TCR-T Cell Therapy on Advanced Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
The primary aim of this study is to evaluate the efficacy of KRAS mutant antigen specific TCR-T cells in the treatment of patients with advanced pancreatic cancer. The secondary aim is to evaluate the pharmacokinetic/pharmacodynamic characteristics of TCR-T cell therapy in patients with advanced pancreatic cancer and the survival of TCR-T cells. The investigators will evaluate the changes of tumor microenvironment after treatment of advanced pancreatic cancer with KRAS mutant antigen specific TCR-T cells; Evaluating the correlation between cytokines and the occurrence of CRS and neurotoxicity

Detailed Description
-----------------
1.This study is a prospective and single arm clinical study. In this trial, 18 patients with advanced pancreatic cancer with KRAS G12V or G12D mutations and matching HLA-A*11:01 subtypes are recruited for autologous Tumor-T Cell Receptor (TCR) -Mediated T Cells therapy(TCR-T) therapy.Within 3 - 5 days after pretreatment, subjects will receive a single TCR-T infusion with an infusion dose of about 1 × 10⁹～1 × 10¹⁰.Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 will be injected intravenously for 14 days . After 3 months of treatment, the patient's condition was evaluated. If the subject did not occur tumor progression and did not occur adverse events (AEs) of level 3 or higher, a second TCR-T cell reinfusion can be performed (informed consent form needs to be signed again). The study will evaluate the safety of TCR-T treatment by observing adverse events after cell therapy; evaluate the effectiveness of TCR-T compared to the results or historical data of the subject's own previous standard treatment regimen;and collect blood before and after cell infusion, measure the number and activity of TCR-T cells, and evaluate the pharmacokinetic (PK) characteristics of TCR-T.

Official Title
-----------------
A Prospective, One Arm Clinical Study on the Safety, Efficacy and Pharmacokinetics of KRAS Mutant Antigen Specific TCR-T Cells in the Treatment of Advanced Pancreatic Cancer

Conditions
-----------------
Pancreatic Cancer

Intervention / Treatment
-----------------
* Biological: TCR-T therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria： Age greater than 18 years old； Pathological diagnosis of recurrent/metastatic pancreatic cancer (except intracranial metastasis). Patients who have had prior therapy with at least one standard treatment regimen remain in stable or progressive disease states and refuse subsequent chemotherapy; Mutations in KRAS G12V or G12D and expression of matched HLA -A*11:01 subtypes are confirmed in previous tumor or biopsy tissues； Expected survival duration of more than 3 months； Eastern Cooperative Oncology Group( ECOG )score ≤2； All participants voluntarily participate in this study and sign an informed consent. And the subjects have good compliance and can cooperate with investigators follow-up study. Patients at least have had at least one measurable lesion as defined by RECIST v1.1 criteria； Female participants can not be pregnant or lactating and their serum or urine human chorionic gonadotropin tests must be negative within 72 hours prior to study enrollment；All subjects must be using a medically accepted means of contraception ( (e.g., oral contraceptives, intrauterine device) during the course of this study and for at least 3 months after completion of study therapy. Organ function and bone marrow reserve are in good condition, and the following requirements must be met: 1)Absolute neutrophil count≥1.5×10⁹/L；2)Platelet count≥50×10⁹/L；3)Hemoglobin≥90g/L；4)Bilirubin < 1.5 times upper limit of normal（Bile duct obstruction due to tumor compression were excluded)；5)Serum creatinine ≤ 1.5 times the upper limit of normal range or creatinine clearance ≥ 60 mL/min.6)Serum alanine aminotransferase or aspartate aminotransferase is < 2.5 times the upper limit of the normal value (ULN) (if patients with liver metastasis, ≤5 times the ULN).7)Coagulation function normalised：INR≤1.5，PTT<1.2 times the upper limit of normal（Tumor - related anticoagulant therapy was excluded). Exclusion Criteria: Intracranial metastasis or Patients with moderate or severe hydrothorax need drain placement to relieve symptoms. Active pulmonary tuberculosis Human immunodeficiency virus (HIV) positive； Active Hepatitis B or Hepatitis C infection； Pregnant women and lactating females； Previous or concurrent history of other malignant tumors. Exceptions include curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy; Patients with central nervous metastases； Serious, uncontrolled comorbidities that may affect protocol compliance or interfere with interpretation of results，or any serious medical condition that may affect the safety of the subjects ; History of clinically significant respiratory diseases or other respiratory diseases that seriously affect Pulmonary function; Any active autoimmune disease,any condition requiring steroid hormones or immunosuppressive therapy( including but not limited to systemic lupus erythematosus, sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc., require > 10 mg/D of prednisone or equivalent hormone） A history of organ transplantation； A history of myocardial infarction and severe arrhythmia within six months；Ineligible also includes uncontrolled hypertension, coronary heart disease, stroke, liver cirrhosis, nephritis and other serious complications; Those who have a history of psychotropic drug abuse and cannot quit or have a history of psychiatric impairment； Participants with an allergic constitution, known sensitivity to human serum albumin, cyclophosphamide, fludarabine and interleukin 2; Those with bleeding or thromboembolic tendency：bleeding symptoms of clinical significance or a clear tendency to bleeding within 2 weeks prior to entering the study. And those with hereditary or acquired bleeding and thrombotic tendencies； serious arterial/venous thromboembolic events occurred in the previous 6 months; Other severe, acute or chronic medical or mental illnesses that in the investigator's judgement will might be increase the risk associated with the patient's participation in the study or interfere with interpretation of research results.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCR-T treatment group<br>Within 3 - 5 days after pretreatment, subjects will receive a single TCR-T infusion with an infusion dose of about 1 × 10⁹～1 × 10¹⁰.Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 will be injected intravenously for 14 days .After 3 months of treatment, the patient's condition was evaluated. If the subject did not occur tumor progression and did not occur adverse events (AEs) of level 3 or higher, a second TCR-T cell reinfusion can be performed . | Biological: TCR-T therapy<br>* 1.Preprocessing strategy： Cyclophosphamide: 500mg/m², dissolved in 100ml 0.9% sodium chloride saline, intravenous drip for 60minutes, and 0.4g Mesna injected at 0hour, 4hours and 8 hours after cyclophosphamide,4days and 5 days before TCR-T cell infusion. Fludarabine: 30mg/m² , dissolved in 100ml 0.9% sodium chloride saline, intravenous drip for 30minutes before 3 to 5days before TCR-T cell infusion. 2.Within 3 - 5 days after pretreatment, subjects will receive a single TCR-T reinfusion with an infusion dose of about 1 × 10⁹～1 × 10¹⁰. 3.Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 (injection unit: 500000 units /m², once every 12 hours, subcutaneous injection) will be injected intravenously for 14 days (24 times in total). 4.After 3 months of treatment, If the subject did not occur tumor progression and did not occur adverse events (AEs) of level 3 or higher, a second TCR-T cell reinfusion can be performed .<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The overall survival(OS) | The overall survival period refers to the time of the TCR-T infusion to the death of the patient for any cause. | At 12months after the TCR-T cell infusion | 
| Progression free survival (PFS) | Progression free survival refers to the time from TCR-T infusion to the first occurrence of disease or death from any cause.According to RECIST version 1.1, the tumor evaluation of all subjects will be evaluated within 12 months after TCR-T treatment. | At 12months after the TCR-T cell infusion | 
| Time to progression (TTP) | Time to progression (TTP) refers to the time from TCR-T infusion to objective tumor progression.According to RECIST version 1.1, the tumor evaluation of all subjects will be evaluated within 12 months after TCR-T treatment. | 12months after the TCR-T cell infusion | 
| Event free survival period | The event free survival period (until the time of treatment failure) refers to the time from entering the trial to any treatment failure, including disease progression or cessation of treatment for any reason (such as disease progression, toxic reactions, subject willingness, initiation of new treatment without clear progression, or death).According to RECIST version 1.1, the tumor evaluation of all subjects will be evaluated within 12 months after TCR-T treatment. | At 12months after the TCR-T cell infusion | 
| The disease-free survival period | The disease-free survival period refers to the time from obtaining disease-free status or reaching complete response until recurrence or death due to acute toxicity of tumors or treatment. | At 12months after the TCR-T cell infusion | 
| The duration of efficacy | The duration of efficacy refers to the time from reaching the treatment effectiveness (i.e. CR or PR) standard until the first definite recurrence or progression is achieved. | At 12months after the TCR-T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) | Peak plasma concentration (Cmax) refers to the maximum concentration of TCR-T cells in peripheral blood after the TCR-T cells infusion. | 12months after the TCR-T cell infusion | 
| Area under the plasma concentration versus time curve (AUC) | Area under the plasma concentration versus time curve (AUC) is used to access the absorbed TCR-T cells dose into human blood circulation after TCR-T cells injection. | 12months after the TCR-T cell infusion | 
| Peak time (Tmax) | Peak time (Tmax) refers to the time when the blood concentration reaches the peak after TCR-T cells injection. | 12months after the TCR-T cell infusion | 
| Cell number of TCR-T cells in peripheral blood | Cell numbers of TCR-T cells after the injection of TCR-T cells | 12months after the TCR-T cell infusion | 
| Peak value of cytokines | The peak value of cytokines within 1 month after TCR-T cell infusion . | 1 month after TCR-T cell infusion | 
| Adverse events | 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 National Cancer Institute general terminology standard for adverse events (NCI CTCAE) version 5.0. | 12months after TCR-T infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pancreatic Cancer, PK/PD, TCR-T, Safety, efficacy