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Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02408016
First Posted: April 3, 2015
Last Update Posted: December 13, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
  Purpose
This phase I/II trial studies the side effects and best dose of genetically modified T cells in treating patients with stage III-IV non-small cell lung cancer (NSCLC) or mesothelioma. Many types of cancer cells, including NSCLC and mesothelioma, but not most normal cells, have a protein called Wilms tumor (WT)1 on their surfaces. This study takes a type of immune cell from patients, called T cells, and modifies their genes in the laboratory so that they are programmed to find cells with WT1 and kill them. The T cells are then given back to the patient. Cyclophosphamide and aldesleukin may also stimulate the immune system to attack cancer cells. Giving cyclophosphamide and aldesleukin with laboratory-treated T cells may help the body build an immune response to kill tumor cells.

Condition Intervention Phase
Advanced Pleural Malignant Mesothelioma HLA-A*0201 Positive Cells Present Recurrent Non-Small Cell Lung Carcinoma Recurrent Pleural Malignant Mesothelioma Stage III Non-Small Cell Lung Cancer AJCC v7 Stage III Pleural Malignant Mesothelioma AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Stage IV Non-Small Cell Lung Cancer AJCC v7 Stage IV Pleural Malignant Mesothelioma AJCC v7 WT1 Positive Biological: Aldesleukin Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes Drug: Cyclophosphamide Other: Laboratory Biomarker Analysis Procedure: Therapeutic Conventional Surgery Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study in WT1-Expressing Non-small Cell Lung Cancer and Mesothelioma, Comparing Cellular Adoptive Immunotherapy With Polyclonal Autologous Central Memory to Naïve CD8+ T Cells That Have Been Transduced to Express a WT1-Specific T-Cell Receptor

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Evidence and nature of toxicity [ Time Frame: Up to 6 months after the first T cell infusion ]
    Based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

  • Feasibility of naive T cell (TN) and central memory T cell (TCM) subsets, measured as the proportion of patients for which T cells are successfully generated and infused and whether only TN or TCM could be generated [ Time Frame: Up to 4 weeks ]
    A simple estimate of the proportion along with its 95% confidence interval will be used.

  • Persistence of transduced T cells [ Time Frame: Up to 100 days after the last T cell infusion ]
    In vivo persistence of cells generated from the TN subset with cells generated from the TCM subset will be directly compared within each patient by high throughput T-cell receptor (TCR) beta sequencing. The one-sample T test will be used to assess the difference in mean persistence between groups, in which the outcome for each patient is the time to disappearance of infused cytotoxic T lymphocytes.


Secondary Outcome Measures:
  • Frequency of transferred T cells at biopsied tumor sites between the T cell (Tn) and memory T cell (Tcm) groups [ Time Frame: Up to 15 years ]
    Frequency of transferred T cells at biopsied tumor sites between the Tn and Tcm groups will be assessed.

  • Functional capacity of transferred cells, measured by production of intracellular cytokines [ Time Frame: Up to 15 years ]
    Tetramer+ cells from peripheral blood, if detectable and available in sufficient number, evaluated for production of intracellular cytokines including interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and IL-2. Intranuclear Ki-67 expression assessed on recovered tetramer+ T cells. Based on available numbers, ex vivo proliferative capacity after infusion assessed by labeling cells with carboxyfluorescein succinimidyl ester dye and measuring dilution in response to peptide stimulation. Phenotype of tetramer+ antigen-specific cells assessed using established immunophenotyping

  • Time to progression (TTP) based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria and RECIST 1.1 mesothelioma modified [ Time Frame: 3 months after last infusion ]
    The potential efficacy of the infused cells will be assessed and the substrate cell (TN or TCM) that is most effective based on the TTP of patients who have persisting TN cells to that of patients who have persisting TCM cells 3 months after the last infusion will be determined.


Estimated Enrollment: 20
Actual Study Start Date: May 20, 2015
Estimated Primary Completion Date: January 11, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I, Stage I (T lymphocytes, cyclophosphamide, IL-2)
Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV on days 0 and 14, cyclophosphamide IV on days 11 and 12, and aldesleukin SC BID for 14 days. Patients who have received radiation to the chest/lung tissue may receive gene-transduced T lymphocytes 90 days after completion of radiation.
Biological: Aldesleukin
Given SC
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2
Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes
Given IV
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm I, Stage II (T lymphocytes, cyclophosphamide, IL-2)
Patients receive cyclophosphamide IV on days -3 and -2, autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV on day 0, and aldesleukin SC BID for 14 days.
Biological: Aldesleukin
Given SC
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2
Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes
Given IV
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm II (T lymphocytes, IL-2, surgery)
Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV between 24-96 hours after the last dose of chemotherapy and receive aldesleukin SC BID for 14 days. Patients then undergo surgery within 3-4 weeks after the T-cell infusion.
Biological: Aldesleukin
Given SC
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2
Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes
Given IV
Other: Laboratory Biomarker Analysis
Correlative studies
Procedure: Therapeutic Conventional Surgery
Undergo surgical resection

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the safety, and potential toxicities associated with treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naive cluster of differentiation (CD)8+ T cells that have been transduced to express a WT1-specific T-cell receptor (TCR) (Arm 1 and Arm 2).

II. Determine the feasibility of treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naive CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2).

III. Determine and compare the in vivo persistence in blood and tumor of transferred polyclonal autologous central memory and naive CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2).

SECONDARY OBJECTIVES:

I. Determine the antitumor efficacy for patients with metastatic NSCLC and mesothelioma (Arm 1), as measured by time to progression (TTP) based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

II. Determine the in vivo functional capacity of adoptively transferred polyclonal autologous CD8+ T cells that have been transduced to express a WT1-specific TCR, and assess the acquisition of phenotypic characteristics associated with T cell exhaustion (Arm 1 and Arm 2).

III. Determine the migration to tumor sites of adoptively transferred polyclonal autologous CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 2).

IV. Evaluate the tumor response and T cell infiltration in tumors of patients with stage IIIA NSCLC treated in the neo-adjuvant setting.

OUTLINE: This is a phase I, dose-escalation study of autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes followed by a phase II study. Patients are assigned to 1 of 3 treatment arms.

ARM I, STAGE I: Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes intravenously (IV) on days 0 and 14, cyclophosphamide IV on days 11 and 12, and aldesleukin (IL-2) subcutaneously (SC) twice daily (BID) for 14 days. Patients who have received radiation to the chest/lung tissue may receive T lymphocytes 90 days after completion of radiation.

ARM I, STAGE II: Patients receive cyclophosphamide IV on days -3 and -2, autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV on day 0, and aldesleukin SC BID for 14 days.

ARM II: Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV between 24-96 hours after the last dose of chemotherapy and receive aldesleukin SC BID for 14 days. Patients then undergo surgery within 3-4 weeks after the T-cell infusion.

After completion of study treatment, patients are followed up at 3, 6, and 12 months and then annually for 14 years.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2): Histopathological documentation of NSCLC or mesothelioma
  • ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2): Patients must be able to give informed consent
  • ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2): Patients must be able to provide blood and tumor samples and undergo the procedures required for this protocol
  • Arm 2 ONLY: Surgically operable NSCLC or mesothelioma
  • ELIGIBILITY FOR TREATMENT ON ARM 1: Patients must express human leukocyte antigen (HLA)-A*0201
  • ELIGIBILITY FOR TREATMENT ON ARM 1: Evidence of WT1 tumor expression
  • ELIGIBILITY FOR TREATMENT ON ARM 1: Patients must have received at least one line of therapy for NSCLC or mesothelioma or previously documented to have declined therapy
  • ELIGIBILITY FOR TREATMENT ON ARM 1: NSCLC patients with a mutation in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) must have demonstrated progression or intolerance to at least one of the corresponding targeted therapies (for example erlotinib or crizotinib)
  • ELIGIBILITY FOR TREATMENT ON ARM 1: Bi-dimensionally measurable disease by palpation, clinical exam, or radiographic imaging (X-ray, computed tomography [CT] scan, positron emission tomography [PET] scan, magnetic resonance imaging [MRI], or ultrasound)
  • ELIGIBILITY FOR TREATMENT ON ARM 1: Ninety days must have passed since the last doses of radiation or chemoradiation treatment involving lung tissue or thorax prior to T cell infusion (to avoid confounding pneumonitis)
  • ELIGIBILITY FOR TREATMENT ON ARM 1: Patients treated with prior immunotherapy including and not limited to vaccines, cytokines, T cell stimulating agents, cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitors and programmed death (PD)-1 check point inhibitors are allowed on therapy provided they did not have any severe grade 4 toxicities due to prior therapy and any toxicities due to prior therapy should have resolved, if resolvable to less than or equal to grade 1
  • ELIGIBILITY FOR TREATMENT ON ARM 2: Patients must express HLA-A*0201
  • ELIGIBILITY FOR TREATMENT ON ARM 2: Evidence of WT1 tumor expression
  • ELIGIBILITY FOR TREATMENT ON ARM 2: Ninety days must have passed since the last definitive doses of radiation or chemoradiation treatment prior to T cell infusion (to avoid confounding pneumonitis)

Exclusion Criteria:

  • EXCLUSION FOR ENROLLMENT/SCREENING (ARMS 1 AND 2)
  • Eastern Cooperative Oncology Group (ECOG) performance status >= 2
  • Active autoimmune disease (e.g., systemic lupus erythematosus, vasculitis, infiltrating lung disease, inflammatory bowel disease) in which possible progression during treatment would be considered unacceptable by the investigators
  • Any condition or organ toxicity deemed by the principal investigator (PI) or the attending physician to place the patient at unacceptable risk for treatment on the protocol
  • Men or women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative urine pregnancy test within 2 weeks prior to first infusion
  • Pregnant women and nursing mothers will be eligible for screening only to test HLA type by saliva or buccal swab and WT1 expression from previously collected tissue sample
  • Clinically significant and ongoing immune suppression including, but not limited to, systemic immunosuppressive agents such as cyclosporine or corticosteroids, chronic lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV) infection, or solid organ transplantation
  • EXCLUSION FOR TREATMENT (ARMS 1 AND 2)
  • Exclusions for the leukapheresis procedure (this can be performed at a later time of symptoms resolve):

    • Infection, with or without antibiotic treatment
    • Recent hepatitis exposure (hepatitis B or C antigenemia)
    • Pregnancy or nursing
    • HIV or human T-lymphotropic virus (HTLV) infection
    • Positive result on standard test for syphilis (STS)
  • Unable to generate antigen-specific WT1-specific CD8+ T cells for infusions; however, the patient will have the option to receive WT1-specific T-cells if a lower than planned number of cells is available
  • Documented infections or known oral temperature > 38.2 degrees Celsius (C) fewer than 72 hours prior to receiving study treatment or systemic infection requiring chronic maintenance; the start of treatment may be delayed
  • Systemic steroids should be stopped 2 weeks before the start of treatment; topical and inhaled steroids are allowed
  • Untreated central nervous system (CNS) metastasis that are > 1 cm or symptomatic are not allowed; (patients with CNS metastases > 1 cm or symptomatic that have been treated and demonstrated to be radiologically and clinically stable for at least 4 weeks are allowed)
  • White blood cells (WBC) < 2,000/ul
  • Hemoglobin (Hb) < 8 g/dL
  • Absolute neutrophil count (ANC) < 1,000/ul
  • Platelets < 50,000/ul
  • New York Heart Association functional class III-IV heart failure, symptomatic pericardial effusion, stable or unstable angina, symptoms of coronary artery disease (CAD), congestive heart failure, clinically significant hypotension or history of an ejection fraction of =< 30% (echocardiogram or multi-gated acquisition scan [MUGA])
  • Clinically significant pulmonary dysfunction, as determined by medical history and physical exam; patients so identified will undergo pulmonary functions testing and those with forced expiratory volume in 1 second (FEV1) < 2.0 L or diffusion capacity of the lungs for carbon monoxide (DLCO) (corrected for Hb) < 50% will be excluded
  • Creatinine > 1.5 x the upper limit of normal
  • Aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 5 x upper limits of normal (ULN)
  • Bilirubin > 3 x ULN that cannot be attributed to NSCLC metastasis
  • HIV or HTLV infection
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02408016


Locations
United States, Washington
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Sylvia Lee Fred Hutch/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT02408016     History of Changes
Other Study ID Numbers: 2727.00
NCI-2015-00329 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2727
2727.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
First Submitted: March 31, 2015
First Posted: April 3, 2015
Last Update Posted: December 13, 2017
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Mesothelioma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Mesothelial
Cyclophosphamide
Aldesleukin
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents