NY-ESO-1 TCR-T Cells for NY-ESO-1 Positive Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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 Design: Patients will undergo screening tests, including imaging procedures, heart and lung tests, and lab tests. Patients will have leukapheresis. Blood will be removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm. Engineered T cells will be re-infused into the patient. Patients will stay in hospital and be evaluated

Official Title
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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.

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Biological: TC-N201 cells
* Drug: IL-2
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

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: dose escalation<br>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 | Biological: TC-N201 cells<br>* T cells genetically engineered with a TCR targeting NY-ESO-1 (NY-ESO-1 TCR) that displays specific reactivity against HLA-A2+, NY-ESO-1+ target cells.<br>Drug: IL-2<br>* Following cell infusion, the patient receives intravenous IL-2. IL-2 improves the survival of TC-N201 cells after infusion.<br>Drug: Fludarabine<br>* Part of the non-myeloablative lymphocyte-depleting preparative regimen.<br>Drug: Cyclophosphamide<br>* Part of the non-myeloablative lymphocyte-depleting preparative regimen.<br>Drug: Nab-paclitaxel<br>* Part of the non-myeloablative lymphocyte-depleting preparative regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity or Maximum Tolerated Dose (MTD) | 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. | Day 28 after the first TC-N201 infusion | 
| Overall response rate | 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). | Day 0 - Day 730 | 
| Treatment-related adverse events as assessed by National Cancer Institute general terminology standard for adverse events (NCI CTCAE) v5.0 | 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. | Day 0 - Day 730 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | The efficacy of TC-N201 will be assessed by duration of response (DOR). DOR refers to the length of time from the first appearance of a treatment response to the first occurrence of progressive disease or recurrence. | Day 0 - Day 730 | 
| Progression free survival | The efficacy of TC-N201 will be assessed by progression free survival (PFS). PFS refers to the time from treatment to progressive disease or death for any reason. | Day 0 - Day 730 | 
| Overall survival | The efficacy of TC-N201 will be assessed by overall survival (OS). OS refers to the time from treatment to death. | Day 0 - Day 730 | 
| Maximum Persistence (Cmax) of TC-N201 | Blood samples were collected to measure persistence of infused TC-N201 using polymerase chain reaction of a vector specific sequence in deoxyribonucleic acid (DNA) extracted from peripheral blood mononuclear cell (PBMC). | Day 0 - Day 730 | 
| Time to Maximum Persistence | Blood samples were collected to measure persistence of infused TC-N201 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC. | Day 0 - Day 730 | 
| Area Under the Plasma Concentration-time Curve From Zero to Day 28 (AUC [0-28]) | Blood samples were collected to measure persistence of infused TC-N201 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC. | Day 28 after the first TC-N201 infusion | 
| Anti-PD-1 single chain antibody concentration | The pharmacodynamics of TC-N201 will be assessed by anti-PD-1 scFv. | Day 0 - Day 730 |