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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Gastric Cancer, Pancreatic Cancer

Intervention / Treatment
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* Biological: CT041


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are eligible for screening for potential inclusion in the study: Voluntarily signed the ICF; 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); Must have CLDN18.2-positive tumor expression as determined by the CLDN18.2 IHC assay; Failed or been intolerant of prior lines of systemic therapy; Estimated life expectancy > 4 months; At least 1 measurable lesion per RECIST 1.1; ECOG performance status of 0 or 1; Sufficient venous access for leukapheresis collection and no other contraindications to leukapheresis; Patients should have reasonable CBC counts, renal and hepatic functions; 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; Men must be willing to use effective and reliable method of contraception for at least 12-months after T-cell infusion; Sufficient nutritional status. Exclusion Criteria: Pregnant or lactating women; HIV, active hepatitis C virus (HCV), or active hepatitis B virus (HBV) infusion; Any uncontrolled active infection; AEs from previous treatment that have not recovered; Patients who have clinically significant thyroid dysfunction; Patients allergic to any drugs of the preconditioning regimen, tocilizumab, dimethyl sulfoxide (DMSO), or CT041 CAR-CLDN18.2 T-cell; Patients who have received prior cellular therapy such as (CAR T, TCR, tumor-infiltrating lymphocytes) or organ transplantation; Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression; Untreated CNS, leptomeningeal disease or cord compression Patients with heavy tumor burden such as significant lung disease Unstable/active ulcer or digestive tract bleeding or recent digestive surgery that may have increased risk of bleeding; Patients who have a history of esophageal or gastric resection with increased risk of bleeding or perforation; Patients requiring anticoagulant therapy such as warfarin or heparin; Patients requiring long-term antiplatelet therapy; Use of prednisone or other equivalent within 14 days before leukapheresis or preconditioning; Anticancer treatment within approximately 2 weeks prior to leukapheresis or approximately preconditioning; Major surgery less than 1 week prior to leukapheresis or 3 weeks prior to preconditioning; Patients have clinical significant cardiac conditions that researchers believe that participating in this clinical trial may endanger the health of the patients; Patients have clinical significant pulmonary conditions; Patients known to have active autoimmune diseases; Patients with second malignancies in addition to STAD or PAAD; Patients have significant neurologic disorders; Patients are unable or unwilling to comply with the requirements of clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 76 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 3+3 dose escalation and expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: anti-claudin18.2 chimeric antigen receptor T-cell therapy<br>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<br>* treatment with anti-claudin18.2 chimeric antigen receptor T-cell infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Incidence of Treatment Related adverse events (AEs) | Incidence of Treatment Related AEs, AEs of special interest and serious adverse events (SAEs) | up to 18 mos | 
| Phase 1b: Identification of Maximum Tolerated Dose (MTD) & incidence of Dose-limiting Toxicities (DLTs) | Incidence of dose-limiting toxicities (DLTs) | day 1 - day 28 | 
| Phase 2: Objective Response Rate (ORR) per independent central read | Rate of subjects experiencing >/= to PR per RECIST 1.1 as determined by IRC assessment | up to 18 mos | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Objective Response Rate (ORR) per local assessment | Rate of subjects experiencing >/= to PR per RECIST 1.1 as determined by investigator | up to 18 mos | 
| Phase 1b/2: Duration of Response | Duration of time from first response to progression of disease as determined by investigator | up to 18 mos | 
| Phase 1b/2: Disease Control Rate | Percentage of patients response at least 90 days as determined by investigator | up to 18 mos | 
| Phase 1b/2: Progression free survival | duration time after CT041 treatment that patient lives without worsening of disease as determined by investigator | up to 18 mos | 
| Phase 1b/2: Overall survival | duration time after CT041 treatment that patient lives as determined by investigator | up to 18 mos | 
| Phase 1b/2: Utilization of Hospital Resources | Days of hospitalization during & after CT041 infusion; days of hospitalization in ICU | up to 18 mos | 
| Phase 1b/2: Health-related Quality of Life (HRQoL) | Change from baseline in how subjects report the satisfaction with their health as reported on the EORTC QLQ-C30; scoring uses a linear transformation to standardize the raw score such that scores range from 0-100 with a higher score requesting a higher level or function or a higher level of symptoms. | Baseline - month 18 | 
| Phase 2: Incidence of Treatment Related adverse events (AEs) | Rate of subjects experiencing >/= to PR per RECIST 1.1 as determined by investigator | up to 18 mos | 
| Phase 1b/2: PK and bio-distribution of CT041 | Persistence of CAR transgene copy number | Baseline - month 18 | 
| Phase 1b/2: CLDN18.2 ICH Assay Performance | Correlation of CLDN18.2 expression level with tumor response | Baseline - month 18 | 
| Phase 1b/2: Anti-CT041 drug antibodies | Number of subjects with anit-CT041 drug antibodies | day 0 - month 18 | 
| Phase 1b/2: Cytokine expression level in blood after CT041 infusion | evaluate cytokine (IL-6 et al) expression levels in patients treated with CT041 | day 0 - month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T