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
  • SECONDARY ID: RG9216011
  • NCT ID: NCT02770820

Conditions

  • Acute Myeloid Leukemia
  • EBV-Positive Neoplastic Cells Present
  • HLA-A*0201 Positive Cells Present
  • Blasts Under 5 Percent of Bone Marrow Nucleated Cells
  • Elevated WT1

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).

      EXPLORATORY OBJECTIVES:

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

      Ia. 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.

      Ib. 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.

      II. 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).

      III. Determine and compare the in vivo functional capacity of transferred polyclonal
      autologous TCRC4-transduced CD8+ TCM, TN cells 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 day 0 and again after a minimum of 3 weeks. 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 day 0 and again after a minimum of 3 weeks. 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.
  • Aldesleukin
  • Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with (non-M3) acute myeloid leukemia (AML)

          -  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 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

          -  Demonstration of disease response to induction chemotherapy, in that patients must
             have achieve a morphologic remission (marrow that is at least 10% cellular with < 5%
             blasts on morphologic review) after 1-2 induction cycles, regardless of minimal
             residual disease or incomplete hematologic recovery (CRi)/incomplete platelet recovery
             (CRp) status

          -  Determination of "high-risk" disease; subjects must meet one of the determinants of
             "high-risk disease", in terms of being at very high risk for relapse without
             allogeneic stem cell transplant, as per one of the follow criteria:

               -  A designation of "adverse" risk disease at the time of diagnosis, as defined by
                  cytogenetic and molecular abnormalities specifically outlined in the 2017
                  European LeukemiaNet (ELN) guidelines for diagnosis and management of AML; these
                  patients will meet "high-risk" designation, regardless of minimal residual
                  disease or CRi/CRp status

               -  Relapsed leukemia; patients with cytogenetic or molecular classification other
                  that adverse risk by ELN who go on to demonstrate disease relapse after a minimum
                  duration of remission of 6 months, but who then attain a second complete
                  remission with repeat induction chemotherapy; these patients will meet
                  "high-risk" designation, regardless of minimal residual disease or CRi/CRp status

               -  Minimal residual disease, as defined by having detectable disease by one of the
                  following criteria, but otherwise being in morphologic remission

                    -  MRD by flow cytometry at any time after induction chemotherapy or during
                       consolidation chemotherapy, when patients are otherwise classified as being
                       in morphologic remission, and as defined by any abnormal myeloid blasts
                       identified by flow cytometric analysis

                    -  Cytogenetic MRD, as defined by a disease-specific abnormal karyotype at any
                       point in patients who are otherwise in morphologic remission

                    -  Molecular minimal residual disease (MRD) with one of the following markers,
                       as specified below, in patients who are otherwise in morphologic remission:

                         -  A normalized copy number (NCN) of > 0.001 for CBFB/MYHI1 or a
                            normalized copy number (NCN) of > 0.050 for AMLI/ETO (RUNXI/RUNX1T1)
                            after at least 4 cycles of consolidation chemotherapy

                         -  A < 2 log reduction in either CBFB/MYH11 or AMLI/ETO (RUNX1/RUNX1T1) in
                            the bone marrow at the time of post-induction disease restaging
                            (immediately after 1-2 cycles of induction therapy)

                    -  CRi/CRp, as defined by neutrophil count < 1000/ul (CRi) and/or platelet
                       count < 100,000/ul (CRp), but otherwise being in morphologic remission; in
                       pediatric patients, a platelet threshold of < 80,000/ ul will be used, as
                       per consensus pediatric response criteria

          -  Human leukocyte antigen (HLA)-A*02:01 expression must be present for patient to be on
             treatment arm, HLA-A*02:01 expression absent in patients designated to observation arm

        ELIGIBILITY FOR APHERESIS/BLOOD COLLECTION:

        • HLA-A*02:01 expression

        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 aforementioned "high-risk" criteria at the time
             of post-induction disease restaging as already outlined above

          -  Hematologic recovery from induction and other post-remission therapy (absolute
             neutrophil count [ANC] > 200/ul, platelet count > 20,000/ul) at the time of the study
             intervention

          -  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 Epstein-Barr virus (EBV)
             seropositive, given the inclusion of T cells derived from an EBV-specific subset in
             this group

          -  Continued morphologic remission (< 5% blasts in the marrow, no circulating blasts or
             known extramedullary relapse) within 6 weeks of receiving the study intervention
             (specified as T cell infusion for cohort 1, or the start of lymphodepleting
             chemotherapy for cohorts 2 and 3)

          -  ELIGIBILITY FOR OBSERVATION ARM

          -  The patient meets all of the eligibility criteria for enrollment, but lacks expression
             of HLA-A*0201 as is needed to be enrolled on the treatment arm and for apheresis

        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 (untreated
             or detectable viral load within 3 months of enrollment)

          -  Acute promyelocytic leukemia (M3 leukemia, per French-American-British classification)

        EXCLUSION FOR TREATMENT WITH TCRC4-TRANSDUCED CD8+ CELLS

          -  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

          -  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

          -  If a patient meets other treatment eligibility but otherwise demonstrates delayed or
             poor recovery of peripheral blood counts to the above neutrophil and/or platelet
             thresholds, then treatment with the T cell intervention will be allowed if:

               -  Neutrophil and/or platelet counts remain below the thresholds after a period of
                  at least 6 weeks from last systemic chemotherapy; OR neutrophil and/or platelet
                  counts remain below the thresholds in the setting of a maintenance therapy, such
                  as midostaurin; and

               -  The patient has detectable leukemia (e.g. flow cytometry positive or MRD by FISH
                  or molecular testing); and

               -  The P.l. or treating physician documents that the likely cause of cytopenias is
                  underlying disease as opposed to another cause (e.g. medication)

          -  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 infusions; 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

          -  Documented new infection within 24 hours of T cell infusion, or concern for new
             infection as suggested by an oral temperature > 38.2 degrees Celsius (C) within 24
             hours of T cell infusion

               -  ln patients who have T cells delayed because of development of fever (oral
                  temperature > 38.2 degrees C) and who subsequently become afebrile (38.2 degrees
                  C or less) for 24 hours without a documented infection, T cells may be
                  administered

               -  ln patients with a documented new infection within 24 hours of planned T cell
                  infusion, they may go on to receive T cells after administration of directed
                  antibiotic therapy and if they subsequently remain afebrile (38.2 degrees C or
                  less) for at least 24 hours, and if it is deemed clinically appropriate by the Pl

               -  Pre-existing infections requiring chronic maintenance therapy (e.g. chronic
                  hepatitis B virus [HBV] or treated bacterial infections) are not an exclusion for
                  T cell infusion as long as patients are on appropriate antimicrobial therapy for
                  at least 1 month (e.g. for chronic hepatitis B or C viral infection) and who
                  remain afebrile and without symptomatic evidence for uncontrolled chronic
                  infection within 24 hours of T cell infusion; patients should also have a
                  negative HIV test by viral load within 3 months of treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evidence and nature of toxicities
Time Frame:Up to 12 months after the last infusion
Safety Issue:
Description:Will be measured according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Secondary Outcome Measures

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: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: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: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: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.
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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

June 30, 2020