The goal of this clinical trial is to learn if CBG131 works to treat advanced gastric cancer or pancreatic cancer in adults whose tumors are CLDN18.2-positive. It will also learn about the safety of CBG131 and find the best dose to use.
The main questions it aims to answer are:
Is CBG131 safe, and what medical problems do participants have when receiving it? Does CBG131 shrink tumors in participants with CLDN18.2-positive cancers? How long do the CAR-T cells stay and work in the body? Researchers will test different doses of CBG131 to see which dose is safest and most effective. This is an early-stage trial, so there is no placebo group-everyone who joins will receive the actual treatment.
Participants will:
Have their blood cells collected through a procedure called leukapheresis (so the CAR-T cells can be made).
Receive chemotherapy for 3 days to prepare their body for the CAR-T cells Get a single infusion of CBG131 CAR-T cells through an IV. Visit the clinic frequently for the first month, then regularly for 2 years for checkups, blood tests, and tumor assessments.
Keep track of their symptoms and any side effects they experience.
Age 18-70 years (inclusive) at the time of informed consent; sex unrestricted.
Voluntary participation: the subject (or legally authorized representative) must provide written informed consent (ICF, Informed Consent Form).
Histologically confirmed advanced gastric or gastroesophageal junction adenocarcinoma that has progressed after ≥ 2 prior systemic regimens, OR histologically confirmed advanced pancreatic adenocarcinoma that has progressed after ≥ 1 prior systemic regimen.
CLDN18.2 positivity in archival or fresh tumor tissue by immunohistochemistry (IHC): ≥ 40% of tumor cells staining ≥ 2+.
Pregnant or lactating women.
Active bacterial or fungal infection within 72 h before lymphodepletion. Subjects receiving prophylactic antibiotics, antifungals or antivirals are allowed if there is no evidence of active infection and the agents are not on the prohibited-medication list.
Systemic corticosteroids equivalent to > 15 mg/day prednisone within 2 weeks before leukapheresis (inhaled or topical steroids permitted). Any systemic glucocorticoids within 7 days before leukapheresis, except inhaled or topical preparations.
Live-attenuated vaccine within 4 weeks before leukapheresis or planned during the study.
Single group
CBG131 CAR-T Cell Infusion
DrugThis Phase I trial follows a conventional 3 + 3 dose-escalation schema. Cohorts: (1) DL1 (de-escalation cohort): 0.5×10⁸ CAR⁺ T cells; (2) DL1 (starting dose cohort): 1×10⁸ CAR⁺ T cells; (3) DL2: 2×10⁸ CAR⁺ T cells. Three subjects are enrolled in each cohort. Absence of Dose-Limiting Toxicity (DLT) permits dose escalation; one DLT triggers expansion of the cohort by three additional subjects at the same dose. If, during expansion, one or more additional DLTs occur: (1) in the DL1 (starting dose cohort), dose escalation is suspended and de-escalation is considered; (2) in DL2 or higher cohorts, dose escalation stops and the preceding dose is declared the Maximum Tolerated Dose (MTD). If no further DLTs appear, dose escalation proceeds.
Incidence and Grading of Adverse Events (AEs) and Serious Adverse Events (SAEs)（Including CRS and ICANS）
This outcome measure assesses the incidence and severity grading of all Adverse Events (AEs) and Serious Adverse Events (SAEs) in subjects. Specifically: a) Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are graded according to the ASTCT (American Society for Transplantation and Cellular Therapy) consensus criteria; b) All other AEs are graded according to the NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 5.0. Data are collected from leukapheresis enrollment to the end of the follow-up period.
Incidence and Determination of Dose-Limiting Toxicity (DLT) Related to CBG131
Dose-Limiting Toxicity (DLT) refers to CBG131-related toxicities (excluding infections and malignancies) occurring within 28 days after CAR-T cell infusion. DLT is determined based on the following criteria: 1) Grade 5 AE; 2) Grade 4 CRS; 3) Grade 4 neurotoxicity; 4) Grade 3 CRS or neurotoxicity that persists for more than 72 hours and fails to improve to ≤Grade 2; 5) Other Grade 4 non-hematologic toxicity that persists for more than 72 hours and fails to improve to ≤Grade 3; 6) Other Grade 3 non-hematologic toxicity that persists for ≥2 weeks; 7) Grade 4 hematologic toxicity that persists for more than 72 hours and fails to improve to ≤Grade 3; 8) Hematologic toxicity of Grade \>3 that persists for more than 2 weeks and fails to improve to ≤Grade 2.
Maximum Tolerated Dose (MTD) and Optimal Dosage of CBG131（Determined by 3+3 Dose-Escalation Schema）
This Phase I trial adopts a conventional 3 + 3 dose-escalation schema to determine the Maximum Tolerated Dose (MTD) of CBG131 and further confirm its optimal dosage. The dose cohorts are designed as follows: (1) DL1 (de-escalation cohort): 0.5×10⁸ CAR⁺ T cells; (2) DL1 (starting dose cohort): 1×10⁸ CAR⁺ T cells; (3) DL2: 2×10⁸ CAR⁺ T cells. Three subjects are enrolled in each cohort. If no DLT occurs in a cohort, dose escalation proceeds to the next higher cohort; if one DLT occurs, the cohort is expanded by an additional three subjects at the same dose. During the expansion phase: (1) If one or more additional DLTs occur in the DL1 (starting dose cohort), dose escalation is suspended and de-escalation is considered; (2) If one or more additional DLTs occur in DL2 or higher cohorts, dose escalation stops, and the previous dose is declared as the MTD. If no additional DLTs occur during expansion, dose escalation continues.
Tumor CLDN18.2 Expression Positivity (Assessed by Immunohistochemistry [IHC])
This outcome measure assesses the positivity of CLDN18.2 expression in primary tumor tissue of subjects. Primary tumor tissue samples obtained within ≤1 year after subject consent must be detected for CLDN18.2 expression by Immunohistochemistry (IHC), and the expression positivity is determined according to the predefined IHC criteria.
Progression-Free Survival (PFS) per RECIST 1.1 Criteria
Progression-Free Survival (PFS) is defined and calculated according to the RECIST (Response Evaluation Criteria in Solid Tumors) Version 1.1 for efficacy evaluation. PFS refers to the interval from the date of CBG131 infusion to the first documented evidence of disease progression or death from any cause, whichever occurs first. Disease progression is determined in accordance with RECIST 1.1 criteria.
Overall Survival (OS)
Overall Survival (OS) is defined as the interval from the date of CBG131 infusion to death from any cause. After CAR-T cell infusion, all subjects who discontinue the study for any reason will undergo survival follow-up every 3 months (±2 weeks) until the end of the follow-up period.
Best Overall Response Rate (BORR) per RECIST 1.1 Criteria（Proportion of Subjects Achieving Complete Response [CR] or Partial Response [PR]）
The Best Overall Response Rate (BORR) is evaluated according to the RECIST 1.1 criteria for antitumor response. Antitumor responses are classified into four categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). BORR is defined as the proportion of subjects who achieve CR or PR during the study period. The number and percentage of subjects achieving CR or PR will be tabulated, and the 95% confidence interval for each percentage will be calculated using the Clopper-Pearson exact method. For the calculation of BORR, each subject's best response recorded at any time during the study will be used.
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First Affiliated Hospital of Wenzhou Medical University
Lead sponsor
Carbiogene Therapeutics Co. Ltd.
Collaborator
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