Clinical Trials /

Laboratory-Treated (Central Memory/Naive) CD8+ T Cells in Treating Patients With Newly Diagnosed or Relapsed Acute Myeloid Leukemia

NCT02770820

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Laboratory-Treated (Central Memory/Naive) CD8+ T Cells in Treating Patients With Newly Diagnosed or Relapsed Acute Myeloid Leukemia
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 9296
  • SECONDARY ID: NCI-2016-00042
  • SECONDARY ID: 9296
  • SECONDARY ID: P01CA018029
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT02770820

Conditions

  • Acute Myeloid Leukemia
  • EBV-Positive Neoplastic Cells Present
  • HLA-A*0201 Positive Cells Present
  • Minimal Residual Disease

Interventions

DrugSynonymsArms
Aldesleukin125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2Treatment (autologous CD8 T cells)
Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn LymphocytesTreatment (autologous CD8 T cells)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (autologous CD8 T cells)ExperimentalBeginning 4 weeks after completion of last course of consolidation chemotherapy, patients receive autologous WT1-TCRc4 gene-transduced CD8+ TCM/TN lymphocytes IV over 1-4 hours on days 0 and 14. Beginning 6 hours after the second infusion of T cells, patients also receive aldesleukin SC 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 PI and the attending physician.

    Eligibility Criteria

            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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Duration of adoptively transferred TCRC4-transduced CD8+ memory T cells and naive T cells in blood and bone marrow
    Time Frame:Up to 12 months after the last infusion
    Safety Issue:
    Description:Memory T cells and naive T cells cell populations will be compared to determine respective persistence

    Secondary Outcome Measures

    Measure:Decrease in disease burden as detected by cytogenetics/fluorescence in situ hybridization or molecular testing
    Time Frame:Up to 15 years
    Safety Issue:
    Description:
    Measure:Decrease in the level of blasts in the blood or marrow (in patients with measurable disease by morphology and flow cytometry)
    Time Frame:Up to 15 years
    Safety Issue:
    Description:
    Measure:Disease-free survival
    Time Frame:Up to 15 years
    Safety Issue:
    Description:Kaplan-Meier estimates will be used to estimate disease free survival.
    Measure:Overall survival
    Time Frame:Up to 15 years
    Safety Issue:
    Description:Kaplan-Meier estimates will be used to estimate overall survival.
    Measure:Percent of minimal residual disease positivity for patients who were treated with minimal residual disease, defined as any detectable blast count
    Time Frame:At 6 months
    Safety Issue:
    Description:Corresponding confidence intervals will accompany each of these estimates.
    Measure:Probability of relapse
    Time Frame:Up to 15 years
    Safety Issue:
    Description:Will summarize the probability of relapse/progression using cumulative incidence estimates, where death without relapse/progression will be regarded as a competing risk.
    Measure:Relative frequencies at primary tumor sites of TCRC4-transduced CD8+ polyclonal memory T cells and naive T cells and Epstein-Barr virus-specific T cells compared to peripheral blood
    Time Frame:Up to 14 days after completion of aldesleukin
    Safety Issue:
    Description:Localization of transferred TCRC4 naive T cells and memory T cells to tumor sites will be evaluated in marrow samples obtained after infusions as well as in extra-medullary samples if available. To assess for the preferential localization of naive T cell/memory T cell, results will be compared to pre-treatment and concurrent peripheral blood mononuclear cell values and, where possible, to pre-infusion extra-medullary tumor sample values.

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Fred Hutchinson Cancer Research Center

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