Claudin18.2 CAR-T (CT041) in Patients with Gastric, Pancreatic Cancer, or Other Specified Digestive Cancers

Open to people ages 18-76

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.

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.