A Phase I/II Clinical Study of TC-N201 Injection for the Treatment of Advanced Solid Tumors With HLA-A2 Expression and Positive NY-ESO-1.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Dose Limiting Toxicity or Maximum Tolerated Dose (MTD)
研究概览
简要总结
New York Esophageal Squamous Cell Carcinoma 1 (NY-ESO-1) is a cancer-testis antigen (CTA) which is expressed in various tumors. In TCR-T therapy, researchers take the blood of a certain patient, select T cells and insert genes into the cell that expressing a kind of protein that targeting NY-ESO-1. The genetically engineered cells are called NY-ESO-1 TCR-T cells. Then the engineered cells are re-infused to the cancer patients to cure the disease or prolong life.
详细描述
This is a single-center, open-label, Phase I clinical study of TCR-T cells for the treatment of the recurrent/metastatic solid tumors patients who had failed standard therapy.
Objective:
To evaluate the safety and efficacy of TCR-T cells for the treatment of advanced solid tumors.
Eligibility:
Adults aging 18-70 with advanced solid tumors
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be able to understand and sign the Informed of Consent Document. Be willing to follow the procedure and protocol of the clinical trial;
- •Age ≥ 18 years and ≤ 70 years;
- •Expected survival time > 3 months;
- •ECOG score 0-1;
- •Metastatic or recurrent solid tumors confirmed by histopathology;
- •Refractory to standard treatment evaluated by radiological assessment;
- •Be able provide fresh or preserved tissue specimen;
- •At least 1 measurable lesion (according to RECIST 1.1);
- •NY-ESO-1 expression positive: Immunohistochemical staining positive cells ≥25% and positive staining intensity is "++" or above;
- •HLA typing is HLA-A2 (excluding HLA-A*0203);
- •Hematology should at least meet the following criteria:
- •Absolute neutrophil count (ANC) ≥ 1.5× 109/L (±20%)；
- •Platelet (PLT） ≥ 75× 109/L (±20%）；
- •Hemoglobin (HGB) ≥ 90 g/L (±20%).
- •Liver and kidney function are normal:
- •Serum creatinine (Cr) ≤ 1.5 times of upper limit of normal (ULN) or creatine clearance ≥ 60 ml/min;
- •Serum Alanine aminotransferase (ALT) or/and Aspartate aminotransferase (AST) ≤ 2.5 times of upper limit of normal;
- •Total bilirubin (TBIL) ≤ 15 times of upper limit of normal.
- •Blood coagulation function is normal: Prothrombin time (PT) ≤ 1.5 ULN, International Normalized Ratio (INR) ≤ 1.5 ULN, or Activated Partial Thromboplastin Time (APTT) ≤ 1.5 ULN;
- •Echocardiogram results show: Left ventricular ejection fraction >45%;
- •Women of childbearing potential should be ascetic or take contraception since the signing of ICF to 24 weeks or later after the last administration of drug Note: Women of childbearing age who have undergone surgical sterilization or who have already experienced menopause are considered to have no possibility of pregnancy.
- •Before the TC-N201 injection was reconstituted, the toxic effects of standard treatment had already recovered, and the corresponding adverse events were judged by the researcher to not pose a safety risk;
- •Catheter insertion is feasible and No White Blood Cells collection contraindications.
排除标准
- •Under pregnancy or lactation, or positive based on blood pregnancy test;
- •Severe allergic to related ingredients in the clinical trial;
- •Received any other investigational treatment within 4 weeks before the first administration or enrolled in another clinical trial the same time;
- •History of other known malignant tumors within the previous 5 years, including carcinoma in situ of the cervix, basal cell carcinoma of the skin, and carcinoma in situ of the prostate; Except for localized tumors that have been cured;
- •Primary central nerve system (CNS) cancer, or subjects with CNS metastasis after localized treatment;
- •Subjects with any active autoimmune disease, a history of autoimmune disease, or a history or syndrome requiring treatment with systemic steroids or immunosuppressive drugs;
- •Immunodeficiency including HIV positive, harvested or natural immunodeficiency;
- •Subjects with ≥ grade 3 thromboembolic events within 2 years or under thrombolysis treatment;
- •Subjects with hereditary or acquired hemorrhagic disease;
- •Have clinical cardiovascular disease or symptoms;
- •Subjects with active infection: active infection requiring systemic anti-infective treatment (except topical antibiotics), fever caused by cancer could be enrolled according to the investigator's judgment;
- •Subjects with active pulmonary tuberculosis infection detected by medical history or Computed Tomography (CT), or a history of active pulmonary tuberculosis infection within 1 year before enrollment, or a history of active pulmonary tuberculosis infection more than 1 year before enrollment but without regular treatment;
- •Subjects with positive hepatitis B surface antigen or positive hepatitis B core antibody or positive hepatitis C virus antibody;
- •Treponema pallidum antibody positive;
- •Subjects received major surgery or under severe injury within 4 weeks before TC-N201 cell infusion;
- •Subjects who received live vaccine or attenuated live vaccine 28 days before leukapheresis;
- •Subjects who have drug addiction history, or alcoholism, drug users;
- •Subjects who received cell therapy before enrollment，such as TCR-T，CAR-T and TIL;
- •Subjects who have previously received treatment targeting NY-ESO-1;
- •Subjects not suitable for the clinical trial according to investigators.
研究组 & 干预措施
dose escalation
This study uses the "3+3" dose escalation method. The initial dose is Dose 1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment. If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose -1 infusion.
Interventions:
Biological: TCR-T cells Drug: IL-2 Drug: Fludarabine Drug: Cyclophosphamide Drug: Nab-Paclitaxel
干预措施: TC-N201 cells (Biological)
dose escalation
This study uses the "3+3" dose escalation method. The initial dose is Dose 1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment. If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose -1 infusion.
Interventions:
Biological: TCR-T cells Drug: IL-2 Drug: Fludarabine Drug: Cyclophosphamide Drug: Nab-Paclitaxel
干预措施: IL-2 (Drug)
dose escalation
This study uses the "3+3" dose escalation method. The initial dose is Dose 1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment. If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose -1 infusion.
Interventions:
Biological: TCR-T cells Drug: IL-2 Drug: Fludarabine Drug: Cyclophosphamide Drug: Nab-Paclitaxel
干预措施: Fludarabine (Drug)
dose escalation
This study uses the "3+3" dose escalation method. The initial dose is Dose 1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment. If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose -1 infusion.
Interventions:
Biological: TCR-T cells Drug: IL-2 Drug: Fludarabine Drug: Cyclophosphamide Drug: Nab-Paclitaxel
干预措施: Cyclophosphamide (Drug)
dose escalation
This study uses the "3+3" dose escalation method. The initial dose is Dose 1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment. If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose -1 infusion.
Interventions:
Biological: TCR-T cells Drug: IL-2 Drug: Fludarabine Drug: Cyclophosphamide Drug: Nab-Paclitaxel
干预措施: Nab-paclitaxel (Drug)
结局指标
主要结局
Dose Limiting Toxicity or Maximum Tolerated Dose (MTD)
时间窗: Day 28 after the first TC-N201 infusion
Dose Limiting Toxicity (DLT) is defined as patients with the adverse event (AE) or laboratory abnormality, and should be possibly related to TC-N201 cell therapy, and should be unrelated to the disease itself, disease progression, concomitant diseases or concomitant medication. MTD is defined as the highest dose at which ≤1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels.
Overall response rate
时间窗: Day 0 - Day 730
The efficacy of TC-N201 will be assessed by the objective response rate (ORR) evaluated according to RECIST 1.1 and iRECIST. ORR is described as patients assessed with partial response (PR) and complete response (CR).
Treatment-related adverse events as assessed by National Cancer Institute general terminology standard for adverse events (NCI CTCAE) v5.0
时间窗: Day 0 - Day 730
The type, incidence and severity of adverse events include abnormal laboratory examination results with clinical significance after treatment, abnormal physical examination and blood examination results, bone marrow examination results, etc. Clinical and laboratory adverse events will be classified according to the CTCAE v5.0.
次要结局
- Maximum Persistence (Cmax) of TC-N201(Day 0 - Day 730)
- Progression free survival(Day 0 - Day 730)
- Overall survival(Day 0 - Day 730)
- Area Under the Plasma Concentration-time Curve From Zero to Day 28 (AUC [0-28])(Day 28 after the first TC-N201 infusion)
- Anti-PD-1 single chain antibody concentration(Day 0 - Day 730)
- Duration of response(Day 0 - Day 730)
- Time to Maximum Persistence(Day 0 - Day 730)