CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.

主要终点：Phase 1b (Cohort A): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with specified advanced digestive system cancers (STAD, PAAD, or BTC). · Incidence of adverse events (AEs), AEs of special interest (cytokine release syndrome \[CRS\], neurotoxicity, secondary malignancy), serious adverse events (SAEs). · up to year 15；Phase 1b (Cohort A): Identify the recommended Phase 2 dose (RP2D) of CT041 therapy in subjects with advanced STAD, PAAD, or BTC. · Incidence of dose-limiting toxicities (DLTs) · day 0 - day 28；Phase 1b (Cohort A): Identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) of CT041 therapy in subjects with STAD, PAAD, or BTC. · The highest dose below the dose where the escalation was stopped when the frequency or severity of DLTs exceeds predefined safety criteria. · day 0 - day 28；Phase 1b (Cohort B): Determine the efficacy of CT041 by ORR in subjects with advanced STAD, PAAD, or BTC. · Objective response rate by IRC assessment (RECIST v1.1) · up to year 15；Phase 2 (Cohort C): Determine the efficacy of CT041 by ORR in subjects with advanced STAD treated at the RP2D. · Objective response rate by IRC assessment (RECIST v1.1) · up to year 15
次要终点：Phase 1b/2: Objective Response Rate (ORR) per investigator assessment；Phase 1b (Cohort A): Duration of Response；Phase 1b (Cohort A): Time to Progression；Phase 1b (Cohort A): Disease Control Rate；Phase 1b (Cohort A): Progression free survival；Phase 1b (Cohort B): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with specified advanced digestive system cancers (STAD, PAAD, or BTC).；Phase 2 (Cohort C): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with advanced STAD.；Phase 1b(Cohort B)/2: Duration of Response

• anti-claudin18.2 chimeric antigen receptor T-cell therapy · EXPERIMENTAL · Phase 1b will include two parts, dose escalation phase (Cohort A) followed by a dose expansion phase (Cohort B). Phase 2 (Cohort C) will evaluate the chosen dose in patients with advanced gastric cancer.

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