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Phase I/II Study of Autologous (Central Memory/Naïve) CD8+ T Cells That Have Been Transduced to Express a WT1-Specific T Cell Receptor for Treatment of AML (NCT02770820)

National Cancer Institute (NCI)
This phase I/II trial studies the side effects of laboratory-treated (central memory/naive) cluster of differentiation 8+ T cells (autologous Wilms tumor [WT]1-T cell receptor [TCRc]4 gene-transduced CD8-positive central memory T-cells [TCM]/naive T cells [TN] lymphocytes) and how well it works in treating patients with acute myeloid leukemia that is newly diagnosed or has come back. Genetically modified therapies, such as autologous WT1-TCRc4 gene-transduced CD8-positive TCM/TN lymphocytes, are taken from a patient's blood, modified in the laboratory so they specifically may kill cancer cells with a protein called WT1, and safely given back to the patient. The "genetically modified" T-cells have genes added in the laboratory to allow them to recognize leukemia cells that express WT1 and kill them.
  • Biological: Aldesleukin
    Given SC
    • 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
      Ages eligible for Study
      all
      Genders eligible for Study
      All
      Accepts Healthy Volunteers
      No
      Inclusion Criteria:
      • Newly diagnosed (non-M3) AML patients
      • Patients must be >= 15 kg
      • Patients or parents/legal guardian must be able to give informed consent
      • Patients must be able to provide blood and marrow samples and to undergo the procedures required for this protocol
      • Elevated expression above of WT1 in pre-treatment bone marrow or peripheral blood by either of two methods:
      • Increased expression of WT1 determined if the number of copies of WT1 divided by the number of copies of ABL x 10^4 is > 250 for bone marrow, or > 50 for peripheral blood;
      • Demonstration of WT1 overexpression will be determined by immunohistochemical staining (IHC) in blasts as compared to adjacent normal myeloid and erythroid precursors, as determined by a Fred Hutchinson/Seattle Cancer Care Alliance pathologist ELIGIBILITY FOR APHERESIS/BLOOD COLLECTION:
      • Human leukocyte antigen (HLA)-A*02:01 expression
      • Elevated expression above of WT1 in bone marrow or peripheral blood: increased expression of WT1 will be determined if the number of copies of WT1 divided by the number of copies of ABL x 10^4 is > 250 for bone marrow, or > 50 for peripheral blood; or when available, demonstration of WT1 overexpression will be determined by immunohistochemical staining (IHC) in blasts as compared to adjacent normal myeloid and erythroid precursors, as determined by Fred Hutchinson/Seattle Cancer Care Alliance hematopathology ELIGIBILITY FOR TREATMENT WITH TCRC4-TRANSDUCED CD8+ CELLS
      • Response to therapy and completion of at least one cycle of consolidation therapy, and with disease status meeting one of the following criterion at the time of post-induction disease restaging:
      • Minimal residual disease, as defined by detectable disease by flow cytometry but with marrow that is at least 10% cellular with < 5% blasts on morphologic review
      • Complete remission with incomplete blood count recovery (CRi)/complete remission with incomplete platelet recovery (CRp), as defined by absence of detectable disease by flow cytometry, and marrow that is at least 10% cellular with < 5% blasts on morphologic review, but with neutrophil count < 1000/ul (CRi) and/or platelet count < 100,000/ul (CRp); in pediatric patients, a platelet threshold of < 80,000/ ul will be used, as per consensus pediatric response criteria
      • Recovery from induction therapy (absolute neutrophil count [ANC] > 200/ul, platelet count > 20,000/ul)
      • Continued CR, CRp, or CRi within 3 weeks of first dose WT-1 specific CD8+ T cells
      • HLA-A*02:01 expression
      • No plan for allogeneic stem cell transplantation within 3 months
      • Elevated expression above baseline of WT1 in bone marrow or peripheral blood
      • Additionally, patients treated in stage 1, cohort #3 must be EBV seropositive, given the inclusion of T cells derived from an EBV-specific subset in this group ELIGIBILITY FOR OBSERVATION ARM
      • Response to therapy and completion of at least one cycle of consolidation therapy, and with disease status meeting one of the following criterion
      • Minimal residual disease, as defined by detectable disease by flow cytometry but with marrow that is at least 10% cellular with < 5% blasts on morphologic review
      • CRi/CRp, as defined by absence of detectable disease by flow cytometry, and marrow that is at least 10% cellular with < 5% blasts on morphologic review, but with neutrophil count < 1000/ul and/or platelet count <100,000/ul. As previously stated, a platelet threshold of < 80,000/ul will be used to define CRp in pediatric patients, as per consensus pediatric response criteria
      • Elevated expression above of WT1 in bone marrow or peripheral blood; (increased expression of WT1 will be determined if the number of copies of WT1 divided by the number of copies of ABL x 10^4 is > 250 for bone marrow, or > 50 for peripheral blood)
      Exclusion Criteria:
      • 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
      • Previous allogeneic hematopoietic cell transplant (HCT)
      • 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
      • Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling or unable to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to enrollment and initiation of treatment
      • Clinically significant and ongoing immune suppression including, but not limited to: systemic immunosuppressive agents such as cyclosporine or corticosteroids (at an equivalent dose of 0.5 mg prednisone/kg per day, or higher), chronic lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV) infection
      • Acute promyelocytic leukemia (M3 leukemia, per French-American-British classification) EXCLUSION FOR TREATMENT WITH TCRC4-TRANSDUCED CD8+ CELLS
      • Lack of HLA-A*02:01 expression
      • Unable to generate antigen-specific WT1-specific CD8+ T cells for infusions; however, if a lower than planned number of cells is available, the patient will have the option to receive the generated WT1-specific T cells
      • The expression of WT1 in the patient's peripheral blood and/or bone marrow will be determined; if WT1 expression in the patient specimen is within the normal physiologic range or is not detected, the patient will be ineligible for treatment with WT1-specific T cells (and will not be included in the observation cohort)
      • Documented infections or oral temperature > 38.2 degree Celsius (C) fewer than 72 hours prior to receiving study treatment or systemic infection requiring chronic maintenance therapy; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule
      • Systemic steroids should be stopped 2 weeks before the start of treatment; topical and inhaled steroids are allowed
      • Symptomatic and refractory central nervous system (CNS) leukemia
      • Absolute neutrophil count (ANC) < 200/ul prior to treatment
      • Platelets < 20,000/ul prior to treatment
      • Ongoing >= grade 3 cardiac, pulmonary, renal, gastrointestinal or hepatic toxicities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 toxicity criteria
      • Karnofsky performance status score (age >= 16 years) or Lansky play score (age < 16 years) =< 40%
      • Medical or psychological conditions that, according to the PI, would make the patient unsuitable candidate for cell therapy
      • Pregnancy or breast-feeding; women of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test result within 14 days before the first dose of WT1-specific T cell infusion; woman of non-childbearing potential will be defined as being postmenopausal greater than one year or who have had a bilateral tubal ligation or hysterectomy; all recipients of WT1-specific T cells will be counseled to use effective birth control during participation in this study and for 12 months after the last T cell infusion
      • Treatment with alemtuzumab or other T cell-depleting antibodies within 6 months of T cell therapy
      PRIMARY OBJECTIVES:

      I. Determine the safety/potential toxicities associated with treating high-risk acute myeloid leukemia (AML) patients with autologous CD8+ T cells (polyclonal Tn and Tcm cells; Epstein-Barr virus-specific T cells [Tebv cells]) that have been genetically-modified to express a high affinity WT1-specific TCR (TCRC4).

      II. Determine the feasibility of reproducibly treating high-risk AML patients with autologous CD8+ T cells (polyclonal TN and TCM cells; Tebv cells) that have been genetically-modified to express a high affinity WT1-specific TCR (TCRC4).

      III. Determine and compare the in vivo persistence in blood and at the primary tumor site (e.g. bone marrow, chloroma) of transferred autologous CD8+ T cells (polyclonal TN and TCM cells; TEBV cells) that have been genetically-modified to express a high affinity WT1-specific TCR (TCRC4).

      SECONDARY OBJECTIVES:

      I. Determine whether adoptively transferred autologous TCRC4-transduced CD8+ cells have anti-tumor activity in patients with acute myeloid leukemia.

      II. In patients with measurable minimal residual disease (MRD) at the time of infusion of TCRC4-transduced CD8+ cells, changes in leukemic tumor burden will be measured by morphology, flow cytometry, cytogenetics/fluorescence in situ hybridization (FISH) and/or molecular testing at baseline and after infusion of T cells.

      III. In all patients (those with or without measurable tumor burden prior to T cell transfer, including patients who convert to MRD-negative status during consolidation), the probability of relapse, disease-free survival and overall survival of patients receiving TCRC4-transduced CD8+ cells will be compared with patients in the observation arm.

      IV. Determine and compare the migration to the primary tumor site of subsets of the adoptively transferred autologous TCRC4-transduced CD8+ T cells (polyclonal TN and TCM cells; TEBV cells).

      V. Determine and compare the in vivo functional capacity of transferred autologous TCRC4-transduced CD8+ TCM, TN and TEBV CD8+ cells.

      OUTLINE:

      Beginning 4 weeks after completion of last course of consolidation chemotherapy, patients receive autologous WT1-TCRc4 gene-transduced CD8+ TCM/TN lymphocytes intravenously (IV) over 1-4 hours on days 0 and 14. Beginning 6 hours after the second infusion of T cells, patients also receive aldesleukin subcutaneously (SC) twice daily (BID) for 14 days in the absence of disease progression or unacceptable toxicity. Patients who have clinically benefitted from T cell therapy may receive additional infusions of T cells and aldesleukin at the discretion of the principal investigator (PI) and the attending physician.

      After completion of study treatment, patients are followed up weekly for 4 weeks, at 2, 3, 6, and 12 months, and then annually for 14 years thereafter.

      1 locations

      United States (1)
      • Fred Hutch/University of Washington Cancer Consortium
        recruiting
        Seattle, Washington, United States, 98109
      Status:
      recruiting
      Type:
      Interventional
      Phase:
      Ⅰ, Ⅱ
      Start:
      14 February, 2018
      Updated:
      28 January, 2018
      Participants:
      35
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