Clinical Trials /

Mismatched Donor Cells to Treat Acute Myeloid Leukemia

NCT01793025

Description:

The purpose of this study is to assess the safety and efficacy of infusing immune cells from a donor as treatment for patients with acute myeloid leukemia that is resistant to chemotherapy or who have experienced relapse. Unlike standard bone marrow or stem cell transplantation which uses donors who are well 'matched' to the patient, this study uses donors whose immune cells are not compatible with the patient. With standard stem cell or bone marrow transplantation, the well-matched immune cells will attack the leukemia but they also attack the patient's organs (a situation called graft-versus-host disease, which can persist in the long term). Our hypothesis is that the mismatched donor cells will fight the leukemia but will then be eliminated from the patient's body, so long-term side effects like graft-versus-host disease should not occur.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Mismatched Donor Cells to Treat Acute Myeloid Leukemia
  • Official Title: Adoptive Transfer of Alloreactive Cells to Treat Patients With Poor-Prognosis Acute Myeloid Leukemia-01

Clinical Trial IDs

  • ORG STUDY ID: ATAC-AML-01
  • NCT ID: NCT01793025

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
ATAC TherapyUnselected Peripheral Blood Mononuclear CellsATAC Therapy

Purpose

The purpose of this study is to assess the safety and efficacy of infusing immune cells from a donor as treatment for patients with acute myeloid leukemia that is resistant to chemotherapy or who have experienced relapse. Unlike standard bone marrow or stem cell transplantation which uses donors who are well 'matched' to the patient, this study uses donors whose immune cells are not compatible with the patient. With standard stem cell or bone marrow transplantation, the well-matched immune cells will attack the leukemia but they also attack the patient's organs (a situation called graft-versus-host disease, which can persist in the long term). Our hypothesis is that the mismatched donor cells will fight the leukemia but will then be eliminated from the patient's body, so long-term side effects like graft-versus-host disease should not occur.

Detailed Description

      The ATAC cell therapy product contains unselected, non-mobilized peripheral blood mononuclear
      cells from related donors who are mismatched to the recipients at 3 or more (out of 6) HLA
      loci. Cohorts of 3 patients will be treated at each of four pre-specified dose levels (T
      cells per kg recipient weight). One ATAC infusion is administered 24-48 hours following
      re-induction chemotherapy (for relapsed or primary refractory AML patients not in remission).
      In situations where ATAC infusion is not available immediately following re-induction
      chemotherapy and patients nonetheless achieve complete remission, one ATAC infusion is given
      24-48 hours after consolidation chemotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
ATAC TherapyExperimental

    Eligibility Criteria

            Recipient Inclusion Criteria:
    
              -  Age ≥ 18 years (no upper age limit, but physician discretion is advised)
    
              -  AML that is refractory to 2 courses of induction therapy (that together constitute the
                 'first-line' therapy) or that has relapsed after a period of morphologic complete
                 remission or morphologic remission with incomplete blood count recovery (CRi)
    
              -  Candidacy for intense induction chemotherapy (ECOG 0-2, adequate renal, liver and
                 cardiac function, absence of uncontrolled infections)
    
              -  Availability of parents, siblings or children who are HLA haploidentical (and not
                 homozygous for the shared haplotype), who are deemed suitable donors after medical
                 evaluation, and who complete peripheral blood mononuclear cell collection
    
              -  No history of autologous or allogeneic stem cell transplant, purine analog
                 chemotherapy or cyclophosphamide, or total body irradiation
    
              -  Ability to comprehend the investigational nature of the study and provide informed
                 consent
    
            Recipient Exclusion Criteria:
    
              -  Acute promyelocytic leukemia (including those with non-classical rearrangements of
                 RARα)
    
              -  History of severe myelodysplastic syndrome clearly preceding the diagnosis of AML
                 (i.e., red cell transfusion dependence or erythropoietin dependence over a 4-month
                 period, or in the absence of a clear cause, any of the following: hemoglobin
                 consistently below 9 g/dL or platelets below 50 x 10^9/L or ANC below 1000/uL on 2 or
                 more occasions 2 weeks apart, or use of G-CSF to maintain the ANC threshold in the
                 absence of infection, in the 3 months preceding the diagnosis of AML). Exception: If
                 ATAC therapy is being considered as a bridge to stem cell transplantation in patients
                 with an available standard transplant donor (familial, unrelated, or cord blood), this
                 exclusion criterion does not apply.
    
              -  Grade 2-3/3 fibrosis in the diagnostic bone marrow biopsy
    
              -  DLCO < 40% predicted
    
              -  Left ventricular ejection fraction < 40% (evaluated by ECHO or MUGA)
    
              -  AST/SGOT > 2.5 x ULN
    
              -  Bilirubin > 1.5 x ULN
    
              -  Creatinine > 1.5 x ULN
    
              -  Creatinine clearance < 50 mL/min
    
              -  HIV positive
    
              -  Major anticipated illness or organ failure incompatible with survival from
                 chemotherapy
    
              -  Concurrent second primary cancer or a prior malignancy that required cytotoxic
                 treatment within the past 12 months, other than cervical carcinoma in-situ or prostate
                 cancer in-situ
    
              -  Severe psychiatric illness or mental deficiency sufficiently severe as to make
                 compliance with the treatment unlikely and informed consent impossible
    
              -  Any congenital or acquired immunodeficiency that would possibly permit permanent
                 engraftment of donor cells
    
              -  Receiving systemic steroid therapy or systemic immunosuppression such as cyclosporine
                 or TNF-inhibitors
    
              -  Prior or concurrent receipt of any marketed or investigational agent deemed on an ad
                 hoc basis to cause immunomodulation, pose a threat of permanent engraftment or
                 increase the risk of GVHD.
    
            Donor inclusion criteria:
    
              -  Mismatched family donor (incompatibility at 3 loci HLA-A, B and DR of the unshared
                 haplotype, or higher-order incompatibility)
    
              -  Age ≥ 16 and ≤ 80 years
    
              -  Fit to undergo apheresis (normal blood counts, normotensive and no history of stroke).
    
              -  Donor has been tested negative for HIV-1, HIV-2, hepatitis B virus (HBV, surface and
                 core antigen), hepatitis C virus, human T-lymphotropic virus types I/II, and Treponema
                 pallidum (syphilis).
    
              -  ECOG performance status of 2 or less.
    
              -  Adequate veins for leukapheresis or agree to placement of a temporary central venous
                 catheter.
    
              -  Donor must provide written informed consent.
    
              -  Where multiple equally-suitable donors are available, sex mismatched donors will be
                 preferred.
    
            Donor exclusion criteria:
    
              -  Medically uncontrolled coronary heart disease
    
              -  Myocardial infarction within the last 3 months
    
              -  History of seizure
    
              -  History of stroke
    
              -  History of malignancy (except basal cell or squamous carcinoma of the skin, or
                 positive PAP smear and subsequent negative follow-up)
    
              -  Presence of a transmissible disease (such as HIV seropositivity)
    
              -  Presence of a major illness or a suspected systemic dysfunction
    
              -  Presence of an an active inflammatory or autoimmune disorder
    
              -  Female donors who are pregnant or nursing
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Safety
    Time Frame:60 days (up to 2 years)
    Safety Issue:
    Description:Maximum tolerated cell dose: Dose at which < 33% of patients experienced dose-limiting toxicity. If no DLT occurs, then dose titration will stop at a pre-specified number of T cells/kg. Four dose-level cohorts are planned.

    Secondary Outcome Measures

    Measure:Treatment-related mortality
    Time Frame:Continuous up to 2 years
    Safety Issue:
    Description:
    Measure:Non-relapse mortality
    Time Frame:Continuous up to 2 years
    Safety Issue:
    Description:
    Measure:Incidence of graft-versus-host disease
    Time Frame:Continuous up to 2 years
    Safety Issue:
    Description:
    Measure:Duration of cytopenias
    Time Frame:Monitored continuously from ATAC infusion until peripheral blood count recovery or maximum 2 years (whichever is earlier)
    Safety Issue:
    Description:
    Measure:Overall survival
    Time Frame:Continuous up to 2 years
    Safety Issue:
    Description:
    Measure:Complete and incomplete remissions (CR, CRi)
    Time Frame:Day 60 post cell infusion
    Safety Issue:
    Description:
    Measure:Relapse-free survival
    Time Frame:Continuous up to 2 years
    Safety Issue:
    Description:

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Maisonneuve-Rosemont Hospital

    Trial Keywords

    • leukemia
    • myeloid
    • acute
    • acute myeloid leukemia
    • allogeneic
    • transient chimerism
    • cell therapy
    • immunotherapy

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