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Mesothelin-Specific Genetically Engineered Lymphocytes with or without Cyclophosphamide and Pembrolizumab in Treating Patients with Malignant Pleural Disease

Trial Status: Active

This phase I / II trial studies the side effects and best dose of mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes and to see how well it works with or without cyclophosphamide and pembrolizumab in treating patients with a malignant disease found in the thin layer of tissue that covers the lungs and lines the interior wall of the chest cavity (pleura), including malignant pleural mesothelioma, or previously treated non-small cell lung cancer or breast cancer that has spread to the pleura. Placing a gene that has been created in the laboratory into white blood cells (lymphocytes) may help the body build an immune response to kill tumor cells expressing the protein mesothelin. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes with or without cyclophosphamide may be a better treatment for malignant pleural disease.

Inclusion Criteria

  • Patients with MPD
  • Karnofsky performance status >= 70%
  • Patients with malignant pleural disease (MPD), pathologically confirmed at Memorial Sloan-Kettering Cancer Center (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): * Malignant pleural mesothelioma – previously treated with at least one prior treatment regimen * Non-small cell lung cancer metastatic to the pleura—previously treated with at least one prior treatment regimen (chemotherapy, surgery, or targeted agent) and documented progression of disease; patients with disease outside of the pleura will be discussed among study principal investigator (PI) and Co-Pls prior to considered eligible for the study; disease outside of the pleura must not require any immediate therapy per PI’s discretion * Breast cancer metastatic to the pleura— previously treated with at least one prior treatment regimen (chemotherapy, surgery or targeted agent) and documented progression of disease; patients with disease outside of the pleura will be discussed among study PI and Co-Pls prior to considered eligible for the study; disease outside of the pleura must not require any immediate therapy per PI’s discretion
  • Only patients with a diagnosis of malignant pleural mesothelioma will be included in cohort 9 and in the Phase II portion of the study; expression of mesothelin must be confirmed by meeting one of the following criteria * Mesothelin expression (> 10% of the tumor expressing mesothelin) by immunohistochemical (IHC) analysis * 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 (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 * 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 video assisted thoracoscopy (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 Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0)
  • White blood cell (WBC) count >= 3000 cells/mm^3
  • Absolute neutrophil count >= 1500 neutrophils/mm^3
  • Platelet count >= 100,000 platelets/mm^3
  • Bilirubin =< 1.5 x upper limit of normal (ULN)
  • Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) =< 5 x ULN
  • Serum creatinine =< 1.5 x ULN or creatinine (Cr) > 1.5 x 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 central nervous system (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
  • Known active infection requiring antibiotic treatment 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

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Marjorie G. Zauderer
Phone: 646-888-4656
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Marjorie G. Zauderer
Phone: 646-888-4656
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Marjorie G. Zauderer
Phone: 646-888-4656

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Marjorie G. Zauderer
Phone: 646-888-4656
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Marjorie G. Zauderer
Phone: 646-888-4656
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Marjorie G. Zauderer
Phone: 646-888-4656
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Marjorie G. Zauderer
Phone: 646-888-4656

PRIMARY OBJECTIVES:

I. To assess the safety, dose requirement, and targeting efficiency of intrapleurally administered genetically directed autologous human T cells targeted to mesothelin - a cell surface cancer antigen widely expressed in mesothelioma, lung cancer, and breast cancer cells - using a chimeric antigen receptor (CAR). (Phase I)

II. To determine the recommended phase II dose of mesothelin-targeted CAR T cells in combination with pembrolizumab in patients with malignant pleural mesothelioma. (Phase I)

III. To determine the clinical benefit rate as defined by the proportion of patients with a best response of complete response (CR), partial response (PR), and stable disease (SD) at 12 weeks following the first dose of pembrolizumab as measured by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the biological and antitumor effects of T cell treatment. (Phase I)

II. To measure serum soluble mesothelin related peptide (SMRP) levels. (Phase I)

III. To assess T cell targeting, accumulation, persistence, and antitumor immune response, using molecular biology techniques on samples from peripheral blood, pleural fluid and tumor biopsies. (Phase I)

IV. To assess the capacity for AP1903, a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity if unacceptable toxicity occurs that is probably or likely related to anti-mesothelin CAR T cells. (Phase I)

V. To assess the safety of combination CAR T cell and pembrolizumab therapy. (Phase II)

VI. To determine response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. (Phase II)

VII. To determine the best response and the duration of best response. (Phase II)

VIII. To determine progression-free survival (PFS) and overall survival (OS) of patients at 6, 12, 18, and 24 months. (Phase II)

IX. To explore changes in patient’s body mass index (BMI) and serum SMRP. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes followed by a phase II study.

PHASE I: Patients receive cyclophosphamide intravenously (IV) on day -7 to -2 (cohorts 2-9), and then receive mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes intrapleurally over 15 minutes to 2 hours on day 0. Patients who experience unacceptable toxicity that is probably or likely related to mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes may receive rimiducid IV to mediate clearance of the genetically engineered cells and resolve toxicity. Patients who obtain clinical benefit and who do not experience any non-hematologic grade 4 toxicities, may receive additional modified T-cells at the discretion of the treating physician. Beginning 4 weeks after mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes infusion, patients with malignant pleural mesothelioma (MPM) (cohort 9) who do not experience adverse events greater than grade 3 related to the modified T-cell infusion receive pembrolizumab IV every 3 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients with MPM receive cyclophosphamide IV on day -7 to -2, and then receive mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes intrapleurally over 15 minutes to 2 hours on day 0. Patients who experience unacceptable toxicity that is probably or likely related to mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes may receive rimiducid IV to mediate clearance of the genetically engineered cells and resolve toxicity. Beginning 3-5 weeks after mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes infusion, patients receive pembrolizumab IV every 3 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 3 days, weekly for at least 3 weeks, and then yearly for 15 years thereafter.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Marjorie G. Zauderer

  • Primary ID 15-007
  • Secondary IDs NCI-2015-00789
  • Clinicaltrials.gov ID NCT02414269