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

Open-label, Multicenter, Phase 1b/2 Clinical Trial to Evaluate the Safety and Efficacy of Autologous Anti-claudin 18.2 Chimeric Antigen Receptor T-cell Therapy in Subjects with Advanced Gastric, Pancreatic, or Other Specified Digestive System Cancers

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

Study Overview

• Status: Active, not recruiting
• Conditions: Gastric Cancer; Pancreatic Cancer
• Intervention / Treatment: Biological: CT041

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5GH 2C1
      • Princess Margaret Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90089
      • University of Southern California
    • San Diego, California, United States, 92093
      • UCSD
    • San Francisco, California, United States, 94143
      • UCSF
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Cancer Hospital
  • New York
    • New Hyde Park, New York, United States, 11042
      • Northwell Cancer Institute
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10029
      • The Mount Sinai Hospital
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Texas
    • Dallas, Texas, United States, 75246
      • TX Oncology-Baylor Charles Sammons Cancer Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital and the Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: anti-claudin18.2 chimeric antigen receptor T-cell therapy; 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.	Biological: CT041; treatment with anti-claudin18.2 chimeric antigen receptor T-cell infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b/2: Objective Response Rate (ORR) per investigator assessment	Rate of subjects experiencing an objective response (a binary variable indicating whether each subject experienced a ≥ partial response [PR] by Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1]), as determined by investigator assessment.	up to year 15
Phase 1b (Cohort A): Duration of Response	Duration of time from first response to progression of disease as determined by investigator	up to year 15
Phase 1b (Cohort A): Time to Progression	Duration of time in months from the date of CT041 infusion until disease progression, excluding deaths as determined by investigator.	up to year 15
Phase 1b (Cohort A): Disease Control Rate	The incidence of a BOR of CR, PR, or SD based on investigator assessments using RECIST 1.1 criteria.	up to year 15
Phase 1b (Cohort A): Progression free survival	The time in months from the date of CT041 infusion to the earliest date of disease progression or death due to any cause as determined by investigator.	up to year 15
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).	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 2 (Cohort C): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with advanced STAD.	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 B)/2: Duration of Response	Duration of time from first response to progression of disease as determined by investigator and IRC assessment.	up to year 15
Phase 1b(Cohort B)/2: Time to Progression	Duration of time in months from the date of CT041 infusion until disease progression, excluding deaths as determined by investigator and IRC assessment.	up to year 15
Phase 1b(Cohort B)/2: Disease Control Rate	The incidence of a BOR of CR, PR, or SD based on investigator and IRC assessments using RECIST 1.1 criteria.	up to year 15
Phase 1b(Cohort B)/2: Progression free survival	The time in months from the date of CT041 infusion to the earlier date of disease progression or death due to any cause as determined by investigator and IRC assessment.	up to year 15
Phase 1b/2: Overall survival	The time in months from the date of CT041 infusion until the date of death by any cause.	up to year 15
Phase 1b/2: Utilization of Hospital Resources	Total days of hospitalization, including ICU days, during & after CT041 infusion as described below: Infusion-related hospital re-admission within 3 months after infusion.; The number and percentages of subjects, and the number of hospitalizations due to non-infusion reasons.; All-cause re-admission within 3 months after infusion, and from infusion to data cutoff date among those who required rehospitalization; Duration of hospitalization in intensive care	Day 0 to 3 months
Phase 1b(Cohort B)/2: PK and bio-distribution of CT041	CAR transgene copy number, peak value, AUC, in vivo persistence.	Baseline - month 18
Phase 1b(Cohort B)/2: Health-related Quality of Life (HRQoL) in STAD patients (Cohorts B & C)	Change from baseline in HRQoL as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30.; Change from baseline in HRQoL as measured by EORTC QLQ-OG25.	Baseline - month 18
Phase 1b(Cohort B)/2: CLDN18.2 ICH Assay Performance	Association of CLDN18.2 expression level versus tumor response; Association of CLDN18.2 expression versus clinical disease characteristics	Baseline - month 18
Phase 1b(Cohort B)/2: Cytokine expression level in blood after CT041 infusion	Evaluate cytokine expression level in blood after CT041 infusion.	Baseline - week 20
Phase 1b (Cohort B)/2: Anti-CT041 drug antibodies	Number of subjects with anti-CT041 drug antibodies	Baseline - month 12
Phase 1b (Cohort B)/2: CT041 product characteristics	Association of CT041 product characteristics with clinical safety/efficacy/PK	Baseline - month 18
Phase 1b (Cohort B)/2: Concordance analysis	Concordance analysis of ORR of IRC assessment vs investigator assessment.	up to year 15

Collaborators and Investigators

• Sponsor: CARsgen Therapeutics Co., Ltd.
• Investigators: Principal Investigator: Harry H Yoon, MD, Mayo; Principal Investigator: Dae Won Kim, MD, Moffitt

Publications and helpful links

General Publications

• Botta GP, Chao J, Ma H, Hahn M, Sierra G, Jia J, Hendrix AY, Nolte Fong JV, Ween A, Vu P, Miller A, Choi M, Heyman B, Daniels GA, Kaufman D, Jamieson C, Li Z, Cohen E. Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells. J Immunother Cancer. 2024 Feb 5;12(2):e007927. doi: 10.1136/jitc-2023-007927.

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2020
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): September 1, 2035

Study Registration Dates

• First Submitted: May 19, 2020
• First Submitted That Met QC Criteria: May 26, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 6, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: CAR-T
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms
• Other Study ID Numbers: CT041-ST-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No