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αPD1-MSLN-CAR T Cells for the Treatment of MSLN-positive Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04503980
Recruitment Status : Recruiting
First Posted : August 7, 2020
Last Update Posted : August 7, 2020
Sponsor:
Collaborator:
Shanghai 10th People's Hospital
Information provided by (Responsible Party):
Shanghai Cell Therapy Group Co.,Ltd

Brief Summary:
This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 nanobodies (αPD1-MSLN-CAR T cells) in patients with solid tumors.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Ovarian Cancer Biological: αPD1-MSLN-CAR T cells Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Exploratory Study of αPD1-MSLN-CAR T Cells Secreting PD-1 Nanobodies for the Treatment of MSLN-positive Advanced Solid Tumors
Actual Study Start Date : March 26, 2020
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : June 2022


Arm Intervention/treatment
Experimental: CAR T cells therapy
The safety and efficacy of αPD1-MSLN-CAR T cells will be assessed in a standard 3+3 dose escalation approach. Four doses of CAR T cells will be evaluated in this study: 1×10^5 CAR+ T cells/kg, 3×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 3×10^6 CAR+ T cells/kg.
Biological: αPD1-MSLN-CAR T cells
Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of αPD1-MSLN-CAR T cells. During αPD1-MSLN-CAR T cells production, subjects will receive cyclophosphamide for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with αPD1-MSLN-CAR T cells by intravenous (IV) injection. The initial dose of 1×10^5 CAR+ T cells/kg will be infused on day 0.




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLT) [ Time Frame: After 28 days of single infusion ]
    Safety


Secondary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: After 28 days of single infusion ]
    Tolerability

  2. Objective response rate (ORR) [ Time Frame: Month 12 ]
    Clinical response will be assessed by RECIST 1.1.

  3. Progression-free survival (PFS) [ Time Frame: Month 12 ]
    PFS of patients receiving αPD1-MSLN-CAR T cells

  4. Overall survival (OS) [ Time Frame: Month 12 ]
    OS of patients receiving αPD1-MSLN-CAR T cells.

  5. Peak Plasma Concentration (Cmax) [ Time Frame: Month 12 ]
    Pharmacokinetics (PK)

  6. Pharmacodynamics (PD) [ Time Frame: Day 28 ]
    PD 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a histological or cytological diagnosis of advanced solid tumors, such as ovarian cancer,Cholangiocarcinoma,colorectal cancer;
  • Patients must have failed established standard medical anti-cancer therapies;
  • 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;
  • Subjects must meet blood coagulation parameters and have adequate venous peripheral access for apheresis. Patients must also have adequate mononuclear cells for CAR T cell manufacturing;
  • Staining of MSLN must be greater than 50% of the cells in the tumor tissue and with apparent expression in the membrane. PD-L1 expression must be positive. Tissue obtained for the biopsy must be ≤1 year prior to enrollment for screening, not have been previously irradiated or exposed to chemotherapy. If unavailable, new tissue material from a recently obtained surgical or diagnostic biopsy is mandatory for this trial;
  • Satisfactory organ and bone marrow function as defined by the following:

    1. Adequate bone marrow function in the opinion of the Investigator for lymphocyte-depleting chemotherapy: 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 (≤2.5x if there is hepatic metastasis);
    3. Creatinine must be less than or equal to one and one half times (≤ 1.5x) the institutional normal upper limit or eGFR ≥ 60ml/min/1.73m^2 [eGFR=186×(age)-0.203×SCr-1.154(mg/dl),for female the eGFR shoud be timed by 0.742];
    4. International normalized ratio (INR) or the PT is not greater than one and one half times (≤ 1.5) the upper limit of normal;
    5. Lung function: ≤ CTCAE grade 1 dyspnea and SaO2≥ 91%
    6. 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;
  • For concurrent medication:

    1. Systemic therapeutic corticosteroids must be stopped 72 hours before CAR-T infusion. However, patients using physiologic replacement doses of corticosteroids, or its equivalent, will be considered eligible;
    2. Immunosuppressive therapy must be stopped within four (4) weeks prior to enrollment;
  • 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:

  • Prior therapy with targeted therapy or cell therapy against MSLN;
  • Prior therapy with any gene therapy (including CAR-T cell therapy) or any T cell therapy home and abroad;
  • Active bacteria, viral or fungal infection, and not contained after anti-infective therapy (positive results in the blood ≤72 hours before infusion);
  • Patient is positive for Syphilis, Human Immunodeficiency Virus (HIV) , active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected);
  • Patient has a medical condition such as autoimmune disease or organ transplantation that requires chronic systemic steroid therapy or requires any other form of immunosuppressive medication;
  • 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;
  • Patient has a history or current evidence of any condition such as neurotic, psychiatric, immune, metabolic and infectious disease, on any therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator;
  • Patient has a known history of a hematologic malignancy, or of another malignant primary solid tumor concurrently, with the exception of :

    1. Patients with in situ cervical cancer or breast cancer with no evidence of disease for ≥ 3 years after curative treatments;
    2. Patients who underwent successful definitive resection of in situ cancer with no evidence of disease for ≥5 years;
  • Has had chemotherapy, radioactive, small molecules, biological cancer therapy, immunotherapy or other investigational drugs within 4 weeks prior to the initiation of the study;
  • Pregnant or breastfeeding women;
  • Investigators think that patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study and cooperation with the requirements of the trial, uncontrolled medical, psychological, familial, sociological, or geographical conditions, or is not in the best interest of the patient to participate.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04503980


Contacts
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Contact: Juemin Fang 021-66302521 435254611@qq.com

Locations
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China, Shanghai
Shanghai Tenth people's Hospital Recruiting
Shanghai, Shanghai, China
Contact: Juemin Fang    021-66302521    435254611@qq.com   
Sponsors and Collaborators
Shanghai Cell Therapy Group Co.,Ltd
Shanghai 10th People's Hospital
Investigators
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Principal Investigator: Qing Qu Shanghai 10th People's Hospital
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Responsible Party: Shanghai Cell Therapy Group Co.,Ltd
ClinicalTrials.gov Identifier: NCT04503980    
Other Study ID Numbers: BZDS1901
First Posted: August 7, 2020    Key Record Dates
Last Update Posted: August 7, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Shanghai Cell Therapy Group Co.,Ltd:
Solid tumors
CAR T cell