Allogeneic Gamma-delta T Cells Combined With Targeted Therapy and Immunotherapy in a Phase 1 Clinical Trial of Hepatocellular Carcinoma Resistant to PD-1 Monoclonal Antibody

Early Phase 1

Not yet recruiting

• Conditions: Hepatocellular Carcinoma
• Interventions: Biological: γδ T cells; Drug: PD-1 monoclonal antibody; Drug: targeted drugs

• Registration Number: NCT06364800
• Lead Sponsor: Beijing 302 Hospital

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of allogeneic γδ T cells combined with targeted therapy and PD-1 monoclonal antibody in patients with hepatocellular carcinoma resistant to PD-1 monoclonal antibody.

Hepatocellular Carcinoma

Detailed Description

This is a double-arm, single-center, randomized, open label phase I clinical trial to evaluate the efficacy and safety of the combination of ex-vivo expanded allogeneic γδ T cells plus targeted therapy and PD-1 monoclonal antibody in patients with BCLC stage B or C hepatocellular carcinoma (HCC). A typical 3+3 dose-escalation design will be used to determine the optimal dose level of γδ T cells based on the incidence of dose-limiting toxicity (DLT). The initial infusion dose level will start from 1×10\^8/kg to 4×10\^8/kg in every 3 weeks.

Study Timeline

• Status Verified: 2024-04
• Study First Submitted: 2024-04-10
• Study First Submitted QC: 2024-04-10
• Last Update Submitted: 2024-04-10
• Study First Posted: 2024-04-15
• Last Update Posted: 2024-04-15
• Study Start: 2024-04-26
• Primary Completion: 2026-04-26
• Study Completion: 2026-09-26

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

1. Patients should sign informed consent form voluntarily before the trail and comply with the requirements of this study.
2. Age 18 years up to the age of 75 (≤75), gender unlimited.
3. Hepatocellular Carcinoma diagnosed according to the 2018 edition of the EASL guidelines.
4. BCLC stage B or C.
5. Liver function: Child-Pugh class A/B (5-9).
6. Eastern Cooperative Oncology Group (ECOG) Performance score≤1.
7. Treated with standard treatment options (anti-PD-1, targeted drugs) ≥3months and experiencing progressive disease according to RECIST 1.1.
8. Life expectancy ≥ 6 months.
9. Patients combined with HBV infection require antiviral treatment with nucleoside analogues; patients combined with HCV infection require direct-acting antiviral agent (DAA) treatment.
10. Adequate organ and marrow function (within 4 weeks prior to study treatment initiation).
11. Male and female patients of reproductive potential must agree to use birth control during the study and for at least 30 days post study.
12. Capable of understanding and complying with the study protocol requirements ( including follow-up visit and examinations).

Be willing to signed a written informed consent document before enrollment.

Exclusion Criteria

1. Patients combined with HAV, HEV, HIV or other infectious diseases.
2. Acute infections, gastrointestinal bleeding, etc. occurred within 30 days before screening.
3. Women who are pregnant (urine/blood pregnancy test positive) or lactating; patients with severe autoimmune diseases; patients with uncontrolled infectious diseases.
4. Major organs dysfunction.
5. Combined with other severe organic diseases or mental illnesses, including any uncontrolled clinically significant systematic diseases such as urinary, circulatory, respiratory, neurological, psychiatric, digestive, endocrine and immune diseases.
6. Allergic constitution, history of allergies to blood products, known to be allergic to test substances.
7. Immunosuppressive or systemic cytotoxic drugs may require within 6 months prior to screening or during the study; 6 months prior to screening accepted other cell therapies including NK, CIK, DC, CTL and stem cell therapy etc.
8. Patients currently participating in other clinical trials who may violate this treatment plan and observations.
9. Those who are unable or unwilling to provide informed consent or who are unable to comply with the research requirements.
10. Any situation that investigators believe the risk of the subjects is increased or results of the trial are disturbed: patients with any serious acute or chronic physical or mental illness, or laboratory abnormalities.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
γδ T cells+ PD-1 monoclonal antibody+ targeted drugs	targeted drugs	Patients will receive 4 cycles of ex-vivo expanded allogeneic γδ T cells treatments, at three-weeks' intervals. Ex-vivo expanded γδ T cells are transfused to patients in a typical 3+3 dose-escalation design (Dose escalation, 1×10\^8/kg, 2×10\^8/kg,4×10\^8/kg).
PD-1 monoclonal antibody+ targeted drugs	targeted drugs	PD-1 monoclonal antibody+ targeted drugs
γδ T cells+ PD-1 monoclonal antibody+ targeted drugs	γδ T cells	Patients will receive 4 cycles of ex-vivo expanded allogeneic γδ T cells treatments, at three-weeks' intervals. Ex-vivo expanded γδ T cells are transfused to patients in a typical 3+3 dose-escalation design (Dose escalation, 1×10\^8/kg, 2×10\^8/kg,4×10\^8/kg).
PD-1 monoclonal antibody+ targeted drugs	PD-1 monoclonal antibody	PD-1 monoclonal antibody+ targeted drugs
γδ T cells+ PD-1 monoclonal antibody+ targeted drugs	PD-1 monoclonal antibody	Patients will receive 4 cycles of ex-vivo expanded allogeneic γδ T cells treatments, at three-weeks' intervals. Ex-vivo expanded γδ T cells are transfused to patients in a typical 3+3 dose-escalation design (Dose escalation, 1×10\^8/kg, 2×10\^8/kg,4×10\^8/kg).

Primary Outcome Measures

Name	Time	Method
Safety evaluation: Dose limited toxicity (DLTs)	up to 60 weeks	The incidence, characteristic and severity of DLTs will be recorded and assessed.
Efficacy evaluation: Objective Response Rate(ORR)	up to 15months	Objective clinical response will be assessed by investigators up to 15months
Safety evaluation: Incidence of Adverse events (AEs)	up to 60 weeks	Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).
Efficacy evaluation: Duration of Response(DOR)	up to 15months	he duration of objective response in patients will be recorded until 15months after the start of 1st cycle of treatment
Efficacy evaluation: Progress Free Survival(PFS)	up to 15months	Observation for progression-free survival (PFS) will be recorded until 15 months after the start of 1st cycle of treatment
Efficacy evaluation: Overall Survival (OS)	up to 15months	Observation for overall survival l (OS) will be recorded until 15 months after the start of 1st cycle of treatment.