CAR-T Cell Therapy Targeting GPC3 in Patients with Advanced GPC3-Positive Hepatocellular Carcinoma

NCT06641453 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: S2024-560-01
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hepatocellular Carcinoma (HCC)

Keywords

HCC; GPC3; CAR-T cells

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  Up to 28 days from the initiation of GPC3-targeted CAR T cell therapy.

Secondary Outcomes (6)

• Number and copy number of GPC3-targeted CAR T cells

  Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.

• Objective response rate (ORR)

  Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.

• Progression Free Survival (PFS)

  Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.

• Time to response (TTR)

  Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.

• Duration of response (DOR)

  Up to 3 years from the initiation of GPC3-targeted CAR T cell therapy.

Study Arms (1)

GPC3 CAR-T cell therapy

EXPERIMENTAL

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

Interventions

GPC3-CART cells BIOLOGICAL

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.

GPC3 CAR-T cell therapy

Fludarabine Phosphate for Injection DRUG

Administered intravenously at a dose of 20-30 mg/m²/day on days -5, -4, and -3.

GPC3 CAR-T cell therapy

Cyclophosphamide for Injection DRUG

Administered intravenously at a dose of 300-500 mg/m²/day on days -5, -4, and -3.

GPC3 CAR-T cell therapy

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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:
• Uncontrolled severe active infection.
• Symptomatic congestive heart failure (NYHA Class II-IV).
• Clinically significant severe aortic valve stenosis or symptomatic mitral valve stenosis.
• QTc \> 450 msec on ECG, or QTc \> 480 msec in patients with bundle branch block.
• Uncontrolled clinically significant arrhythmias within six months before signing informed consent.
• Acute coronary syndrome (e.g., unstable angina or myocardial infarction) within six months before signing informed consent.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (1)

Biotherapeutic Department of Chinese PLA General Hospital

Beijing, Beijing Municipality, 100853, China

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

fludarabine phosphate; Injections; Cyclophosphamide

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Yangbin Zhao, Ph.D.

  UTC Therapeutics Inc.

  STUDY DIRECTOR

Central Study Contacts

Weidong Han, Ph.D.

CONTACT

+86-010-55499341; hanwdrsw@sina.com

Guanghua Rong, M.D.& Ph.D.

CONTACT

+8613811969943; shengfandayeren@126.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the Department of Biotherapeutics

Study Record Dates

• First Submitted: October 12, 2024
• First Posted: October 15, 2024
• Study Start: November 15, 2024
• Primary Completion (Estimated): November 15, 2027
• Study Completion (Estimated): November 15, 2028
• Last Updated: October 16, 2024

Record last verified: 2024-10

Locations

CN (1)