A Clinical Study on the Safety and Efficacy of Chimeric Antigen Receptor T-cell (CART) in the Treatment of Solid Tumors

Study Overview
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Brief Summary
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This is a single-arm, investigator-initiated exploratory study.The study is designed to evaluate the safety and the tolerability of HER2-E-CART cells for the treatment of patients with HER2-positive, refractory advanced solid tumors in three dose groups: low, medium and high.

Detailed Description
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This study was a one-arm,investigator-initiated exploratory study. According to the 3+3 principle, three dose groups with increasing dose were set up, namely low, medium and high dose groups, with separate cell counts. A total of 9-12 subjects were enrolled in the group and given intravenous infusion. Dose-limited toxicity was observed from the beginning of preconditioning to 28 days after CAR T infusion.

Official Title
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A Phase I Clinical Study on the Safety and Efficacy of Chimeric Antigen Receptor T-cell (CART) in the Treatment of Human Epidermalgrowth Factor Receptor-2 (HER2) Positive and Refractory Advanced Solid Tumors

Conditions
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Solid Tumor

Intervention / Treatment
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* Biological: HER2-E-CART cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily signed an informed consent form and were able to complete the study procedures and follow-up examinations and treatment Age ≥ 18 years and ≤ 70 years, regardless of gender Weight > 40 kg Eastern Cooperative Oncology Group (ECOG) physical status score of 0 to 1 Patients with refractory advanced solid tumors who have failed or are intolerant of existing standard regimens or whose patients have refused standard regimens The presence of at least one measurable lesion according to Response Evaluation Criteria In Solid Tumors 1.1 criteria With good organ function Positive HER2 cell membrane expression Women of childbearing potential must have a pregnancy test with negative results within 7 days prior to initiation of treatment Exclusion Criteria: Any systemic antitumor therapy within 2 weeks prior to the single blood collection History of organ transplantation Pregnant or lactating women Uncontrolled infectious disease, such as baseline Hepatitis B Virus DNA ≥ 1000 IU/ml, anti-HIV positive, Hepatitis C Virus-RNA positive Other clinically significant active infections Other active malignancies within the previous 5 years, such as basal or squamous skin cancer, superficial bladder cancer, or in situ breast cancer that has been completely cured and does not require follow-up treatment subjects are not included Patients with severe autoimmune or immunodeficiency diseases, such as subjects with a confirmed diagnosis of a severe autoimmune disease requiring systemic immunosuppressive (steroid) therapy for a prolonged period of time (more than 2 months) or with immune-mediated symptomatic diseases, including ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune vasculitis (e.g., Wegener's granulomatosis), etc Subjects with known severe allergic reactions to pretreatment drugs such as injectable cyclophosphamide, injectable paclitaxel (albumin-bound), or CAR-T cell preparations including adjuvants, dimethylsulfoxide Any unstable systemic disease: including but not limited to unstable angina pectoris, cerebrovascular accident or transient ischemia (within 6 months prior to screening), myocardial infarction (within 6 months prior to screening), New York Heart Association (NYHA) classification ≥ Class III congestive heart failure, severe arrhythmias poorly controlled by medications, liver, kidney or metabolic disease, and hypertension uncontrolled by standard therapy 10 Those with active bleeding, thrombotic disorders requiring treatment Patients with pericardial, thoracic, or abdominal effusions requiring clinical management or intervention The presence of known or suspected brain metastases, including central nervous system and spinal cord compressions or meningeal metastases Subjects undergoing treatment with systemic steroids or steroid inhalers Subjects with any psychiatric disorder, including dementia, altered mental status, that may interfere with informed consent and understanding of relevant questionnaires Having participated in another clinical trial within the previous 30 days Have received a live or attenuated vaccine within 4 weeks prior to pretreatment Those who have been judged by the investigator to have a serious uncontrollable disease or have other conditions that may interfere with receiving treatment in this study and are considered unsuitable

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HER2-E-CART cells<br>HER2-E-CART cells were intravenously transfused and followed up to 2 years after the last cell transfusion | Biological: HER2-E-CART cells<br>* E-CAR-T is a novel second-generation CAR-T product targeting HER2 protein<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurence of Adverse event rate | The occurrence of all adverse events (AEs), serious adverse events (SAEs) and treatment-related adverse events (TEAEs). | Adverse events will be collected from the beginning to the end of the study, up to 2 years after the last cell transfusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to peak of serum cytokine Interleukin-2 | Time to peak of serum cytokine Interleukin-2 | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Time to peak of serum cytokine Interleukin-6 | Time to peak of serum cytokine Interleukin-6 | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Time to peak of serum cytokine Interleukin-10 | Time to peak of serum cytokine Interleukin-10 | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Time to peak of serum cytokine Tumor Necrosis Factor-α | Time to peak of serum cytokine Tumor Necrosis Factor-α | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Time to peak of serum cytokine Tumor Necrosis Factor-γ | Time to peak of serum cytokine Tumor Necrosis Factor-γ | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Overall survival (OS) | From randomization to the time of death from any cause | Baseline up to death event. | 
| Objective Response Rate (ORR) | The proportion of patients with tumor size reduction of a predefined amount and for a minimum time period | Baseline up to 144 weeks | 
| Disease Control Rate (DCR) | The percentage of patients with advanced or metastatic cancer who have achieved complete response (CR), partial response (PR) and stable disease (SD) to a cancer treatment in clinical trials | Baseline up to 144 weeks | 
| Duration of Response (DOR) | The time from the date of first documentation of a CR or PR or PD to the date of first documentation of tumor progression. | Baseline up to 144 weeks | 
| Progression Free Survival (PFS) | The time from the first dose to the first documentation of progressive disease (PD) or death from any cause,whichever occurs first | Baseline up to 144 weeks | 
| Effects on subjects' health-related quality of life | Quality of life related scale ，for questions 1 to 28, choose a number from 1 to 4, 1 means none and 4 means very good. For questions 29 and 30, choose a number from 1 to 7, with 1 being very poor and 7 being very good. | Baseline up to 144 weeks | 
| Peak concentration (Cmax) | Maximum plasma drug concentration | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Area Under The Curve（AUC） | Area under the plasma concentration-time curve Single dose | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Time to Maximum Plasma Concentration（Tmax） | The time required to reach peak concentration after administration | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. | 
| Elimination half-life (t1/2)-Single dose | t1/2 is time it takes for the blood concentration of HER2-E-CART cells or metabolite(s) to drop by half | Within 72 hours before lymphodepletion pretreatment, within 24 hours before and 1 hour after reinfusion, 24 hours, Day 4, Day 7, Day 10, Day 14, Day 28, Day 60, Day 90, Day 180, Day 270, Day 360. |