An Exploratory Study on the Treatment of Advanced Solid Tumors by Fast CAR T Cells

An Exploratory Study on the Treatment of Advanced Solid Tumors by Secretory PD1 Nanoantibody Targeting Mesothelin Fast CAR T Cells

This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of fast autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 nanobodies in patients with solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor
• Intervention / Treatment: Biological: Fast CAR T cells

Detailed Description

The main aim of this study is to determin the safety and efficacy of BZT2312 in patients with solid tumors. BZT2312 is an autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 nanobodies.

This study comprises of a screening phase(less than or equal to 28 days prior to apheresis) followed by apheresis(will occur upon enroiiment); Apheresis phase(less than or equal to 10 days prior to infusion ) followed by lymphodepletion. lymphodepletion phase (from day -5 to day -3) followed by infusion.Treatment Phase including infusion of BZT2312 on Day0 and then post-infusion assessments from Day1 to Day 28; and a Post-treatment Phase(Day 29 and up to end of the study). Efficacy will be explored to assessed and safety will be closely monitored during the study.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Yong Xia; Phone Number: 021-67091399; Email: xiay@shcell.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China
      • Recruiting
      • Shanghai Mengchao Cancer Hospital
      • Contact: Lou jinxing

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients diagnosed with advanced solid tumors through histopathological diagnosis have a positive rate of ≥ 50% for mesothelin expression membrane in tumor tissue samples, PD-L1 positive expression, and sample sources within 2 years；
• Late stage malignant solid tumor patients who have failed standard treatment or are intolerant to such treatment and do not have a standard effective treatment plan；
• Greater than or equal to 18 years of age and less than or equal to 70 years of age on day of signing informed consent；
• Life expectancy >3 months；
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1；

• Satisfactory organ and bone marrow function as defined by the following:

  1. absolute neutrophil count must be greater than ≥ 1.5×109/L, lymphocyte count must be greater than ≥ 0.5×109/L, platelets must be greater than ≥ 90×109/L, hemoglobin must be greater than ≥ 90g/L without transfusion within 7 days or dependency on EPO;
  2. Total bilirubin must be less than or equal to two times (≤2.0x) the institutional normal upper limit; transaminases, serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), must be less than or equal to 2.5 times (≤2.5x) the institutional normal upper limit (≤5x if there is hepatic metastasis);
  3. International normalized ratio (INR) or the PT is not greater than one and one half times (≤ 1.5) the upper limit of normal;
  4. Lung function: ≤ CTCAE grade 1 dyspnea and SaO2≥ 91%
  5. Cardiac function: cardiac ejection fraction (LVEF) must be greater than fifty percent (≥50%) by echocardiogram or MUGA one month before enrollment.
• Subjects must have measureable disease as defined by RECIST 1.1 criteria;
• Subjects sufficiently understand the trial and willingly sign the informed consent；
• Male and Female subjects agree to use approved contraceptive methods (e.g. birth control pills, barrier device, intrauterine device, abstinence) during the study and for at least 12 months following the last dose of the study cell infusion and until no CAR-T cells can be detected after two consecutive PCR tests.

Exclusion Criteria:

• Subjects who have undergone other anti-tumor treatments (including radiation therapy, chemotherapy, small molecule, biological or immunotherapy, and other study drugs) other than lymphocytes depletion allowed by the protocol within one month prior to CAR-T infusion;
• Prior therapy with any gene therapy (including CAR-T cell therapy) or any T cell therapy home and abroad;
• Pregnant or breastfeeding women;
• Positive serological reactions for HIV and syphilis; Hepatitis B surface antigen positive, hepatitis B core antibody positive, and hepatitis B virus DNA copy number higher than the detection limit and/or greater than or equal to 1000 copies/mL; Or Hepatitis C virus infected individuals;
• Any uncontrollable active infection, coagulation disorders, or any other major illness;
• Patients with autoimmune diseases, organ transplantation and other immune related diseases under treatment, or long-term use of immunosuppressive drugs such as glucocorticoids: a. Glucocorticoids: users cannot stop using CAR-T cells 72 hours before infusion; b. Immunosuppressants other than glucocorticoids cannot be stopped ≥ 4 weeks before enrollment;
• Patients who are allergic to BZT2312 components;
• History of severe cardiac or pulmonary disease, including hypertension that cannot be controlled by medication, and any of the conditions occurred within the past 6 months: congestive heart failure (New York Heart Association functional classification ≥3), cardiac angioplasty and stents, myocardial infarction, unstable angina, or other clinically significant heart disease;
• Detectable clinically relevant central nervous system (CNS) metastases and/or pathology such as epilepsy/seizure, brain Ischemia/ hemorrhage, dementia, cerebellar disease, or autoimmune disease affecting central nervous system
• Patients at high risk of causing bleeding or perforation;
• Patients who had undergone major surgical procedures or significant trauma within 4 weeks before apheresis, or who were expected to require major surgery during the study period;
• Patient has a known history of a hematologic malignancy, or of another malignant primary solid tumor concurrently, with the exception of :Patients with in situ cervical cancer or breast cancer with no evidence of disease for ≥ 3 years after curative treatments;Patients who underwent successful definitive resection of in situ cancer with no evidence of disease for ≥5 years;
• Other circumstances that were deemed by the investigator to be inappropriate for trial participation.

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: Fast CAR T cells; The safety and efficacy of BZT2312 will be assessed in a standard 3+3 dose escalation approach. Three doses of CAR T cells will be evaluated in this study: 5×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 5×10^6 CAR+ T cells/kg.

Biological: Fast CAR T cells; Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of Fast CAR T cells. During Fast CAR T cells production, subjects will receive cyclophosphamide and fludarabine for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with Fast CAR T cells by intravenous (IV) injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity(DLT)	Safety	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Clinical response will be assessed by RECIST 1.1	Month 12
Peak Plasma Concentration (Cmax)	Pharmacokinetics (PK)	Month 12
Maximum tolerated dose (MTD)	Tolerability	28 days
AUC	Pharmacokinetics (PK)	Month 12
Progression-free survival (PFS)	PFS of patients receiving Fast CAR T cells	Month 12
Overall survival (OS)	OS of patients receiving Fast CAR T cells	Month 12
Pharmacodynamics (PD)	D of IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α and MCP1 will be analysed after CAR T cell infusion	Day 28

Collaborators and Investigators

• Sponsor: Shanghai Cell Therapy Group Co.,Ltd
• Investigators: Principal Investigator: Jinxing Lou, Shanghai Mengchao Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: January 31, 2024
• First Submitted That Met QC Criteria: February 7, 2024
• First Posted (Actual): February 8, 2024

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: BZT2312-A-01

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: No
• Studies a U.S. FDA-regulated device product: No