Clinical Trials /

Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant

NCT03068819

Description:

Donor Lymphocyte Infusion (DLI) following salvage chemotherapy is the one of the most widely used treatment approaches in patients who relapse after allogeneic hematopoietic cell transplant (allo-HCT). However, the complete remission (CR) rates and long term survival remain very poor in these patients and, therefore, there is an unmet need to develop more effective treatment approaches in patients who relapse after allo-HCT. Based on the initial promising results with our ongoing cytokine-induced memory-like (CIML) natural killer (NK) cell trial, the investigators hypothesize that combining the CIML NK cells with DLI approach will significantly enhance the graft versus leukemia and therefore potentially provide potentially curative therapy for these patients with otherwise extremely poor prognosis. Combining CIML NK cells with the DLI platform will also potentially allow these adoptively transferred cells to persist for longer duration as they should not be rejected by donor T cells as the CIML NK cells are derived from the same donor. The use of CIML NK cells is unlikely to lead to excessive graft versus host disease (GVHD) as previous studies have not been associated with excessive GVHD rates.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant
  • Official Title: A Pilot Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant in Children and Young Adults

Clinical Trial IDs

  • ORG STUDY ID: 17-x035
  • NCT ID: NCT03068819

Conditions

  • Acute Myeloid Leukemia in Children

Purpose

Donor Lymphocyte Infusion (DLI) following salvage chemotherapy is the one of the most widely used treatment approaches in patients who relapse after allogeneic hematopoietic cell transplant (allo-HCT). However, the complete remission (CR) rates and long term survival remain very poor in these patients and, therefore, there is an unmet need to develop more effective treatment approaches in patients who relapse after allo-HCT. Based on the initial promising results with our ongoing cytokine-induced memory-like (CIML) natural killer (NK) cell trial, the investigators hypothesize that combining the CIML NK cells with DLI approach will significantly enhance the graft versus leukemia and therefore potentially provide potentially curative therapy for these patients with otherwise extremely poor prognosis. Combining CIML NK cells with the DLI platform will also potentially allow these adoptively transferred cells to persist for longer duration as they should not be rejected by donor T cells as the CIML NK cells are derived from the same donor. The use of CIML NK cells is unlikely to lead to excessive graft versus host disease (GVHD) as previous studies have not been associated with excessive GVHD rates.

Trial Arms

NameTypeDescriptionInterventions
CIML NK cell after T cell DLTExperimental-The recipient will receive standard of care salvage chemotherapy consisting of fludarabine, ara-C, and G-CSF (FLAG) to be started 2 to 4 weeks prior to the CIML NK cell infusion, with Day -1 the day of T cell DLI, and Day 0 denoting the CIML NK cell infusion day. The donor will undergo non-mobilized large volume (20L) leukapheresis on Day -2 or -1, anticipating processing for T cell DLI and NK cell isolation on Day -1.

    Eligibility Criteria

            Recipient Inclusion Criteria:
    
              -  Relapsed AML after HLA-matched related or unrelated allogeneic hematopoietic cell
                 transplant (per IWG definition of relapse)
    
                 -≥1 and ≤30 years of age
    
              -  Available original donor (same donor as used for the initial stem cell transplant)
                 that is willing and eligible for non-mobilized collection
    
              -  Patients with known central nervous system (CNS) involvement with AML are eligible
                 provided that they have been treated and cerebrospinal fluid (CSF) is clear for at
                 least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or
                 radiation) should continue as medically indicated during the study treatment.
    
              -  Karnofsky performance status > 60 %
    
              -  Adequate organ function as defined below:
    
                   -  Total bilirubin < 2 mg/dl
    
                   -  AST(SGOT)/ALT(SGPT) < 3.0 x IULN
    
                   -  Creatinine within normal institutional limits OR creatinine clearance > 60
                      mL/min/1.73 m2 by Cockcroft-Gault Formula
    
                   -  Oxygen saturation ≥90% on room air
    
              -  Not currently requiring systemic corticosteroid therapy (10 mg or less of prednisone
                 or equivalent doses of other systemic steroids are allowed) or any other immune
                 suppressive medications
    
              -  Women of childbearing potential must have a negative pregnancy test within 28 days
                 prior to study registration. Female and male patients (along with their female
                 partners) must agree to use two forms of acceptable contraception, including one
                 barrier method, during participation in the study including throughout the initial
                 evaluation period (100 days after CIML NK cell infusion).
    
              -  Ability to understand and willingness to sign an IRB approved written informed
                 consent document (or that of legally authorized representative, if applicable).
    
            Recipient Exclusion Criteria:
    
              -  Acute or chronic GvHD with ongoing active systemic treatment.
    
              -  Circulating blast count >30,000/uL by morphology or flow cytometry (cyto-reductive
                 therapies including leukapheresis or hydroxyurea are allowed).
    
              -  Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B, or Hepatitis C
                 infection.
    
              -  Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive
                 of acute ischemia or active conduction system abnormalities.
    
              -  New or progressive pulmonary infiltrates concerning for new or uncontrolled
                 infectious process.
    
              -  Known hypersensitivity to one or more of the study agents
    
              -  Received any investigational drugs within the 14 days prior to CIML NK cell infusion
                 date
    
              -  Pregnant and/or breastfeeding
    
            Donor Inclusion Criteria:
    
              -  At least 18 years of age
    
              -  Same donor as used for the allo-HCT
    
              -  In general good health, and medically able to tolerate leukapheresis
    
              -  Ability to understand and willingness to sign an IRB approved written informed
                 consent document
    
            Donor Exclusion Criteria:
    
              -  Active hepatitis, positive for HTLV, or HIV on donor viral screen
    
              -  Pregnant and/or breastfeeding
          
    Maximum Eligible Age:30 Years
    Minimum Eligible Age:1 Year
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Feasibility of regimen defined as the number of participants who are successfully infused with T cell DLT and CIML NK cells
    Time Frame:Completion of all patients through Day 0 (estimated to be 36 months)
    Safety Issue:
    Description:-Will be considered successful if doses above the minimum can be delivered in at least 9 of 12 patients. Target and minimum doses are: T cell DLI (5x106/kg with a minimum dose of 1x106/kg) and CIML NK cells (dose capped at 10x106/kg with a minimum dose of 0.5x106/kg).

    Secondary Outcome Measures

    Measure:Complete remission rate (CR/CRi)
    Time Frame:Day 30 (+/- 5 days)
    Safety Issue:
    Description:Complete remission (CR):Morphologically leukemia free state (i.e. bone marrow with <5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions Complete remission with incomplete blood count recover (CRi): All of the above criteria for CR must be met, except that absolute neutrophils <1000 /μL or platelets <100,000 /μL in the blood.
    Measure:Rate of leukemia-free survival (LFS)
    Time Frame:100 days post CIML NK cell infusion
    Safety Issue:
    Description:-LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up.
    Measure:Overall survival (OS)
    Time Frame:100 days post CIML NK cell infusion
    Safety Issue:
    Description:-OS is defined as the time from the date of Day 0 until death from any cause.
    Measure:Rate of leukemia-free survival (LFS)
    Time Frame:1 year post CIML NK cell infusion
    Safety Issue:
    Description:-LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up.
    Measure:Overall survival (OS)
    Time Frame:1 year post CIML NK cell infusion
    Safety Issue:
    Description:-OS is defined as the time from the date of Day 0 until death from any cause.
    Measure:Incidence and severity of acute GVHD rates
    Time Frame:Day 14 through 6 months
    Safety Issue:
    Description:-Incidence and severity of acute GVHD will be assessed based on the modified Glucksberg criteria and Seattle criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).
    Measure:Incidence and severity of chronic GVHD rates
    Time Frame:Day 100 through 12 months
    Safety Issue:
    Description:-Incidence and severity of chronic GVHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Washington University School of Medicine

    Last Updated

    March 2, 2017