Chimeric Antigen Receptor T Cells Targeting claudin18.2 in Solid Tumors.

Study Overview
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Brief Summary
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An open label, single/multiple dose exploratory clinical study to evaluate the safety, efficacy, and pharmacokinetics of autologous humanized anti-claudin18.2 chimeric antigen receptor T cell in advanced solid tumor.

Detailed Description
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This study is an open, single/multiple infusion, dose escalation/dose regimen finding study to assess the safety and pharmacokinetics of CAR-CLDN18.2 T cell therapy, and to obtain the preliminary efficacy results in subjects who have been diagnosed with advanced solid tumor with positive claudin 18.2 expression and failed to standard systemic treatment.

Official Title
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An Open Label, Single/Multiple Dose Exploratory Clinical Study to Evaluate the Safety, Efficacy, and Cytokinetics of Autologous Humanized Anti-claudin18.2 Chimeric Antigen Receptor T Cell in Advanced Solid Tumor Subjects

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: CAR-CLDN18.2 T-Cells
* Drug: PD-1 Monoclonal Antibody
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 75 years, male or female; Subjects with pathologically confirmed solid tumors (ie, advanced gastric cancer, esophagogastricgastroesophageal junction cancer, and pancreatic cancer) and have been failed to at least first-one prior line of systemic treatment; Tumor tissue samplessample was positive for claudin 18.2 positive through for claudin18.2 IHC staining;assay(≥2+, and ≥40%); Estimated life expectancy > 12 weeks; According to the RECIST 1.1, there is at least one measurable or unmeasurable tumor lesionslesion； ECOG physical status score 0   1, within 24 hours prior to apheresis, and at baseline (prior to pre-treatment); Sufficient venous access for mononuclear cell collection (abbreviation: apheresis) Subjects should have adequate organ functions before screening and pre-treatment (at baseline). Female subjects of childbearing age must undergo a serum pregnancy test at screening and prior to preconditioning and the results must be negative, and are willing to use a very effective and reliable method of contraception within 1 year after the last study treatment. The methods that can be used are: bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusion; or approved oral, injection or hormone-imparting contraceptive methods; or barrier contraceptive method: containing spermicidal foam / Gel/film/cream/suppository condom or occlusive cap (diaphragm or cervix/cap); Men who have actively sexual intercourse with women with child-bearing potential, must agree to use barrier-based contraception if they have no vasectomy, for example, a condom containing a spermicidal foam/gel/film/paste/suppository, or use a contraceptive method for their spouse (see article 9 of the inclusion criteria). Moreover, all men are absolutely forbidden to donate sperm within 1 year after receiving the last study treatment infusion； Subject participates in this clinical trial and sign Informed Consent Form voluntarily. Exclusion Criteria: Pregnant or lactating women; HIV, Treponema pallidum or HCV serologically positive; Any uncontrollable active infection, including but not limited to active tuberculosis, HBV infection (HBsAg positive, or HBcAb positive and HBV DNA positive); Subjects have clinically significant thyroid dysfunction determined by investigator (serum thyroid hormone assays TT4, TT3, FT3, FT4, and serum thyroid stimulating hormone TSH) which is not suitable for entering into the study; The side effects caused by the previous treatment of the subjects did not return to CTCAE ≤1; except hair loss and, hyperpigmentation or other tolerable events determined by investigator or laboratory abnormalities allowed by the protocol; Subjects who are using steroidshave recieved ≥15 mg/day glucocorticoid systemically currently within 7 days prior to apheresis; those using inhaled steroids recently or currently are not excluded; Previously allergic to immunotherapy and related drugs, history of severe allergiespreconditioning drug such as cyclophosphamide, fludarabine, or allergiestocilizumab or allergic to components of CT041CAR-CLDN18.2T injection, allergic to β-lactam antibiotics;the CT041 infusion; Previously received any chimeric antigen receptor-modified T-cells(including CAR-T、TCR-T) . Subjects have untreated or symptomatic brain metastases; Subjects have central or extensivelywith centralcor diffused metastases in lung and .extensiveor diffused metastases in liver;liveror with rapid tumor progression since screening period evaluated by the investigator preconditioning (at baseline)； The largest target tumor lesion>4cm Subjects with unstable or active ulcers and gastrointestinal bleeding currently; Subjects with a history of organ transplantation or awaiting organ transplantation; Subjects requiring anticoagulant therapy; Subjects requiring continuous anti-platelet therapy; Subjects who have undergone major surgery or significant trauma within 4 weeks prior to apheresis, or who are expected to undergo major surgery during the study; There are no other serious diseases that may limit subjects' participation in this trial; The investigator assessed that the subject was unable or unwilling to comply with the requirements of the study protocol; Blood oxygen saturation ≤ 95% before pre-treatmentapheresis or preconditioning (accept finger oxygen detection method); Prior to pretreatmentpreconditioning, subjects developed, including but not limited to, new arrhythmias that could not be controlled with drugs, hypotension requiring pressor agent, bacterial, fungal or viral infections that required intravenous antibiotics. Creatinine clearance rate <40mL / min; The investigator judges that the subject is not suitable for continuing the trial. Subjects who use antibiotics to prevent infection can continue the trials if judged by the investigator; The subject has a central nervous system disease sign or an abnormal neurological test result with clinical significance; The subject is currently suffered from or have suffered from other incurable malignant tumors within previous 3 years, except in situ cervical cancer or skin basal cell cancer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR-CLDN18.2 T-Cells<br>The subjects enrolled will be sequentially assigned to the corresponding dose level. | Drug: CAR-CLDN18.2 T-Cells<br>* Preconditioning with fludarabine, cyclophosphamide, based chemotherapy regimen at sub-clinical doses • Chimeric Antigen Receptor T Cells Targeting Claudin18.2<br>* Other names: Chimeric Antigen Receptor T Cells Targeting Claudin18.2;Drug: PD-1 Monoclonal Antibody<br>* Chimeric Antigen Receptor T Cells Targeting Claudin18.2 with PD-1<br>* Other names: Toripalimab;Drug: Chemotherapy<br>* First-line systemic therapy according to physician's choice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | Safety | 28 days of single infusion | 
| Maximum tolerated dose (MTD) | tolerability | 28 days of single infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (the number of cell copies and cell persistence duration in peripheral blood) | CAR-CLDN18.2 DNA in peripheral blood detected by q-PCR at each visit after infusion | 26 weeks | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Adverse events occurring through 26 weeks and 12 months post infusion of CAR-CLDN18.2 T-Cell infusion, such as abnormalities or changes in laboratory examinations, physical examinations, vital signs, etc. | 1 year | 
| Antitumor efficacy-Progression-free survival (PFS) | The period from the day when the subject receives the infusion of cells to the first recorded tumor progression (whether treated or not) or death of any cause, which occurs first. | 1 year | 
| Antitumor efficacy-Duration of response (DOR) | The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause | 1 year | 
| Antitumor efficacy-Duration of disease control (DDC) | The period from the first evaluation of clinical benefit to the first evaluation of PD or any cause of death. | 1 year | 
| Antitumor efficacy-Overall survival (OS) | The period from the first infusion to any cause of death | 1 years | 
| Antitumor efficacy-Objective response rate (ORR) | The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%). In the event of PR or CR, the subjects should confirm it no less than 4 weeks after the first evaluation | 1 year | 
| Antitumor efficacy-Disease control rate (DCR) | The number of cases in which response are achieved from the start of cell infusion/the total number of evaluable cases (%). | 1 year | 
| Long term survival follow up | The period from the first infusion to any cause of death | 15 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumor, claudin18.2, CAR-T cell therapy