxicities (DLT) and adverse events, and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary objectives include evaluating preliminary efficacy using mRECIST criteria, and exploring the pharmacokinetic properties of EU307 and changes in immune cells. The study is currently underway at four institutions in South Korea, with enrollment of the first participant in September 2023 and recruitment expected to be completed by 2024.

Clinical trial identification

NCT05783570.

Editorial acknowledgement

Legal entity responsible for the study

Eutilex Co., Ltd.

Funding

Eutilex Co., Ltd.

Disclosure

H. Park, Y. Choi: Financial Interests, Institutional, Full or part-time Employment: Eutilex. Co., Ltd. Y. Chang: Financial Interests, Institutional, Full or part-time Employment: Eutilex Co., Ltd; Financial Interests, Institutional, Stocks/Shares: Eutilex Co., Ltd. All other authors have declared no conflicts of interest.