A Phase 1b/2, open label, multi-center, clinical study of Chimeric Antigen Receptor T Cells (CAR-T) targeting claudin18.2 in patients with advanced gastric, pancreatic or other specified digestive system cancers

This is an open label, multi-center, Phase 1b/2 clinical trial to evaluate the safety and efficacy of autologous claudin18.2 chimeric antigen receptor T-cell therapy in patients with advanced gastric, pancreatic or other specified digestive system cancers.

Following consent, patients must have tumor tissue evaluated by CLDN18.2 IHC assay. Patients meeting all eligibility criteria will undergo a leukapheresis procedure to collect autologous mononuclear cells for manufacture of investigational drug product (CT041). Following manufacture of the drug product, subjects will receive preconditioning prior to CT041 infusion. All subjects will be asked to continue to undergo long-term gene safety follow-up.

Inclusion Criteria:

Patients are eligible for screening for potential inclusion in the study (* indicates inclusion criteria at Baseline (for subjects to be eligible for preconditioning)):

1. Voluntarily signed the ICF;

2. Age ≥ 18 and < 76 years with pathologically/histologically confirmed diagnosis of adenocarcinoma of the stomach or gastroesophageal junction, referred to collectively as STAD, or pancreatic adenocarcinoma (PAAD);or biliary tract cancers (BTCs, including intrahepatic/extrahepatic cholangiocarcinoma and gallbladder cancer but not ampullary carcinoma);

3. Must have CLDN18.2-positive tumor expression as determined by the CLDN18.2 IHC assay;

4. Estimated life expectancy > 4 months*;

5. Failed or been intolerant of prior lines of systemic therapy:

   1. For screening:

      • Leukapheresis can be performed for subjects with STAD who have progressed or were intolerant of at least 1 prior line of systemic therapy, or,
      • Leukapheresis can be performed for subjects with PAAD who are receiving first-line treatment, or,
      • Leukapheresis can be performed for subjects with BTC who are receiving first-line treatment.

   2. Baseline*:

      • Subjects with STAD who have progressed or were intolerant of at least 2 prior lines of systemic therapy, or,
      • Subjects with PAAD who have progressed or were intolerant of at least 1 prior line of systemic therapy, or,
      • Subjects with BTC who have progressed or were intolerant of at least 1 prior line of systemic therapy. For subjects with CCA with who has FGFR2 fusions or rearrangements, or IDH1-mutant must have received FDA-approved target therapies.

6. At least 1 measurable lesion per RECIST 1.1*;

7. ECOG performance status of 0 or 1*;

8. Sufficient venous access for leukapheresis collection and no other contraindications to leukapheresis;

9. Patients should have adequate CBC counts, renal and hepatic functions*;

10. Women of childbearing age must undergo a serum pregnancy test with negative results before screening and infusion and be willing to use effective and reliable method of contraception*;

11. Men must be willing to use effective and reliable method of contraception for at least 12-months after T-cell infusion*;

12. Sufficient nutritional status.

Exclusion Criteria for screening (* indicates exclusion criteria for baseline as well):

1. Pregnant or lactating women*;

2. HIV, active hepatitis C virus (HCV), active hepatitis B virus (HBV), or active syphilis infection;

3. Any active infection requiring systemic treatment*;

4. AEs from previous treatment that have not recovered*;

5. Patients who have clinically significant thyroid dysfunction;

6. Patients allergic to any drugs of the preconditioning regimen, tocilizumab, dimethyl sulfoxide (DMSO), or CT041 CAR-CLDN18.2 T-cell;

7. Patients who have received:

   1. prior cellular therapy such as (CAR T, TCR, tumor-infiltrating lymphocytes) within one year.
   2. organ transplantation.
   3. previous anti-claudin18.2 CAR T-cell therapy, mRNA-based cancer immunotherapy, or bispecific T cell engager.

8. Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression;

9. Patients with heavy tumor burdens;

10. Unstable/active ulcer, anastomotic recurrence with full-thickness tumor infiltration or tumor involving any major vessels, digestive tract bleeding, or recent digestive surgery that may have increased risk of bleeding*;

11. Patients who have a history of esophageal or gastric resection plus current evidence of locally recurrent tumor that involves any major blood vessels or that has evidence of recent bleeding or perforation*;

12. Patients requiring anticoagulant therapy such as warfarin or heparin;

13. Patients requiring long-term antiplatelet therapy;

14. Use of prednisone >/= 10mg daily or other equivalent steroids within 14 days before leukapheresis or preconditioning*;

15. Anticancer treatment within approximately 2 weeks prior to leukapheresis or preconditioning*;

16. Major surgery less than 1 week prior to leukapheresis or 3 weeks prior to preconditioning*;

17. Patients who have clinically significant cardiac conditions that researchers believe that participating in this clinical trial may endanger the health of the patients*;

18. Inadequate pulmonary function*;

19. Patients known to have active autoimmune diseases;

20. Patients with second malignancies;

21. Patients have significant neurologic disorders;

22. Patients are unable or unwilling to comply with the requirements of clinical trial.

    Additional exclusion criteria solely for baseline (prior to conditioning regimen):

23. Fever > 38.0°C;

24. Active illness or existing toxicity that would place the subject at undue risk;

25. Abrupt deterioration of clinical status or condition;

26. Subjects who have received a live attenuated vaccine 4 weeks before preconditioning.

Inclusion Criteria Before Infusion: There are no inclusion criteria at this timepoint.

Exclusion Criteria Before Infusion:

1. Patients who have clinically significant cardiac conditions that researchers believe that participating in this clinical trial may endanger the health of the patients;
2. Inadequate pulmonary function;
3. Active infection requiring systemic therapy or causing fever within 7 days prior to investigational infusion;
4. Active illness or toxicity that would place the subject at undue risk;
5. Abrupt deterioration of clinical status or condition;
6. New or worsening Grade ≥ 3 non-hematologic toxicities.