Claudin18.2-redirected Chimeric Antigen Receptor T Cells With Co-expression of Cytokines in Solid Tumors

Study Overview
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Brief Summary
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An Open-Label, Single-Arm, Dose-Exploration Study to Evaluate the Safety, Tolerability, Preliminary Efficacy and Pharmacokinetics of CT048 in Subjects with Advanced Solid Tumors

Detailed Description
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This is an open-label, single-arm, dose-escalation and dose-expansion, single/multiple infusion(s) exploratory study to evaluate the safety, tolerability, PK/PD and preliminary efficacy of CT048 in patients with advanced CLDN18.2+ solid tumors who had failed to at least 1 prior line of treatment.

Official Title
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An Open-Label, Single-Arm, Dose-Exploration Study to Evaluate the Safety, Tolerability, Preliminary Efficacy and Pharmacokinetics of CT048 in Subjects With Advanced Solid Tumors

Conditions
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Gastric Adenocarcinoma, Pancreatic Cancer, Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Drug: CT048 Autologous Injection (CT048)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 75 years, male or female; Estimated life expectancy > 12 weeks; Pathologically/histologically confirmed diagnosis of advanced G/GEJ adenocarcinoma or pancreatic cancer or other digestive system malignancies G/GEJA: refractory to or intolerable of at least 2 prior lines of treatment; HER2+ subjects must be refractory or intolerable of anti-HER2 treatment PC: refractory to or intolerable of at least 1 prior line of treatment; Positive expression of CLDN18.2 in tumor tissue specimens; According to the RECIST 1.1, there is measurable or unmeasurable tumor lesions; ECOG physical status score 0   1 at screening, within 24 hours prior to apheresis; Sufficient venous access for leukapheresis (central venous catheter) Subjects should have adequate organ functions before screening : Women of childbearing age (WOCB) be willing to use effective and reliable method of contraception (annual failure<1%) for at least 1 year after last infusion, and must refrain from donating sperms/eggs Men who have actively sexual intercourse with women with child-bearing potential, must agree to use barrier-based contraception if they have no vasectomy. Moreover, all men are absolutely forbidden to donate sperm within 1 year after receiving the last infusion. Exclusion Criteria: High risks that may cause bleeding or perforation; CNS metastasis, with or without related symptoms; The presence of extensive lung metastases, or extensive liver metastases, or extensive bone metastases History or current unstable or active digestive ulcers, gastrointestinal (GI) bleeding, GI obstruction; Anti-tumor treatment for the investigational disease; treatment with anti-PD-1/PD-L1, anti-CTLA4, and any other immunotherapy or investigational therapy； Prior treatment with any genetically modified cell therapy; Treatment with systemic corticosteroids within 7 days prior to leukapheresis; Prior solid organ transplantation, or allogeneic stem cell, or in the waiting list for organ transplantation; Major surgical procedure or serious wound within 4 weeks prior to leukapheresis, or anticipation of need for a major surgical procedure during the study; Positive serological tests of HIV, syphilis or HCV (subjects with positive HCV antibody but are negative for HCV RNA are eligible); Any active or severe infection, incl. but not limited to active tuberculosis, HBV infection, etc.; Active autoimmune disease; Uncontrolled significant cardiovascular disease, pulmonary disease or CNS disease History of malignancy other than investigational diseases within 3 years, with the exception of malignancies with a negligible risk of metastasis or death; Pregnancy or lactating women; History of allergic anaphylactic reactions to immunotherapy, and/or tocilizumab, cyclophosphamide, fludarabine or nab-paclitaxel, and/or CT048 components, or other history of severe allergic anaphylactic reactions ； Blood oxygen saturation ≤95% before leukapheresis; AEs from previous treatment that have not recovered to CTCAE ≤ grade 1, excluding hair loss, pigmentation, and other tolerable events and laboratory abnormalities permitted by the protocol;

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: Experimental: CAR-CLDN18.2 T-Cells (CT048)<br>The subjects will be initially enrolled in the lymphodepletion cohort. Subsequent subjects will be enrolled in the non-lymphodepletion cohort after reviewing the data in the lymphodepletion cohort. | Drug: CT048 Autologous Injection (CT048)<br>* up to 3 times CT048 Autologous Injection infusion<br>* Other names: CT048 Autologous CAR T-cell Injection;|

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 | Tolerability | 28 days of single infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nature, incidence, severity and seriousness of TEAEs, TRAEs and AESI; graded according to the NCI-CTCAE (Version 5.0) or ASTCT | Adverse events occurring through 24 weeks and 12 months post CT048 indusion, such as abnormalities or changes in laboratory tests, physical examinations, vital signs, etc. | 1 year | 
| Pharmacokinetics(the number of CAR copies and CAR persistence duration in peripheral blood) | CAR-CLDN18.2 DNA in peripheral blood detected by q-PCR at each visit after each infusion | 1 year | 
| Antitumor efficacy-Overall response rate (ORR), Duration of response (DOR), Disease control rate (DCR) | 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 6 weeks after the first evaluation | 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-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 | 
| Antitumor efficacy-Progression-free survival | The period from the date of leukapheresis to the first recorded tumor progression or death of any cause, whichever occurs first (ITT). | 1 year | 
| Antitumor efficacy-Overall survival (OS) | The period from the date of leukapheresis to death of any cause (ITT). The period from the date of first CT048 infusion to death of any cause (mITT). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Claudin18.2, CAR-T cell therapy