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Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin

NCT02414269

Description:

The purpose of this Phase I study is to test the safety of different doses of specially prepared immune cells (called "T cells") collected from blood. The Investigators want to find a safe dose of these modified T cells for patients who have malignant pleural disease. They want to find out what effects these T cells have on the patient and the cancer (MPD). Phase 2 part of the study, the investigators will test the dose in combination with another drug, pembrolizumab, to see what effects the study treatment has on malignant pleural mesothelioma.

Related Conditions:
  • Breast Carcinoma
  • Malignant Pleural Mesothelioma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin
  • Official Title: A Phase I Clinical Trial of Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin

Clinical Trial IDs

  • ORG STUDY ID: 15-007
  • NCT ID: NCT02414269

Conditions

  • Malignant Pleural Disease
  • Mesothelioma
  • Metastases
  • Lung Cancer
  • Breast Cancer

Interventions

DrugSynonymsArms
cyclophosphamidemodified T cells with cyclophosphamide
pembrolizumabCAR T cell and pembrolizumab

Purpose

The purpose of this Phase I study is to test the safety of different doses of specially prepared immune cells (called "T cells") collected from blood. The Investigators want to find a safe dose of these modified T cells for patients who have malignant pleural disease. They want to find out what effects these T cells have on the patient and the cancer (MPD).

Detailed Description

      This is an open-label, dose-escalating, non randomized, single-center, phase I study of
      mesothelin-targeted T cells administered intrapleurally as a single infusion in patients with
      a diagnosis (histologically or cytologically documented) of MPD from mesothelioma, lung
      cancer, or breast cancer. The total number of patients studied will depend on the number of
      dose levels tested, up to a maximum dose of 2×10^8 mesothelin-targeted T cells/kg or until
      the maximum tolerated dose (MTD) is reached.

      For patients who were treated and were removed from study, duplicate enrollment is permitted
      if it is determined the patients could receive benefit. If the patients meet all eligibility
      criteria, they may receive treatment in a higher dose level cohort. Patients who are
      re-treated with CAR T cell therapy will not be considered new accruals. Outcomes of
      re-treated patients will be analyzed separately.

      Patients may receive palliative radiotherapy for symptom management prior to or following the
      CAR T cell infusion. If a patient receives palliative radiotherapy, the study PI, treating
      Radiation Oncologist, and treating Medical Oncologist will decide whether to proceed with the
      infusion. Palliative radiotherapy must be completed at least 2 days prior to the
      administration of cyclophosphamide.
    

Trial Arms

NameTypeDescriptionInterventions
modified T cells alone (without chemotherapy)ExperimentalFollowing enrollment, leukapheresis product will be obtained in the blood donor facility at MSKCC and cryopreserved in the Cell Therapy and Cell Engineering Facility (CTCEF). Before protocol treatment, the leukapheresis product will be thawed, and T cell isolation, transduction, and expansion of iCasp928z T cells will be performed in the MSKCC CTCEF Facility. It is estimated that it will take approximately 3 to 6 weeks to generate T cells for treatment.
    modified T cells with cyclophosphamideExperimentalPatients will receive cyclophosphamide intravenously (at 1.5 g/m^2) , 2 - 7 (Day (-7) -(-2) days before T cell infusion. On Day 1 , patients will be admitted to the MSKCC Inpatient Service (if not already inpatients) for intravenous hydration, clinical monitoring, and blood work for immune monitoring. Standard MSKCC antiemetic therapy will be administered prior to chemotherapy to prevent nausea/vomiting. Administration of corticosteroids will be avoided as steroids may impede the efficacy of CAR T cells.
    • cyclophosphamide
    CAR T cell and pembrolizumabExperimentalPembrolizumab 4 weeks (+3/-1 week window) after completing CAR T cell administration. Patients will receive 3 doses of pembrolizumab given on a recurring schedule followed by reassessment. Those responding or deriving clinical benefit, without unacceptable toxicity, will continue pembrolizumab. Patients will be followed weekly for the first four weeks.
    • pembrolizumab

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients with MPD aged ≥18 years
    
              -  Karnofsky performance status ≥70%
    
              -  Patients with malignant pleural disease (MPD), pathologically confirmed at MSKCC
                 (radiographic confirmation is acceptable for screening phase eligibility), and defined
                 as one of the following (patients who have not yet received treatment may enroll in
                 the screening portion only):
    
                   1. Malignant pleural mesothelioma - previously treated with at least one prior
                      treatment regimen.
    
                   2. Non-small cell lung cancer metastatic to the pleura—previously treated with at
                      least one prior treatment regimen (chemotherapy or targeted agent) and documented
                      progression of disease. Patients with disease outside of the pleura will be
                      discussed among study PI and Co-PIs prior to considered eligible for the study.
                      Disease outside of the pleura must not require any immediate therapy per PI's
                      discretion.
    
                   3. Breast cancer metastatic to the pleura— previously treated with at least one
                      prior treatment regimen (chemotherapy or targeted agent) and documented
                      progression of disease. Patients with disease outside of the pleura will be
                      discussed among study PI and Co-PIs prior to be considered eligible for the
                      study. Disease outside of the pleura must not require any immediate therapy per
                      PI's discretion.
    
              -  Expression of mesothelin must be confirmed by meeting one of the following criteria.
    
                   1. Mesothelin expression (>10% of the tumor expressing mesothelin) by
                      immunohistochemical (IHC) analysis
    
                   2. Elevated serum SMRP levels (>1.0 nM/L).
    
              -  Free flowing pleural effusion requiring management by placement of a pleural catheter.
                 Patients with a functional pleural catheter already in place are eligible for the
                 study, as long as there are no clinical concerns of infection.
    
            OR
    
              -  No free-flowing pleural effusion: an Interventional Radiologist has agreed that
                 radiology-guided intrapleural or peritumoral injection of the CAR T cells is feasible.
    
              -  Chemotherapy, targeted therapy (such as a tyrosine kinase inhibitor) or therapeutic
                 radiotherapy must have been completed at least 14 days prior to administration of T
                 cells. Continuation of hormonal therapy (ie for breast cancer) is acceptable. Prior
                 immunotherapy with checkpoint blockade (i.e. PD1 inhibitor, PDL1 inhibitor or
                 CTL4-antagonist or similar agent) must have been completed more than 1 month1prior to
                 the T cell infusion.
    
              -  Chemotherapy must have been completed at least 7 days prior to leukapheresis
    
              -  Palliative radiotherapy must be completed at least 2 days prior to administration of
                 cyclophosphamide
    
              -  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.
    
              -  All acute toxic effects of any previous therapeutic or palliative radiotherapy,
                 chemotherapy, or surgical procedures must have resolved to grade I or lower according
                 to CTCAE (version 4.0).
    
              -  Lab requirements (hematology)
    
              -  White blood cell (WBC) count ≥3000 cells/mm3
    
              -  Absolute neutrophil count ≥1500 neutrophils/mm3
    
              -  Platelet count ≥100,000 platelets/mm3 Lab requirements (serum chemistry)
    
              -  Bilirubin ≤ 1.5x upper limit of normal (ULN)
    
              -  Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) ≤.5x ULN
    
              -  Serum creatinine ≤ 1.5x ULN or Cr > 1.5x ULN, but calculated clearances of >60
    
              -  Negative screen for human immunodeficiency virus (HIV), hepatitis B virus (HBV)
                 antigen, and hepatitis C virus (HCV). If testing was performed during the previous 3
                 months, there is no need to repeat testing, as long as documentation of results is
                 provided to the study site. Subjects must receive counseling and sign a separate
                 informed consent form for HIV testing.
    
              -  Subjects and their partners with reproductive potential must agree to use an effective
                 form of contraception during the period of drug administration and for 4 weeks after
                 completion of the last administration of the study drug. An effective form of
                 contraception is defined as oral contraceptives plus 1 form of barrier or
                 double-barrier method contraception (condom with spermicide or condom with diaphragm).
    
              -  Subjects must be able to understand the potential risks and benefits of the study and
                 must be able to read and provide written, informed consent for the study
    
            Exclusion Criteria:
    
              -  Untreated or active CNS metastases (progressing or requiring anticonvulsants or
                 corticosteroids for symptomatic control); patients with a history of treated CNS
                 metastases are eligible, provided that all of the following criteria are met:
    
                   -  Presence of measurable or evaluable disease outside of the CNS;
    
                   -  Radiographic demonstration of improvement upon completion of CNS-directed therapy
                      and no evidence of interim progression between completion of CNS-directed therapy
                      and the screening radiographic study;
    
                   -  Completion of radiotherapy ≥8 weeks prior to the screening radiographic study;
    
                   -  Discontinuation of corticosteroids and anticonvulsants ≥4 weeks prior to the
                      screening radiographic study.
    
              -  Non-small cell lung cancer metastatic to the pleura that extends outside of the pleura
                 requiring immediate therapy
    
              -  Breast cancer metastatic to the pleura that extends outside of the pleura requiring
                 immediate therapy
    
              -  Prior history of seizure disorder
    
              -  Patients currently receiving treatment for concurrent active malignancy Continuation
                 of hormonal therapy (i.e. for breast cancer) is acceptable. Prior immunotherapy with
                 checkpoint blockade (i.e. PD1 inhibitor, PDL1 inhibitor or CTL4-antagonist or similar
                 agent) must have been completed more than 1 month prior to the T cell infusion.
    
              -  Autoimmune or antibody-mediated disease, including but not limited to systemic lupus
                 erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and temporal
                 arteritis (Patients with a history of hypothyroidism will not be excluded)
    
              -  History of myocarditis or congestive heart failure (as defined by New York Heart
                 Association Functional Classification III or IV), as well as unstable angina, serious
                 uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction 6
                 months prior to study entry
    
              -  Subjects with left ventricular ejection fraction (LVEF) less than 50%
    
              -  Patients with active interstitial lung disease (ILD)/pneumonitis or a history of
                 ILD/pneumonitis requiring treatment with systemic steroids
    
              -  Baseline pulse oximetry is less than 92% on Room air
    
              -  Pregnant or lactating women
    
              -  An infection requiring antibiotic treatment within 7 days before the start of
                 treatment (day 0)
    
              -  A requirement for daily systemic corticosteroids for any reason or a requirement for
                 other immunosuppressive or immunomodulatory agents. Topical, nasal, and inhaled
                 steroids are permitted.
    
              -  Administration of live, attenuated vaccine within 8 weeks before the start of
                 treatment (day 0) and throughout the study
    
              -  Any other medical condition that, in the opinion of the PI, may interfere with a
                 subject's participation in or compliance with the study
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Composite measure of severity and number of adverse events (AEs); changes in clinical laboratory test findings (hematologic and chemistry); and physical examination.
    Time Frame:1 year
    Safety Issue:
    Description:All AEs and laboratory toxicities will be graded using version 4 of the CTCAE.

    Secondary Outcome Measures

    Measure:Changes in serum levels of the biomarker soluble mesothelin related peptide (SMRP)
    Time Frame:60 days (+/-5 days) after treatment
    Safety Issue:
    Description:Mesothelin is an immunogenic cell surface antigen, that is expressed at high levels in MPD and mesothelioma pleural fluid will be drained from the chest by thoracentesis or through a pleural catheter and will be preserved for analysis .

    Details

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

    Trial Keywords

    • modified T cells
    • cyclophosphamide
    • CAR T cells
    • 15-007
    • CAR
    • immunotherapy

    Last Updated

    August 23, 2019