A Phase 1/2 interventional study of GPC3-CART cells and Fludarabine Phosphate for Injection in Hepatocellular Carcinoma (HCC), sponsored by Chinese PLA General Hospital. Not yet recruiting at 1 site in China. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-10-16.
Sponsored by Chinese PLA General Hospital · Phase 1/2, Interventional, and Treatment
In this single-center, single-arm, prospective, open-label Phase 1/2 study, the safety and efficacy of autologous GPC3-targeted chimeric antigen receptor (CAR) T-cell therapy will be evaluated in patients with GPC3-positive advanced hepatocellular carcinoma.
Phase 1 will involve the enrollment of six eligible patients to receive hepatic arterial infusion of GPC3-CAR T cells at a fixed dose of 1×10\^6 cells/kg, with or without a standard lymphodepleting conditioning regimen (fludarabine and cyclophosphamide). Based on the results, it will be assessed whether the FC lymphodepletion regimen is necessary. Subsequently an additional six patients will be enrolled in a "3+3" dose-escalation design to adjust the dose of GPC3-CAR T cells to achieve optimal safety and efficacy. The recommended Phase 2 dose (RP2D) will then be established.
Phase 2 will involve the enrollment of 10-20 additional eligible patients to receive GPC3-CAR T cell therapy at the RP2D.
Glypican-3 (GPC3) is a member of the glypican family, a group of heparan sulfate proteoglycans that are anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) linkage. Structurally, GPC3 is composed of a core protein and covalently attached heparan sulfate chains. The core protein consists of an N-terminal domain, a large cysteine-rich region, and a C-terminal region that interacts with the cell membrane. Functionally, GPC3 is involved in regulating cell growth, differentiation, and apoptosis through interactions with various growth factors, including Wnt, Hedgehog, and fibroblast growth factors (FGFs). GPC3 plays a critical role during embryonic development but is largely absent in most adult tissues. However, its re-expression in certain cancers, particularly hepatocellular carcinoma (HCC), makes it an attractive target for therapeutic intervention.
GPC3 is highly and specifically expressed in hepatocellular carcinoma, a common form of primary liver cancer, while being minimally expressed in normal adult liver tissues. This differential expression makes GPC3 an appealing and specific target for cancer therapy.In HCC, GPC3 has been shown to play a role in promoting tumor growth and angiogenesis, enhancing tumor invasiveness, and protecting cancer cells from apoptosis. Due to its overexpression in HCC tumor tissues, GPC3 has been widely recognized as a potential biomarker for diagnosis, prognosis, and targeted therapies. Its selective expression in cancerous tissue with limited distribution in normal tissues makes it an ideal candidate for chimeric antigen receptor (CAR) T cell therapy, which aims to specifically target and destroy cancer cells while minimizing off-target effects.
Several studies have explored the use of GPC3-targeted CAR T cell therapies in hepatocellular carcinoma. These early clinical trials were designed to evaluate the safety and preliminary efficacy of GPC3-CAR T cell treatments in patients with advanced-stage, GPC3-positive HCC. The results from these trials demonstrated that GPC3-CAR T cell therapy is generally safe, with manageable adverse effects, and some patients exhibited clinical responses, such as tumor regression or disease stabilization. However, despite these promising results, the overall efficacy of GPC3-CAR T cell therapy did not meet the threshold required for routine clinical application. The responses were often transient, and relapse occurred in many patients due to challenges such as T cell exhaustion, limited CAR T cell persistence, and the immunosuppressive tumor microenvironment (TME) associated with HCC. These limitations highlighted the need for further optimization of the CAR T cell design and administration strategies to improve the efficiency of GPC3-targeted therapies in HCC.
Building on the foundation of these earlier studies, the investigators aim to conduct a prospective, open-label, phase 1/2 clinical trial to evaluate our newly optimized GPC3-targeted CAR T cell therapy in patients with advanced-stage, GPC3-positive HCC. Our approach introduces two major innovations compared to previous studies:
By leveraging these two innovative strategies, the investigators aim to achieve improved clinical outcomes in terms of both safety and efficacy. The investigators hypothesize that the inclusion of immune microenvironment-activating elements will enhance the activation of not only CAR T cells but also the broader immune system, creating a more hostile environment for tumor cells. Furthermore, direct tumor delivery of CAR T cells may increase their local concentration and activity, reducing the tumor burden more effectively. Through this optimized approach, the investigators hope to provide a more potent and durable therapeutic option for patients with GPC3-positive hepatocellular carcinoma, addressing the limitations encountered in previous trials.
3,249 studies on the registry are indexed under Carcinoma, Hepatocellular; 974 are open to participants now.
This study's planned enrollment of 30 is below the median of 55 across 2,347 interventional studies indexed under Carcinoma, Hepatocellular.
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Diagnosis of advanced Hepatocellular Carcinoma (HCC), meeting the following requirements:
Hematology:
Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L (no granulocyte colony-stimulating factor support within 7 days prior to testing).
Absolute lymphocyte count (ALC) ≥ 0.5 × 10\^9/L; hemoglobin (HGB) ≥ 80 g/L (no red blood cell transfusion within 7 days prior to testing).
Platelet count (PLT) ≥ 75 × 10\^9/L (no transfusion support within 7 days prior to testing).
Liver Function:
Aspartate aminotransferase (AST ) and alanine aminotransferase (ALT ) ≤ 3.0 × upper limit of normal (ULN).
Total bilirubin (TBIL) ≤ 2.0 × ULN (≤ 3.0 × ULN for patients with Gilbert's syndrome and direct bilirubin ≤ 1.5 × ULN).
Coagulation Function:
International normalized ratio (INR) ≤ 1.5 × ULN. Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (except for patients receiving therapeutic anticoagulants).
Renal Function: Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min.
Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 50% (confirmed by echocardiography).
Pulmonary Function: Pulse oxygen saturation (SpO2) > 93% at rest without supplemental oxygen.
Exclusion Criteria:
Presence of clinically significant systemic disease (e.g., severe active - - infections, significant heart, lung, liver, kidney, or neurological dysfunction) that, in the investigator's opinion, may impair the patient's ability to tolerate the study treatment or increase the risk of complications. Including but not limited to:
Enrolled patients will receive a single infusion of GPC3 CAR-T cells at a starting dose of 1×10\^6 cells/kg.
Biological: GPC3-CART cells · Drug: Fludarabine Phosphate for Injection · Drug: Cyclophosphamide for Injection
Phase 1: Dose escalation (3+3): Dose 1 (1 × 10\^6 cells/kg) with or without FC regimen, Dose 2 (3 × 10\^6 cells/kg), Dose 3 (6 × 10\^6 cells/kg). Phase 2: Dose at RP2D.
Administered intravenously at a dose of 20-30 mg/m²/day on days -5, -4, and -3.
Administered intravenously at a dose of 300-500 mg/m²/day on days -5, -4, and -3.
Incidence of treatment-related adverse events
Treatment-related adverse events are defined as any medical events occurring since the initiation of GPC3-targeted CAR T cell therapy. CRS or CRES will be graded based on the American Society for Transplantation and Cellular Therapy (ASTCT) criteria, and other adverse events will be graded according to CTCAE v5.0.
Time frame: Up to 12 months since the initiation of GPC3-targeted CAR T cell therapy.
Incidence of dose-limiting toxicities (DLTs)
Dose-limiting toxicities are defined as GPC3-targeted CAR T cell therapy-related adverse events within the first 28 days that meet the following criteria: grade 3 or higher CRS or CRES, and any other grade 4 adverse events.
Time frame: Up to 28 days from the initiation of GPC3-targeted CAR T cell therapy.
Number and copy number of GPC3-targeted CAR T cells
The number and copy number of GPC3-targeted CAR T cells are evaluated in peripheral blood and tumor tissue.
Time frame: Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.
Objective response rate (ORR)
Objective response rate includes complete response and partial response, as defined by investigators according to RECIST 1.1 criteria.
Time frame: Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.
Progression Free Survival (PFS)
Progression Free Survival is defined as the time from the initiation of GPC3 targeted CAR T cell therapy to documented disease progression or death.
Time frame: Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.
Time to response (TTR)
TTR is defined as the time from the initiation of GPC3 targeted CAR T cell therapy to first assessed CR or PR by investigators according to RECIST 1.1 criteria.
Time frame: Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.
Duration of response (DOR)
Duration of response is defined as the time from objective response until documented tumor progression among responders.
Time frame: Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.
Overall Survival (OS)
Overall Survival is defined as the time from the initiation of GPC3 targeted CAR T cell therapy to documented disease progression or death.
Time frame: Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.
Plan to share: Undecided
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Studies of the drugs tested here: Fludarabine phosphate · Cyclophosphamide
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