Study of Autologous T-cells in Patients With Metastatic Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This is a study in which pancreatic cancer patients receive a immunotherapy with CART-meso cells administered at 3 days after one dose of cyclophosphamide. CART-meso cells are patients' own T cells lentivirally transduced to express anti-mesothelin scFv fused to TCRζ and 4-1BB costimulatory domains.The lymphodepletion with cyclophosphamide may prolong the persistence of CART cells.

Detailed Description
-----------------
This study is being conducted to assess the safety and efficacy of immunotherapy with CART-meso cells in dose escalation design. The trial will begin in Cohort 1 and progress to Cohorts 2, depending upon dose limiting toxicity (DLT) assessment . Subjects will be enrolled serially, but infusions will be staggered to allow assessment of DLTs for determination of cohort progression, expansion, or dose de-escalation. Cohort 1 subjects will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced CART-meso cells after conditioning chemotherapeutic regimen. Cohort 2 subjects will receive a single dose of 1-3x10^8 /m^2 lentiviral transduced CART-meso cells cells after conditioning chemotherapeutic regimen. Dose limiting toxicity is defined as any adverse reactions at level 3 or above that may be associated with CART-meso within 4 weeks after infusion.

Official Title
-----------------
Study of Autologous T-cells Redirected to Mesothelin With a Chimeric Antigen Receptor in Patients With Metastatic Pancreatic Cancer

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

Intervention / Treatment
-----------------
* Biological: CART-meso cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent Unresectable or metastatic pancreatic cancer Persistent cancer after at least one prior standard of care chemotherapy for advanced stage disease 18 - 70 years of age ECOG performance status of 0 or 1 Life expectancy greater than 3 months Satisfactory organ and bone marrow function Meets blood coagulation parameters Male and Female subjects of reproductive potential agree to use approved contraceptive methods Exclusion Criteria: Participation in a therapeutic investigational study within 4 weeks prior to the screening visit Anticipated need for systemic chemotherapy within 2 weeks before apheresis and infusion Active invasive cancer other than pancreatic cancer HIV, HCV, or HBV infections Active autoimmune disease requiring immunosuppressive therapy within 4 weeks prior to screening visit, with exception of thyroid replacement Ongoing or active infection Planned concurrent treatment with systemic high dose corticosteroids Patients requiring supplemental oxygen therapy Prior therapy with gene modified cells Previous experimental therapy with SS1 moiety, murine or chimeric antibodies History of allergy to murine proteins History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40) Clinically significant pericardial effusion, CHF, or cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study Pregnant or breastfeeding women

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: CART-meso cells<br>A single dose of CART-meso T cells will be administered intravenously.The dose is 1-3×10^7/m^2 CART positive cells(chort 1)or 1-3×10^8/m^2 CART positive cells(chort 2). | Biological: CART-meso cells<br>* CART-meso is a 2nd CAR, with mesothelin as target protein, 4-1BB as co- stimulator. The infusion will be scheduled to occur 3 (±1) days after a single dose of 1.5 grams/m^2 of cyclophosphamide, which will be administered according to standard procedures, Thereby enhancing the efficacy of anti-tumor, reducing the potential of side effects.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CART-meso infusion: number of adverse events | Number of Adverse Events evaluated with NCI CTC AE, version 4.0[Safety evaluation] | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response of CART-meso | Number of patients with tumor response including overal remission ,complete ression,progression-free survival，progressive disease ,etc. | 60 months | 
| CAR-T cell detection | Detection of transferred T cells in peripheral blood or bone marrow using multi-parameter flow cytometer. | 60 months |