Early Phase I Study of Autologous T Cells (EX02 CAR-T) for Unresectable Pancreatic/Bile Duct Cancer

This is a early Phase 1 open-label study to explore the safety and possible efficacy of EX02 CAR T cell therapy in the treatment of patients with unresectable and/or metastatic pancreatic/bile duct cancer.

Each participant will undergo leukapheresis after enrolment, receive treatment of the conditioning chemotherapy of cyclophosphamide and fludarabine, and an intra-tumoral injection or intraperitoneal infusion of Ex02 CAR T cells, probably followed by an intravenous infusion of EX02 CAR T cells.

Each participant will proceed through the following study procedures:

* Screening
* Enrollment/Leukapheresis
* Conditioning chemotherapy
* CAR T treatment
* Post-treatment assessment
* Long-term follow-up


Eligibility Criteria:
Inclusion Criteria:

* 1) Must have a confirmed diagnosis of unresectable or metastatic pancreatic cancer or bile duct cancer 2) Ineligible for, refractory to or relapsed after first or second line of chemotherapy 3) Presence of at least one measurable target lesion according to RECIST v1.1 4) EX02 positive tumor cell membrane (as shown in IHC staining of tumor specimen or in flow cytometry of ascites cells) 5) Male or female, ≥18 years 6) ECOG performance status 0 to 1 7) Expected life expectancy \>3 months 8) Negative pregnancy test at screening and prior to initiating lymphodepletion chemotherapy or study drug administration, and willingness to practice birth control for woman with childbearing potential 9) Adequate hematology function indicated by followings (without blood transfusion or administration with growth factors in last four weeks):

  1. Neutrophil count ≥ 1.5×10\^9/L
  2. Hemoglobin ≥ 90g/L
  3. Platelet count ≥ 100×10\^9/L
  4. Lymphocyte count ≥ 0.5×10\^9/L 10) Adequate liver, kidney, heart and lung functions at least indicated by:

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  1. Creatinine clearance ≥ 60ml/min
  2. ALT and AST ≤ 2.5 ULN (≤ 5 ULN when liver is involved)
  3. LVEF ≥ 50%; absence of pericardial fluid; no significant abnormality in ECG exam
  4. No or only small amount of pleural fluid or ascites; blood oxygen saturation ≥ 95% 11) Voluntary participation in the trial and signing informed consent form

Exclusion Criteria:

* 28 participants fulfilling the following criteria will be enrolled.

Inclusion criteria:

1. Must have a confirmed diagnosis of unresectable or metastatic pancreatic cancer or bile duct cancer
2. Ineligible for, refractory to or relapsed after first or second line of chemotherapy
3. Presence of at least one measurable target lesion according to RECIST v1.1
4. EX02 positive tumor cell membrane (as shown in IHC staining of tumor specimen or in flow cytometry of ascites cells)
5. Male or female, ≥18 years
6. ECOG performance status 0 to 1
7. Expected life expectancy \>3 months
8. Negative pregnancy test at screening and prior to initiating lymphodepletion chemotherapy or study drug administration, and willingness to practice birth control for woman with childbearing potential
9. Adequate hematology function indicated by followings (without blood transfusion or administration with growth factors in last four weeks):

   1. Neutrophil count ≥ 1.5×10\^9/L
   2. Hemoglobin ≥ 90g/L
   3. Platelet count ≥ 100×10\^9/L
   4. Lymphocyte count ≥ 0.5×10\^9/L
10. Adequate liver, kidney, heart and lung functions at least indicated by:

    1. Creatinine clearance ≥ 60ml/min
    2. ALT and AST ≤ 2.5 ULN (≤ 5 ULN when liver is involved)
    3. LVEF ≥ 50%; absence of pericardial fluid; no significant abnormality in ECG exam
    4. No or only small amount of pleural fluid or ascites; blood oxygen saturation ≥ 95%
11. Voluntary participation in the trial and signing informed consent form

Exclusion criteria:

1. Active viral infection including but not limiting hepatitis A, hepatitis B, hepatitis C or HIV
2. History of acquired immunodeficiency syndrome (AIDS)
3. Is pregnant or lactating
4. Unwilling to practice birth control
5. Planned intraperitoneal chemotherapy (such as HIPEC) within 28 days
6. Received systemic immune inhibitors or corticosteroids (prednisone 15mg/day or above equivalent dose) within 2 weeks of the time of initiating conditioning chemotherapy
7. Current involvement of:

   1. Active infection which requires treatment with systemic administration
   2. Active coagulation disorders or receiving anti-coagulant treatment (except for aspirin)
   3. Active hemolytic anemia
   4. Significant arrhythmia, or history of myocardial infarction, ventricular tachycardia, or ventricular fibrillation
   5. Active obstructive or constrictive lung disease
   6. Active autoimmune disease such as rheumatoid arthritis or immunodeficiency disease
   7. Active CNS metastases or cerebrospinal malignancy
   8. Uncontrolled diseases including disorders of cardiovascular, respiratory, renal, gastrointestinal, urogenital or immune systems
8. Active second malignancy in addition to the studied one, excluding low-risk neoplasms such as non-metastatic basal cell or squamous cell skin carcinoma
9. History of hypersensitivity to any drugs planning to be used in this study
10. History of treatment with any genetically modified T cell therapy (including CAR T cells and TCR T cells)
11. Any conditions that investigator consider as ineligibility of participation