Brief Summary:

This is an open label,phase 1 study,to evaluate the safety , tolerability and efficacy of LCAR-C182A/LCAR-C182B/LCAR-C182C cells targeting Claudin 18.2 in the treatment of patients with advanced gastric cancer and Pancreatic Ductal Adenocarcinoma.

Gastric Cancer

Pancreatic Ductal Adenocarcinoma

 

Biological: LCAR-C182A/LCAR-C182B/LCAR-C182C cells

Arms and Interventions

Arm

Experimental: chimeric Antigen Receptor T cell

LCAR-C182A/LCAR-C182B/LCAR-C182C Cells

Intervention

Biological: LCAR-C182A/LCAR-C182B/LCAR-C182C cells

Patients receive fludarabine phosphate(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 IV as multiple infusions.

Primary Outcome Measures  :

1. Number of Participants With Adverse Events [ Time Frame: within 90 days after cell infusion ]

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.

2. Transgene Levels of LCAR-C82 CAR-T Cells [ Time Frame: 4 years ]

Transgene Levels of LCAR-C82CAR-T Cells using sensitive assay methods will be assessed

3. Chimeric Antigen Receptor T (CAR-T) Positive Cell Concentration [ Time Frame: 4 years ]

Venous blood samples will be collected for measurement of CAR-T positive cellular concentration

4. Systemic Cytokine Concentrations [ Time Frame: 4 years ]

Serum cytokine concentrations such as Interleukin IL-6, TNF-α, IL-10, 1L-15, IFN-γ，will be measured for biomarker assessment

Secondary Outcome Measures  :

1. Overall Response Rate (ORR) [ Time Frame: 4 years ]

The ORR is defined as the percentage of participants who achieve partial response (PR) or better according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria.

2. Duration of Overall Response(DOR) [ Time Frame: 4 years ]

The DOR is defined as the time from documentation of tumor response to disease progression according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria.

3. progression-free survival(PFS) [ Time Frame: 4 years ]

The PFS is defined as the Time from enrollment until disease progression or death according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria.

4. Overall Survival (OS) [ Time Frame: 4 years ]

The PFS is defined as Time from enrollment until death from any cause according to Response Evaluation Criteria In Solid Tumors（RECIST) criteria.

Criteria

Inclusion Criteria:

·       the subject has fully understood the possible risks and benefits of participating in this study, and has signed informed consent form;

·       aged 18-75 years;

·       histologically confirmed metastatic or unresectable advanced gastric adenocarcinoma or advanced pancreatic duct carcinoma;

·       Claudin18.2 positive was detected by immunohistochemistry (at least 50% of the tissues, staining degree 2 (level 3));

·       have previously received second-line and above system chemotherapy combined with or without combined targeted drug treatment;

·       There were measurable nidus of > 1cm by CT scan or MRI（RECIST 1.1） (only patients with measurable nidus, those where the target lesion is lymph node metastasis, need permission from the principal investigator)

·       ECOG 0 ~ 1;

·       expected survival period≥ 3 months

·       blood routine was in line with the following standards: ANC≥ 1.0× 10^9/L;Hemoglobin≥ 9g/dL;Platelet count ≥75×10^9/L;

·       blood biochemical test meets the following criteria: total bilirubin ≤1.5 times of the normal upper limit (ULN);AST and ALT ≤3 times ULN (in the presence of liver metastasis, ULN 5 times);Creatinine clearance > 60 mL/min;Fasting serum cholesterol <300 mg/dL or <7.75 mmol/L;Fasting triglyceride < 2.5 times of ULN;INR≤ 3.5 (for patients with warfarin);

·       blood pregnancy test of school-age women was negative;After completion of study treatment, fertile subjects must use an effective contraceptive for at least 4 months (for the purposes of this study, oral, implantable or injectable emergency contraception is not considered an effective contraceptive).

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 was defined as > 1.5 times of fasting serum glucose ULN;

·       serious impairment of lung function;

·       pyloric obstruction and gastric perforation;

·       known liver diseases (such as cirrhosis, chronic active hepatitis or chronic protracted hepatitis);Chronic active HBV/HCV infection;

·       known HIV infection;

·       have any active autoimmune diseases or medical history, including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, etc.;

·       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;

·       simultaneously use hematopoietic growth factor prophylaxis;

·       anticancer drugs or therapies (including radiotherapy) used at the same time;

·       other parallel clinical trials;

·       received surgery, radiotherapy, chemotherapy or other experimental treatment within 4 weeks before signing the informed consent

·       stroke or convulsion occurred within 6 months before enrollment;

·       inoculated with live attenuated vaccine within 4 weeks before single component blood collection;

·       major surgery should be performed within 2 weeks before the single component blood collection, or surgery should be planned during the study period or within 2 weeks after the study treatment is given.(note: subjects planning local anesthesia may participate in this study.)

·       have a severe and rapid allergic reaction to any medication.

·       the investigator considered that other patients in this study should not be enrolled.