Clinical Trials /

Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma

NCT04577326

Description:

This study will test the safety of MSLN-targeted CAR-T cells at different doses to find the safest dose to give to people with MPM. The researchers want to see what effects, if any, the study treatment has on people with this type of cancer. This study is the first time that an MSLN-targeted CAR-T cell treatment with an anti-PD1 component is being given to people.

Related Conditions:
  • Malignant Pleural Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma
  • Official Title: A Single-Arm, Open-Label, Phase I Trial to Assess the Safety of Genetically Engineered Autologous T Cells Targeting the Cell Surface Antigen Mesothelin With Cell-Intrinsic Checkpoint Inhibition in Patients With Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: 20-328
  • NCT ID: NCT04577326

Conditions

  • Malignant Pleural Mesothelioma (MPM)

Interventions

DrugSynonymsArms
cyclophosphamideEngineered Autologous T Cells
CAR T cellsEngineered Autologous T Cells

Purpose

This study will test the safety of MSLN-targeted CAR-T cells at different doses to find the safest dose to give to people with MPM. The researchers want to see what effects, if any, the study treatment has on people with this type of cancer. This study is the first time that an MSLN-targeted CAR-T cell treatment with an anti-PD1 component is being given to people.

Trial Arms

NameTypeDescriptionInterventions
Engineered Autologous T CellsExperimentalFollowing eligibility screening and enrollment, patients will undergo leukapheresis for the collection of peripheral blood mononuclear cells (PBMCs), to enable generation of M28z1XXPD1DNR. Following successful M28z1XXPD1DNR CAR T-cell manufacturing, patients will be reevaluated for eligibility. A preconditioning regimen of one dose of intravenous (IV) cyclophosphamide 1.5 g/m2 will be administered 2-7 days before the infusion. A single dose of M28z1XXPD1DNR CAR T cells will be instilled into the pleural cavity via a pleural catheter or through an interventional radiology-guided needle. All patients will be monitored in the hospital for a minimum of 48 h following the administration of CAR T cells.
  • cyclophosphamide
  • CAR T cells

Eligibility Criteria

        Inclusion Criteria:

        1. Aged ≥18 years 2. Karnofsky performance status ≥70% 3. Pathologically confirmed MPM

          1. Epithelioid or biphasic histologic diagnosis provided that ≥10% of the tumor expresses
             MSLN by IHC analysis

          2. Patients with peritoneal mesothelioma with pleural involvement are eligible only if
             there is radiographic and pathologic confirmation of mesothelioma in the pleural
             cavity and ≥10% of the tumor expresses MSLN by IHC analysis. 4. Previously treated
             with at least 1 treatment regimen 5. Measurable or evaluable disease (disease is
             considered evaluable but not measurable if it does not meet the eligibility criteria
             for mRECIST but is a manifestation of malignancy that can be followed qualitatively as
             an indicator of disease progression or treatment response) 6. Chemotherapy, targeted
             therapy, or radiotherapy must be completed at least 7 days before leukapheresis.

        a. CPI must be completed at least 21 days before leukapheresis. 7. Chemotherapy, targeted
        therapy, or therapeutic radiotherapy must be completed at least 14 days before
        administration of T cells.

        a. Palliative radiotherapy can be completed 2 days before lymphodepletion. Immunotherapy
        with CPI must be completed at least 42 days before administration of T cells. 9. Any major
        thoracic (thoracotomy with lung or esophageal resection) or abdominal (laparotomy with
        organ resection) operation must have occurred at least 28 days before study enrollment.
        Patients who have undergone diagnostic VATS or laparoscopy can be included in the study.
        10. All acute toxic effects of any previous therapeutic or palliative radiotherapy,
        chemotherapy, or surgical procedures must have resolved to grade 1 (CTCAE v5.0).

        11. Lab requirements (hematology):

          1. Absolute neutrophil count ≥1.5 K/mcL

          2. Platelet count ≥100 K/mcL 12. Lab requirements (serum chemistry):

          1. Bilirubin ≤1.5x upper limit of normal (ULN)

          2. Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level
             ≤5x ULN

          3. Serum creatinine level ≤1.5x ULN or creatinine >1.5x ULN but calculated clearances of
             >60 by Cockcroft-Gault Equation 13. Negative screen for infectious disease markers
             including Hepatitis B core antibody, Hepatitis B surface antigen, Hepatitis C
             antibody, HIV 1-2 antibody, HTLV 1-2 and Syphilis (rapid plasma regain profile) 14.
             Life expectancy at the time of screening ≥4 months

        Exclusion Criteria:

          1. Patients receiving therapy for concurrent active malignancy a. Patients receiving
             treatment for in situ skin malignancies are not excluded.

          2. Patients who received prior CAR T-cell therapy

          3. Untreated or active central nervous system (CNS) metastases (progressing or requiring

          4. anticonvulsants or corticosteroids for symptomatic control). Patients with a history
             of treated CNS metastases are eligible if all the following criteria are met:

               1. Presence of measurable or evaluable disease outside of the CNS

               2. Radiographic demonstration of improvement upon completion of CNS-directed therapy
                  and no evidence of interim progression between completion of CNSdirected therapy
                  and the screening radiographic study

               3. Completion of radiotherapy ≥8 weeks before the screening radiographic study

               4. Discontinuation of corticosteroids and anticonvulsants ≥4 weeks before the
                  screening radiographic study

          5. History of seizure disorder

          6. Active autoimmune disease that has required systemic treatment in the past year (with
             use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) a.
             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency) is not considered a form
             of systemic treatment and is allowed.

          7. Patients who are receiving daily systemic corticosteroids that are above physiological
             doses for any reason or who are under immunosuppressive or immunomodulatory treatment

          8. Patients with the below cardiac conditions:

               1. New York Heart Association stage III or IV congestive heart failure

               2. Myocardial infarction ≤6 months before enrollment

               3. History of myocarditis

               4. Serious uncontrolled cardiac arrhythmia, unstable angina, or uncontrolled
                  infection

          9. Patients with left ventricular ejection fraction ≤40%

         10. Patients with active interstitial lung disease/pneumonitis or a history of
             interstitial lung disease/pneumonitis requiring treatment with systemic steroids

         11. Baseline pulse oximetry <90% on room air at the screening timepoint

         12. Pregnant or lactating women

             a. Subjects and their partners with reproductive potential must agree to use an
             effective form of contraception during treatment and for 1 year following treatment.

         13. Known active infection requiring antibiotic treatment 7 days before the start of
             treatment (Day 0). Note: treatment can be delayed at the discretion of the treating
             physician to allow the patient to recover from the infection.

         14. Administration of live, attenuated vaccine within 8 weeks before the start of
             treatment (Day 0) and for 100 days following treatment.

         15. Any other medical condition that, in the opinion of the PI, may interfere with a
             subject's participation in or compliance with the study

         16. Any patient deemed to be noncompliant by the study team for administration of a high
             risk treatment agent and for close follow-up after treatment as required by the
             protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD of M28z1XXPD1DNR
Time Frame:2 years
Safety Issue:
Description:CTCAE v5.0 will be used to assess the severity of all treatment emerging toxicities/adverse events regardless

Secondary Outcome Measures

Measure:overall response rate (ORR)
Time Frame:2 years
Safety Issue:
Description:modified RECIST (mRECIST; v1.0)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Genetically Engineered Autologous T Cells
  • 20-328

Last Updated

October 7, 2020