临床试验/NCT04151186

NCT04151186Unknown不适用

A Clinical Study on the Safety and Efficacy of Chimeric Antigen Receptor T-cell Therapy for the TM4SF1- and EpCAM-positive Recurrent/Refractory Solid Tumors

suhaichuan0 个研究点目标入组 72 人开始时间: 2019年11月20日最近更新: 2019年11月5日

适应症

试验速览

阶段: 不适用
发起方
入组人数: 72
主要终点: Safety assessed by Incidence of Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

研究概览研究设计入排标准结局指标研究者记录与标识符相似试验

研究概览

简要总结

Transmembrane 4 L Six Family Member 1 (TM4SF1) and Epithelial cell adhesion molecule (EpCAM) are both highly expressed in many epithelial-derived solid tumors.
The Chimeric Antigen Receptor T-cells (CAR-T) that target TM4SF1 or EpCAM have been generated respectively in our good manufacturing practices (GMP) facility and their anti-tumor effects have been demonstrated in multiple in vitro and in vivo studies.
Clinical studies are proposed here to evaluate the anti-tumor activity of these cell therapy products for treatment of patients with TM4SF1 or EpCAM positive tumors. In this study, the safety, tolerance, and preliminary efficacy of CART-TM4SF1 and CART-EpCAM cells will be examined inpatients with refractory/recurrent advanced pancreatic cancer, colorectal cancer, gastric cancer or lung cancer. And 9 patients for each cancer will be evaluated.
Clinical and immunological responses will be evaluated about 30 days and last up to 2 years after CAR-T cell infusion.

详细描述

Background:

While great progress has been made in CAR T-cell therapy for the treatment of hematologic malignancies, its use in solid tumors is still at the exploratory stage.
Transmembrane 4 L Six Family Member 1 (TM4SF1) protein mediates signal transduction events that play a role in the regulation of cell development, activation, growth and motility. It is a cell surface antigen and is highly expressed in different carcinomas. Epithelial cell adhesion molecule (EpCAM),is a transmembrane glycoprotein of 40 kilodaltons (kDa). EpCAM is highly expressed in many epithelial-derived tumors, such as colon, stomach, pancreas, lungs, ovaries and breasts. Recently, EpCAM has been identified as the surface marker of circulating tumor cells (CTCs) and cancer stem cells (CSCs).
The investigators have developed novel TM4SF1-targeting CAR T-cells (CART-TM4SF1 cells) and EpCAM-targeting CAR T-cells (CART-EpCAM cells) for solid tumor treatment. These engineered T-cells can target and kill the TM4SF1- or EpCAM-positive tumor cells in vitro or in mice. Both of the CAR molecules contain a safety switch based on epidermal growth factor receptor (EGFR) to ensure the safety.
The investigators propose to investigate the feasibility, safety, and efficacy of CART-TM4SF1 cells and CART-EpCAM cells for solid cancers in patients.

Objectives:

Primary objectives:

To determine the safety/tolerance dosages and adverse effects of CART-TM4SF1 cells or CART-EpCAM cells in the treatment of TM4SF1- or EpCAM-positive recurrent/refractory advanced solid tumors.
To preliminarily evaluate the efficacy of CART-TM4SF1 cells and CART-EpCAM cells in the treatment of TM4SF1- and EpCAM-positive recurrent/refractory 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 75 Years（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Aged≥18 years old and ≤75 years old when signing the informed consent; regardless of gender;
•Body weight>40kg;
•Pathologically confirmed as pancreatic cancer, colorectal cancer, gastric cancer or lung cancer;
•Recurrent/refractory solid tumors unresponsive to the current standard treatment;
•At least one measurable lesion according to the RECIST 1.1 criteria, that is, the long diameter of the non-lymph-node lesion≥10 mm, or the short diameter of the lymph node lesion ≥15 mm on CT or MRI cross-sectional imaging; the longest axis of the measurable lesion≥10 mm on CT scan (slice thickness≤5 mm in CT scan);
•Acceptable hemopoietic ability: absolute neutrophil count (ANC) >1.5×10^9/L, platelet count >1.0×10^11/L, hemoglobin (HGB) >90g/L (no blood transfusion within two weeks), absolute lymphocyte count (ALC )>500×10^9/L;
•Acceptable liver and kidney functions: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ULN in subjects without liver metastases and ≤3.5 upper limit of normal (ULN) in those with liver metastases; bilirubin≤1.5 ULN (excluding hyperbilirubinemia or non-liver-derived hyperbilirubinemia); creatinine ≤1.5 ULN and creatinine clearance rate≥40 mL/min;
•prothrombin time (PT)/international normalized ratio (INR) <1.5 ULN and partial thromboplastin time (PTT)/activated partial thromboplastin time (APTT) <1.5 ULN;
•Positive for TM4SF1 or EpCAM expression (expression≥25%), with three classifications; (1) Recurrent or existing lesions at the primary site with tumor tissue samples collected within 1 year, which are positive for TM4SF1 or EpCAM by immunohistochemistry; (2) New metastatic lesions at the non-primary sites, which are positive for TM4SF1 or EpCAM by immunohistochemistry; (3) Remaining tumor lesions at the primary site with tumor tissue samples collected more than 1 year ago, and the lesions are positive for TM4SF1 or EpCAM by immunohistochemistry based on re-biopsy.
•Women of child-bearing age (15-49 years old) must be negative for pregnancy test at 7 days before initiation of the treatment.
•Eastern Cooperative Oncology Group (ECOG) scores≤
•Expected survival no less than 12 weeks.

排除标准

•History of any radiotherapy and chemotherapy within 4 weeks before a single blood collection;
•History of any anti-programmed cell death protein 1 (PD1) and anti-Programmed cell death 1 ligand 1 (PD-L1) treatments within 12 weeks before a single blood collection;
•History of organ transplantation;
•Pregnancy or lactation;
•Uncontrolled infectious diseases, such as baseline hepatitis B virus (HBV) DNA≥2000 IU/ml, positive for anti-human immunodeficiency virus （HIV） antibody and hepatitis C virus (HCV)-RNA;
•Other active infection with clinical significance;
•History of other active malignancies in the past 5 years, excluding basal or squamous skin carcinoma, superficial bladder cancer, and breast cancer in situ which have completely healed and require no follow-up treatment;
•Serious autoimmune diseases or immunodeficiency disease, including those with confirmed severe autoimmune diseases and requiring long-term use (over 2 months) of systemic immunosuppressants (steroids) or having immune-mediated symptomatic diseases, such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus (SLE) and autoimmune vasculitis (eg., Wegener's granulomatosis);
•Allergic diathesis and allergic to immunotherapy or relevant drugs;
•Organ failure; Heart: Grade III and IV ; or with hypertension uncontrolled by the standard treatment, history of myocarditis or myocardial infarction within 1 year; Liver: Class C according to the Child-Turcottei-Pugh System (CTP); Kidneys: Kidney failure and uremic syndrome; Lungs: Serious symptoms of respiratory failure; Brain: Disturbance of consciousness;
•Active bleeding, and thrombotic diseases requiring treatment;
•Uncontrollable pleural and peritoneal effusion requiring clinical treatment or intervention;
•T-cell cancers, such as T-cell lymphoma;
•Current on systemic steroid or steroid inhalers;
•Any mental diseases, including dementia and changes in mental status that may influence the understanding about the informed consent and questionnaire;
•Participating in other clinical trials in the past 30 days;
•Judged as serious uncontrollable diseases by the researchers, or other conditions that may interfere with the treatment and therefore being ineligible.

结局指标

主要结局

Safety assessed by Incidence of Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

时间窗: 2 years

1. After CAR-T cell infusion,the investigators will observe the potential adverse events related to the CAR-T cells infusion such as high fever, kidney failure and so on. 2. Adverse events are coded according to MedDRA 22.0. List total number of AEs and SAEs; Number of subjects with different types of AEs and SAEs, case-times and incidence.AEs and SAEs are graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC AE version 5.0).

次要结局

CAR-T cell testing(2 years)
Overall response rate (ORR)(2 years)

研究者

发起方

suhaichuan

申办方类型

Other

责任方

Sponsor Investigator

主要研究者

suhaichuan

professor

Tang-Du Hospital

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