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

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ClinicalTrials.gov Identifier: NCT02414269
Recruitment Status : Recruiting
First Posted : April 10, 2015
Last Update Posted : August 27, 2019
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE April 2, 2015
First Posted Date  ICMJE April 10, 2015
Last Update Posted Date August 27, 2019
Actual Study Start Date  ICMJE May 2015
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2015)
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 ]
All AEs and laboratory toxicities will be graded using version 4 of the CTCAE.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02414269 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2015)
Changes in serum levels of the biomarker soluble mesothelin related peptide (SMRP) [ Time Frame: 60 days (+/-5 days) after treatment ]
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 .
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin
Official Title  ICMJE A Phase I Clinical Trial of Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Malignant Pleural Disease
  • Mesothelioma
  • Metastases
  • Lung Cancer
  • Breast Cancer
Intervention  ICMJE
  • Genetic: iCasp9M28z T cell infusions
    Administration through the pleural catheter- On day 0 patients will be treated with genetically modified T cells. Thirty to 60 minutes before T cell infusion, patients will be given 650 mg of acetaminophen orally and 25- 50 mg of diphenhydramine orally or intravenously, to prevent infusion-related reactions. The genetically modified T cells will be infused for at least 15 minutes and no more than 2 hours through the indwelling pleural catheter depending on the volume of the T cells. A physician will be available during the infusion. Please note, during formulation of iCasp9M28z T cells, under or over estimation of CAR modified T Cells may occur. Patient may receive an altered fractionation of the total dose or up to 35% over or under total cell dose with approval of the PI. Patients who do not have enough cells to match the current dose cohort will be treated in the cohort in which they have cells available
  • Drug: cyclophosphamide
    Patients will receive cyclophosphamide intravenously (at 1.5 g/m^2)
  • Drug: pembrolizumab
    Pembrolizumab will be given as 200 mg flat dose infusion intravenously.
Study Arms  ICMJE
  • Experimental: modified T cells alone (without chemotherapy)
    Following 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.
    Intervention: Genetic: iCasp9M28z T cell infusions
  • Experimental: modified T cells with cyclophosphamide
    Patients 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.
    Interventions:
    • Genetic: iCasp9M28z T cell infusions
    • Drug: cyclophosphamide
  • Experimental: CAR T cell and pembrolizumab
    Pembrolizumab 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.
    Intervention: Drug: pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 15, 2019)
66
Original Estimated Enrollment  ICMJE
 (submitted: April 9, 2015)
24
Estimated Study Completion Date  ICMJE April 2020
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Prasad Adusumilli, MD 212-639-8093
Contact: Marjorie Zauderer, MD 646-888-4656
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02414269
Other Study ID Numbers  ICMJE 15-007
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Prasad Adusumilli, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP