Trial Title:
CAR-T Cell Therapy Targeting GPC3 in Patients with Advanced GPC3-Positive Hepatocellular Carcinoma
NCT ID:
NCT06641453
Condition:
Hepatocellular Carcinoma (HCC)
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Conditions: Keywords:
HCC
GPC3
CAR-T cells
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
GPC3-CART cells
Description:
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.
Arm group label:
GPC3 CAR-T cell therapy
Intervention type:
Drug
Intervention name:
Fludarabine Phosphate for Injection
Description:
Administered intravenously at a dose of 20-30 mg/m²/day on days -5, -4, and -3.
Arm group label:
GPC3 CAR-T cell therapy
Intervention type:
Drug
Intervention name:
Cyclophosphamide for Injection
Description:
Administered intravenously at a dose of 300-500 mg/m²/day on days -5, -4, and -3.
Arm group label:
GPC3 CAR-T cell therapy
Summary:
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.
Detailed description:
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:
1. Novel CAR T Cell Design Strategy: In addition to the traditional CAR structure
comprising a single-chain variable fragment (scFv) specific for GPC3, a
co-stimulatory domain (41BB/CD28), and a CD3ζ activation domain, we have
incorporated novel immune microenvironment-activating elements. These elements are
designed to enhance the activation and proliferation of CAR T cells while
simultaneously recruiting and activating antigen-presenting cells (APCs) and
bystander immune effector cells. This dual activation strategy aims to overcome the
immunosuppressive TME and promote a more robust and sustained anti-tumor response.
2. New Administration Route: Unlike previous studies that primarily used intravenous
administration, the investigators have developed a new method of delivering CAR T
cells directly into the tumor site. This strategy is intended to facilitate
immediate and direct contact between the CAR T cells and the tumor cells, allowing
for more efficient tumor infiltration and modification of the TME. By altering the
local immune landscape, the investigators aim to enhance CAR T cell persistence and
efficacy while reducing the likelihood of tumor escape.
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age: 18 to 70 years old (inclusive); gender unrestricted.
Diagnosis of advanced Hepatocellular Carcinoma (HCC), meeting the following requirements:
- Pathologically Confirmed: Diagnosis of HCC confirmed by histopathology. Staging:
Classified as China Liver Cancer (CNLC) stage IIb-IIIb, having undergone treatments
recommended by the "Primary Liver Cancer Diagnosis and Treatment Guidelines (2024
Edition)" with disease progression and either no further recommended treatments
available or intolerance to the recommended treatment options.
- Measurable Lesion: At least one measurable lesion as defined by RECIST v1.1
criteria.
- Tumor Sample Availability: Availability of tumor tissue samples or samples obtained
by tumor biopsy for GPC3 expression quantification and other related analyses.
- GPC3 Positivity: Confirmed positive GPC3 expression by immunohistochemistry (IHC),
where positivity is defined as a quantified immunohistochemical score of "+" or
above.
- ECOG Performance Status: Eastern Cooperative Oncology Group (ECOG) score of 0-1.
- Life Expectancy: Expected survival time of ≥ 3 months.
- Cirrhosis Status: Child-Pugh class A or B for liver cirrhosis.
- Organ Function: Must meet the following organ function 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.
- Contraception: Women of childbearing potential must have a negative pregnancy test,
and both male and female participants with reproductive potential must agree to use
effective contraception throughout the screening and study period until one year
after the last cellular infusion.
- Informed Consent: Willingness to provide voluntary written informed consent and
compliance with the study protocol.
Exclusion Criteria:
- Pregnant or breastfeeding women.
- Positive HCV RNA quantification, positive human immunodeficiency virus (HIV)
antibodies, or active syphilis infection.
- Chronic HBV infection with serum HBV-DNA levels ≥ 500 IU/mL.
- Unresolved non-hematologic toxicities (excluding alopecia and peripheral sensory
neuropathy) from prior treatments (surgery, chemotherapy, radiotherapy, targeted
therapy, immunotherapy) that have not improved to ≤ Grade 1 according to CTCAE.
- History of allogeneic tissue/organ transplantation (including bone marrow, stem
cell, liver, or kidney transplants), except those that do not require
immunosuppressive therapy (e.g., corneal or hair transplants).
- Prior treatment targeting GPC3.
- Receipt of anti-tumor treatment for liver cancer or any other medical intervention
that could impair major organ function within four weeks before signing informed
consent.
- Known central nervous system metastasis.
- 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:
1. Uncontrolled severe active infection.
2. Symptomatic congestive heart failure (NYHA Class II-IV).
3. Clinically significant severe aortic valve stenosis or symptomatic mitral valve
stenosis.
4. QTc > 450 msec on ECG, or QTc > 480 msec in patients with bundle branch block.
5. Uncontrolled clinically significant arrhythmias within six months before
signing informed consent.
6. Acute coronary syndrome (e.g., unstable angina or myocardial infarction) within
six months before signing informed consent.
7. Hypertension not controlled by medication (systolic BP ≥ 160 mmHg and/or
diastolic BP ≥ 100 mmHg).
8. Cerebrovascular accidents, including transient ischemic attack (TIA), cerebral
infarction, cerebral hemorrhage, or subarachnoid hemorrhage within six months
before signing informed consent.
9. Active, chronic, or recurrent severe autoimmune disease (within one year before
signing informed consent), or liver cirrhosis/liver cancer caused by autoimmune
hepatitis.
10. Any form of primary or secondary immunodeficiency, such as severe combined
immunodeficiency (SCID).
11. Risk of organ perforation or hemorrhage, as determined by the investigator.
- History of severe systemic hypersensitivity to study drugs/components [e.g.,
fludarabine, cyclophosphamide, dimethyl sulfoxide (DMSO), low molecular weight
dextran, human serum albumin (HSA)].
- Receipt of live attenuated vaccine within four weeks before signing informed
consent.
- Participation in another clinical trial within four weeks before signing informed
consent.
- History of another malignancy within the past five years, excluding adequately
treated non-melanoma skin cancer or carcinoma in situ (e.g., breast, stomach, colon,
bladder, cervix, or melanoma).
- History of neuropsychiatric disorders diagnosed by ICD-11 criteria, or any
neuropsychiatric disorder deemed by the investigator to warrant exclusion, including
but not limited to epilepsy, schizophrenia, dementia, or addiction to drugs/alcohol.
- Any other condition that, in the investigator's opinion, makes the patient
unsuitable for this clinical trial.
Gender:
All
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Biotherapeutic Department of Chinese PLA General Hospital
Address:
City:
Beijing
Zip:
100853
Country:
China
Contact:
Last name:
Guanghua Rong
Phone:
+8613811969943
Email:
shengfandayeren@126.com
Start date:
November 15, 2024
Completion date:
November 15, 2028
Lead sponsor:
Agency:
Chinese PLA General Hospital
Agency class:
Other
Source:
Chinese PLA General Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06641453
