A Phase 1 Study of LCAR-C182A Cells in the Treatment of Advanced Gastric Cancer and Pancreatic Ductal Adenocarcinoma

Study Overview
=================
Brief Summary
-----------------
This is an open label, single center, single arm phase 1 study to evaluate the safety , tolerability, pharmacokinetics and efficacy and immunogenicity of LCAR-C182A cells targeting Claudin18.2 in the treatment of patients with advanced gastric cancer and Pancreatic Ductal Adenocarcinoma.

Official Title
-----------------
A Phase 1, Open-Label Study Evaluating the Safety, Tolerability and Efficacy of LCAR-C182A, an Anti-Claudin18.2 CAR-T Cell Therapy in Patients With Advanced Gastric Cancer and Pancreatic Ductal Adenocarcinoma

Conditions
-----------------
Gastric Cancer, Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
-----------------
* Biological: LCAR-C182A cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: the subject has fully understood the possible risks and benefits of participating in this study, and has signed informed consent form (ICF); Age 18-75 years; Histologically confirmed unresectable advanced gastric adenocarcinoma (including gastric esophageal junction adenocarcinoma) or advanced pancreatic ductal carcinoma; Claudin18.2 positive by immunohistochemistry; Previously accepted the recommendations of the national comprehensive cancer network (NCCN 2019 V1) or the gastric cancer guidelines of the cooperative professional committee on clinical oncology (CSCO 2018 V1) of the Chinese anti-cancer association, or the standard treatment regimen considered to be equivalent by the investigator； Pancreatic cancer: ≥1 line standard chemotherapy, or regimens considered equivalent by the investigator, have recently failed or cannot be tolerated in the first line； By CT scan or MRI, patients with a measurable lesion ≥1cm or a single lymph node with a short diameter ≥1.5cm (RECIST 1.1) are required to obtain permission from the principal investigator if the lesion is measurable, i.e. the target lesion is lymph node metastasis； ECOG 0   1; expected survival period≥ 3 months； blood routine was in line with the certain standards； blood biochemical test meets the certain criteria； blood pregnancy test of women of child-bearing age was negative； Exclusion Criteria: has received CAR-T therapy targeting any target. ever received any treatment targeting Claudin18.2. brain metastasis with central nervous system symptoms; pregnant or lactating women; uncontrolled diabetes; Oxygen absorption is required to maintain adequate blood oxygen saturation; Patients with pyloric obstruction, gastric perforation, partial or complete intestinal obstruction and complete biliary obstruction that cannot be relieved after active treatment; Hepatic disease;Chronic hepatitis infection with HBV/HCV; Seropositive for human immunodeficiency virus (HIV); Any active autoimmune disease or history of autoimmune disease; have obvious bleeding tendency, such as gastrointestinal bleeding, coagulation dysfunction, and hypersplenism; unstable angina within the past 6 months, symptomatic congestive heart failure or myocardial infarction; severe uncontrolled arrhythmias;Left ventricular ejection fraction <50%; activity requiring parenteral antibiotics or uncontrolled infection;There is evidence of severe active viral, bacterial or uncontrolled systemic fungal infection other malignancies in the past 5 years except for non-melanoma skin cancer or in-situ cervical cancer; chronic diseases treated with steroids or other immunosuppressive agents; Concurrent use of hematopoietic growth factor; Concurrent use of anticancer drugs or therapy (except radiotherapy for pain relief, etc., for non-target lesions); Concurrent investigational treatment; Have undergone chemotherapy, radiotherapy, or other experimental treatment within 4 weeks prior to apheresis stroke or convulsion within 6 months before signing ICF; Have received any live, attenuated vaccine within 4 weeks prior to apheresis; Have underwent major surgical operation within 2 weeks prior to apheresis, or anticipate to undergo a major surgical operation during the study process or within 2 weeks posterior to study treatment (with the exception of anticipated local anesthesia surgery) Allergic to the study drug expient and related expients (including but not limited to DMSO and dextran 40), or allergic to other immunotherapy and related drugs Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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: chimeric Antigen Receptor T cell<br>LCAR-C182A Cells | Biological: LCAR-C182A cells<br>* Patients receive fludarabine (3×300 mg/ m^2) and cyclophosphamide (3×30 mg/m^2) IV on days -5 to-3, and then Patients receive CAR-T cells. PS：The specific dose of fludarabine and cyclophosphamide is adjusted according to the individual condition of the subject and the judgment of the investigator.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | An adverse event is any untoward medical event that occurs in a participant administered an investigational product,and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | 90 days post infusion | 
| MTD）/ RP2D regimen finding | Maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) | 90 days post infusion | 
| Transgene Levels of LCAR-C182A CAR-T Cells | Transgene Levels of LCAR-C182A CAR-T Cells using sensitive assay methods will be assessed | 2 years post infusion | 
| Chimeric Antigen Receptor T (CAR-T) Positive Cell Concentration | Venous blood samples will be collected for measurement of CAR-T positive cellular concentration | 2 years post infusion | 
| Systemic Cytokine Concentrations | Serum cytokine concentrations such as IL-2, IL-6, IL-8, 1L-10, TNF-α, IFN-γ will be measured for biomarker assessment | 2 years post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) after administration | The ORR is defined as the proportion of patients with complete or partial response according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria. | 2 years post infusion | 
| Duration of remission (DOR) after administration | The DOR is defined as the time between the initial onset of complete or partial remission and the onset of disease progression in patients with objective remission according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria. | 2 years post infusion | 
| Progress Free Survival (PFS) after administration | The PFS is defined as the Time from enrollment until disease progression or death according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria. | 2 years post infusion | 
| Overall Survival (OS) after administration | The OS is defined as Time from enrollment until death from any cause according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria. | 2 years post infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Gastric cancer, Pancreatic Ductal Adenocarcinoma