A Clinical Study to Evaluate CAR-T Cell-based Medicinal Product in the Treatment of Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is a prospective, single-arm, open-label Phase 1 dose-finding and expansion study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor efficacy profiles of the cell-based LCAR-C18S (hereinafter LCAR-C18S) in subjects with Claudin18.2-positive advanced solid Tumors.

Detailed Description
-----------------
This is a prospective, single-arm, open-label Phase 1 dose-finding and expansion study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor efficacy profiles of the cell-based LCAR-C18S (hereinafter LCAR-C18S) in subjects with Claudin18.2-positive advanced solid Tumors. Patients who meet the eligibility criteria will receive LCAR-C18S infusion. The study will include the following sequential phases: screening, pre-treatment , treatment and follow up

Official Title
-----------------
A Phase 1, Open-Label Study Evaluating the Safety, Tolerability and Efficacy of LCAR-C18S, an CAR-T Cell Therapy Targeting Claudin18.2 in Patients With Advanced Solid Tumors

Conditions
-----------------
Solid Tumors, Adult

Intervention / Treatment
-----------------
* Biological: LCAR-C18S cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The subjects have been fully informed of the possible risks and benefits of participating in the study and have signed the informed consent form; Age 18-70 years; Immunohistochemistry of tumor tissue samples indicates Claudin18.2 positive ; Recurrent or metastatic advanced solid tumors (including advanced gastric cancers and non-gastric cancers) and have been failed to prior lines of systemic treatment According to the RECIST v1.1, at least one measuable tumor lesion; ECOG performance status score of 0-1; Expected survival ≥ 3 months; Subjects should have adequate organ functions before screening and treatment. Women of childbearing age must have a negative blood pregnancy test; subjects of childbearing potential must use effective contraception for ≥ 1 year after the final study treatment. Exclusion Criteria: Previous CAR-T cell therapy or other cell therapies or therapeutic tumor vaccination against any target; Any previous therapy targeting Claudin18.2; Prior antitumor therapy with insufficient washout period; Pregnant or lactating women; Brain metastases with central nervous system symptoms; Uncontrolled diabetes; Oxygen is required to maintain adequate blood oxygen saturation; Gastric perforation, pyloric obstruction, complete biliary obstruction, complete or incomplete intestinal obstruction requiring clinical intervention, or pleural effusion or peritoneal effusion requiring clinical intervention; Clinically significant liver disorders (including liver cirrhosis, active viral hepatitis or other hepatitis); HIV, Treponema pallidum or HCV serologically positive; Severe underlying disease New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50%; unstable angina, myocardial infarction or coronary artery bypass grafting (CABG) in the past 6 months; history of severe non-ischemic cardiomyopathy; or severe uncontrolled arrhythmia; Any condition that, in the opinion of the investigator, will make the subject unsuitable for participation in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 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: LCAR-C18S Cells<br>Each subject will receive LCAR-C18S Cells | Biological: LCAR-C18S cells<br>* Before treatment with LCAR-C18S cells, subjects will receive a conditioning regimen<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) and incidence, severity, and type of treatment-emergent adverse events (TEAEs),Safety | Dose-limiting toxicity (DLT) and incidence, severity, and type of treatment-emergent adverse events (TEAEs),Safety | Minimum 2 years after LCAR-C18S infusion (Day 1) | 
| To determine the recommended dose of the phase Ⅱ trial of this cell therapy (RP2D) | To determine the recommended dose of the phase Ⅱ trial of this cell therapy (RP2D) | 90 days post infusion | 
| Pharmacokinetic (PK) parameters | Blood samples will be collected for determination of cellular concentrations and transgenic levels of serum LCAR-C18S for pharmacokinetic analysis | Minimum 2 years after LCAR-C18S infusion (Day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) after administration | Objective Response Rate (ORR) is defined as the proportion of subjects who achieve CR or PR after treatment via LCAR-C18S cell infusion, and the objective tumor response rate will be calculated for patients with measurable disease per RECIST 1.1 only | Minimum 2 years after LCAR-C18S infusion (Day 1) | 
| Progress Free Survival (PFS) after administration | Progression Free Survival (PFS) is defined as the time from the date of first infusion of the LCAR-C18S to the first documented disease progression (according to RECIST 1.1) or death (due to any cause), whichever occurs first | Minimum 2 years after LCAR-C18S infusion (Day 1) | 
| Overall Survival (OS) after administration | Overall Survival (OS) is defined as the time from the date of first infusion of LCAR-C18S to death of the subject. | Minimum 2 years after LCAR-C18S infusion (Day 1) |