Clinical Trials /

Study of CRISPR-Cas9 Mediated PD-1 and TCR Gene-knocked Out Mesothelin-directed CAR-T Cells in Patients With Mesothelin Positive Multiple Solid Tumors.

NCT03545815

Description:

Multiple solid tumors have positive targets of mesothelin expressed on the surfaces of the tumor cells, we use the technique of CRISPR-Cas9 to knocked out the PD-1 and TCR of chimeric antigen receptor (CAR) T cells to effect the immuno-microenvironment around tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of CRISPR-Cas9 Mediated PD-1 and TCR Gene-knocked Out Mesothelin-directed CAR-T Cells in Patients With Mesothelin Positive Multiple Solid Tumors.
  • Official Title: Phase I Study to Evaluate Treatment of CRISPR-Cas9 Mediated PD-1 and TCR Gene-knocked Out Chimeric Antigen Receptor (CAR) T Cells in Patients With Mesothelin Positive Multiple Solid Tumors.

Clinical Trial IDs

  • ORG STUDY ID: CHN-PLAGH-BT-028
  • NCT ID: NCT03545815

Conditions

  • Solid Tumor, Adult

Interventions

DrugSynonymsArms
anti-mesothelin CAR-T cellsanti-mesothelin CAR-T cells

Purpose

Multiple solid tumors have positive targets of mesothelin expressed on the surfaces of the tumor cells, we use the technique of CRISPR-Cas9 to knocked out the PD-1 and TCR of chimeric antigen receptor (CAR) T cells to effect the immuno-microenvironment around tumors.

Detailed Description

      1. To evaluate the feasibility and safety of CRISPR-Cas9 mediated PD-1 and TCR gene-knocked
           out chimeric antigen receptor (CAR) T cells in patients with mesothelin positive
           multiple solid tumors.

        2. To evaluate the duration of in vivo persistence of transferred CAR-T cells.

        3. To observe and measure anti-tumor responses for patients with detectable mesothelin
           positive tumor lesions.
    

Trial Arms

NameTypeDescriptionInterventions
anti-mesothelin CAR-T cellsExperimentalPatients receive mesothelin-directed CAR-T cells infusion with dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de- escalation. Patients receive anti-mesothelin-CAR T cells on days 0, 1, 2 in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Histologically confirmed with mesothelin positive multiple solid tumors.
    
              2. Failure of at least one prior standard of care chemotherapy for advanced stage
                 disease.
    
              3. Subjects must have measureable disease as defined by RECIST 1.1 criteria or modified
                 RECIST criteria.
    
              4. Patients > 18 years of age.
    
              5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2.
    
              6. Life expectancy > 12 weeks.
    
              7. Satisfactory organ and bone marrow function as defined by the following (of note, the
                 minimal blood counts should be in the absence of transfusion or cytokine support):
    
                 i. Absolute neutrophil count > 1,000/μl ii. Platelets >75,000/μl iii. Hemoglobin > 9
                 g/dL iv. Bilirubin < 2.0x the institutional normal upper limit unless secondary to
                 bile duct obstruction by tumor v. Creatinine < 1.5x the institutional normal upper
                 limit vi. Albumin ≥2 vii. Serum alanine aminotransferase (ALT) or aspartate
                 aminotransferase (AST) < 5x the institutional normal upper limit viii. Cardiac
                 ejection fraction of >55% as measured by resting echocardiogram, with no significant
                 pericardial effusion.
    
              8. Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤
                 1.5 and a PTT < 1.2 time the upper limit of normal unless the patient is
                 therapeutically anti-coagulated for history of cancer-related thrombosis and has
                 stable coagulation parameters.
    
              9. Ability to understand and the willingness to provide written informed consent.
    
             10. Male and Female subjects of reproductive potential agree to use approved contraceptive
                 methods (e.g. birth control pills, barrier device, intrauterine device, abstinence)
                 and abstain from other methods of conception during the study and for 6 months
                 following the study cell infusion or proof of sterility.
    
            Exclusion Criteria
    
              1. Sarcomatoid MPM histology which is known in the literature to not express mesothelin;
                 biphasic MPM is also excluded.
    
              2. This refers to non-commercially approved investigational drugs different than those
                 used in this protocol.Participated in any other trial in which receipt of an
                 investigational study drug occurred within 28 days prior to enrollment and anticipated
                 treatment with another investigational product while on study.
    
              3. Anticipated need for systemic chemotherapy within 2 weeks before apheresis and
                 infusion of CART-meso cells.
    
              4. Active invasive cancer other than the one of the three cancers in this study. Patients
                 with active non-invasive cancers (such as non-melanoma skin cancer, superficial
                 cervical and bladder and prostate cancer with PSA level < 1.0) are not
                 excluded.CART-meso in mesothelin expressing cancers
    
              5. HIV, HCV, or HBV infections
    
              6. Active autoimmune disease (including but not limited to: systemic lupus
                 erythromatosis, Sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple
                 sclerosis, inflammatory bowel disease, etc.) requiring immunosuppressive therapy
                 within the past 4 weeks, with exception of thyroid replacement.
    
              7. Patients with ongoing or active infection.
    
              8. Planned concurrent treatment with systemic high dose corticosteroids. Patients may be
                 on a stable low dose of steroids (<10mg equivalent of prednisone) for chronic
                 respiratory conditions.
    
              9. Patients requiring supplemental oxygen therapy.
    
             10. Prior therapy with gene modified cells.
    
             11. Previous experimental therapy with SS1 moiety, murine or chimeric antibodies (human
                 and humanized antibodies are allowed).
    
             12. History of allergy to murine proteins
    
             13. History of allergy or hypersensitivity to study product excipients (human serum
                 albumin, DMSO, and Dextran 40)
    
             14. Any clinically significant pericardial effusion; CHF (NY Heart Association Grade
                 II-IV) or cardiovascular condition that would preclude assessment of mesothelin
                 induced pericarditis or that may worsen as a result of toxicities expected for this
                 study. This determination will be made by a cardiologist.
    
             15. Any clinically significant pleural or peritoneal effusion that cannot be drained with
                 standard approaches. An indwelling drainage device placed prior to enrollment is
                 acceptable.
    
             16. Pregnant or breastfeeding women. Female study participants of reproductive potential
                 must have a negative urine pregnancy test of enrollment. A serum pregnancy test will
                 be performed within 2 weeks before infusion.
          
    Maximum Eligible Age:70 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:study of related adverse events
    Time Frame:24 weeks
    Safety Issue:
    Description:Grade 3 signs/symptoms, toxicities and clinical

    Secondary Outcome Measures

    Measure:clinical responses to anti-mesothelin cell infusions
    Time Frame:24 weeks
    Safety Issue:
    Description:Disease control rate(DCR)

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Chinese PLA General Hospital

    Trial Keywords

    • mesothelin, CRISPR-Cas9, PD-1, TCR

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