Study Of B7H3 CAR-T Cells in Treating Advanced Liver Cancer

Official title

A Single-Arm, Open-Label Study to Evaluate Safety and Efficacy of B7H3 or HBsAg Targeting CAR-T in Treating Advanced Hepatocellular Carcinoma

Overview

This is single center, open-label phase I/II, non-randomized study which will enroll patients with recurrent advanced hepatocellular carcinoma to evaluate the safety, feasibility, and efficacy of fully human B7H3 CAR-T in treating hepatocellular carcinoma.

Detailed description

Chimeric antigen-modified T cells are genetically modified T cells that use gene transduction technology to introduce CARs, containing tumor antigen-specific recognition single-chain antibodies and T cell activation motifs, into patient T cells, so that these transduction CAR-T cells can directly recognize the specific antigen on tumor cells, thereby killing tumor cells.

Previous studies have confirmed that B7H3 is highly expressed in hepatocellular carcinoma cell lines, which is negatively correlated with the ten-year survival of patients. It is suggested that B7H3 is a specific therapeutic target for liver cancer.

The purpose of this study is to test the safety and efficacy of a newly developed fully human scFv-armed B7H3 targeting chimeric antigen receptor T cells (fhB7H3.CAR-Ts), which are supposed to attack and eliminate B7H3-positive cancer cells.

The investigators designed a single-arm open-label clinical study, the participants' peripheral blood mononuclear cells will be collected and used to manufacture fhB7H3.CAR-Ts. Before infusion, the patients will receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine for three consecutive days. Two days later after lymphodepletion, the fhB7H3.CAR-Ts would be given through transhepatic arterial infusion. From the day of infusion, participants' peripheral blood will be collected twice a week in the first month to monitor the survival of fhB7H3.CAR-Ts and evaluate the therapeutic efficacy. Additional follow-up and examination will be performed monthly for the first three month and then trimonthly until two year. Thereafter, annual follow-up will be completed for 5 years.

This is an investigator-initiated clinical study to assess clinical performance of novel fhB7H3.CAR-Ts which may help other advanced and recurrent liver cancer patients in the future.

Interventions

• Biological fhB7H3.CAR-Ts
  fhB7H3.CAR-Ts will be transhepatic arterial infused after lymphodepletion. Three dose levels will be evaluated: Dose Level 1 (1×10\^6/kg), dose Level 2 (3×10\^6/kg) and dose Level 3 (5×10\^6/kg). If dose limiting toxicities (DLTs) are observed in each doses, Dose Level -1 (0.5×10\^6/kg /infusion) will be evaluated.
• Drug Fludarabine
  30 mg/m2 i.v. for 3 consecutive days (Day -5\~Day -3)
• Drug Cyclophosphamide
  750 mg/m2 i.v. for once (Day -5)

Primary outcome measures

• Safety of fhB7H3.CAR-T cells [Time frame: 1 month]
• Objective response of fhB7H3.CAR-T cells [Time frame: 1 month]

Secondary outcome measures (1)

• In vivo persistence of fhB7H3.CAR-T cells [Time frame: 1 month]

Eligibility criteria

Inclusion criteria

• Subjects should be 18-70 years old.
• Subject has adequate performance status as defined by ECOG score of≤ 2.
• Expected life expectancy is no less than 12 weeks.
• Subjects must have histologically or cytologically confirmed unresectable, recurrent and / or metastatic hepatocellular carcinoma (HCC). And tumor tissues are measured positive for B7H3 expression.
• Child-Pugh A, B grade.
• Blood routine:

white blood cell count≥ 2.5 × 10\^9 / L; hemoglobin≥ 9 g/dL; platelet count≥ 50 × 10\^9 / L; lymphocyte proportion≥ 15 %;

• Adequate organ function. Patients' main organs ( heart, lung, liver, kidney, etc. ) function well:

ALT and AST≤ 5 × ULN; ALB≥ 30 g/L； Total bilirubin≤ 2.5 × ULN； Serum creatinine< 220μmol/L; Indoor oxygen saturation ≥ 95 %; Left ventricular ejection fraction≥ 40%;

• No allergic reaction to contrast agents.
• Procurement and T-cell production eligibility: a previously evaluation confirmed autologous peripheral blood mononuclear cells can be used for T-cell production.
• Patients or their legal guardians voluntarily participate in and sign the informed consent form.

Exclusion criteria

• The subject is a pregnant or lactating woman.
• The subjects have infectious diseases (such as HIV, syphilis, active tuberculosis, etc.);
• The subject has active infection or coagulation dysfunction.
• Subjects with previous hepatic encephalopathy.
• The subject is on anticoagulation or antiplatelet therapy.
• The subject is an organ transplant or waiting for transplant.
• Subjects with mental or psychological diseases who cannot cooperate with treatment and efficacy evaluation.
• The subjects are highly allergic or have a history of severe allergies.
• The subject has received chemotherapy/radiotherapy within the past 4 weeks.
• The subject has a history of cellular immunotherapy or antibody therapy.
• The subject is receiving systemic hormone therapy.
• Subjects with systemic infection or severe local infection requiring anti-infection treatment.
• The subject has dysfunction of important organs such as heart, lung, brain, liver, and kidney.
• The subject is participating in other clinical research.
• The doctor believes that there are other reasons not to be included in the treatment.
• Unwilling or unable to provide consent/assent for participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The Affiliated Hospital of Xuzhou Medical University — Xuzhou

Identifiers

NCT: NCT05323201 · XYFY2021-KL272-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗