Clinical Trials /

Cytokine-induced Memory-like NK Cells in Combination With Chemotherapy in Pediatric Patents With Refractory or Relapsed AML

NCT04354025

Description:

This phase 2 clinical trial investigates the effectiveness of cytokine-induced memory-like natural killer (CIML NK) cells in combination with FLAG chemotherapy as a treatment for refractory or relapsed AML. Previous studies in adults with AML sowed successful induction of remission and a previous phase 1 study demonstrated that CIML NK cells can be used safely in pediatric patients. This phase 2 study uses FLAG chemotherapy to lower leukemic burden and suppress the recipient's immune system to provide an optimal environment for CIML NK cell expansion and anti-leukemic activity.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cytokine-induced Memory-like NK Cells in Combination With Chemotherapy in Pediatric Patents With Refractory or Relapsed AML
  • Official Title: A Phase 2 Study of Cytokine-induced Memory-like NK Cells in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed AML

Clinical Trial IDs

  • ORG STUDY ID: 20-x130
  • NCT ID: NCT04354025

Conditions

  • Refractory Acute Myeloid Leukemia
  • Relapsed Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cytokine induced memory-like NK cellsCIML NK cellsRecipient: FLAG + CIML NK Cells + IL-2
FludarabineRecipient: FLAG + CIML NK Cells + IL-2
Ara-CCytarabineRecipient: FLAG + CIML NK Cells + IL-2
G-CSFFilgrastimRecipient: FLAG + CIML NK Cells + IL-2
Interleukin-2IL-2Recipient: FLAG + CIML NK Cells + IL-2

Purpose

This phase 2 clinical trial investigates the effectiveness of cytokine-induced memory-like natural killer (CIML NK) cells in combination with FLAG chemotherapy as a treatment for refractory or relapsed AML. Previous studies in adults with AML sowed successful induction of remission and a previous phase 1 study demonstrated that CIML NK cells can be used safely in pediatric patients. This phase 2 study uses FLAG chemotherapy to lower leukemic burden and suppress the recipient's immune system to provide an optimal environment for CIML NK cell expansion and anti-leukemic activity.

Trial Arms

NameTypeDescriptionInterventions
Recipient: FLAG + CIML NK Cells + IL-2Experimental-The recipient will begin a chemotherapy regimen of fludarabine, cytarabine and GCSF starting on Day -7. The haploidentical donor identified by HLA matching of the immediate family members will undergo non-mobilized large volume (20 L) leukapheresis on Day -1, and the NK cell product will be infused into the recipient on Day 0. CIML NK cells will be infused at maximum cell dose of 10 x 106/kg. Subcutaneous IL-2 will begin approximately 2-4 hours after infusion and will continue every other day through Day 12 for a total of 7 doses.
  • Cytokine induced memory-like NK cells
  • Fludarabine
  • Ara-C
  • G-CSF
  • Interleukin-2
Donor:Other-On Day -1 (one day before the planned NK cell infusion), peripheral blood mononuclear cells will be collected by a single standard apheresis over 4-5 hours (with a target volume of at least 20 L) from the identified haploidentical donor. The apheresis procedure will be done as per standard institutional procedures (which may include placement of a central line if necessary). If the goal minimum NK cell dose will not be met based on the initial assessment of the leukapheresis product, a second collection/procedure may be performed.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Refractory AML without complete remission (CR) after induction therapy (primary
                 induction failure) or relapsed AML after obtaining a CR. Disease defined by one of the
                 following:
    
                 *≥ 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary
                 disease
    
                 *absolute blast count greater than 1,000 per microliter in the peripheral blood with
                 or without extramedullary disease.
    
              -  Age requirement for pediatric cohort: 1-21 years of age.
    
              -  Available HLA-haploidentical donor that meets the following criteria:
    
                   -  Related donor (parent, sibling, offspring, or offspring of sibling)
    
                   -  At least 18 years of age
    
                   -  HLA-haploidentical donor/recipient match by at least Class I serologic typing at
                      the A&B locus.
    
                   -  In general, good health and medically able to tolerate leukapheresis required for
                      harvesting the NK cells for this study.
    
                   -  Negative for hepatitis, HTLV, and HIV on donor viral screen
    
                   -  Not pregnant
    
                   -  Voluntary written consent to participate in this study
    
              -  Patients with known CNS involvement with AML are eligible provided that they have been
                 treated and 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/Lansky performance status > 50 %
    
              -  Adequate organ function as defined below:
    
                   -  Total bilirubin < 2 mg/dL
    
                   -  AST(SGOT)/ALT(SGPT) < 3.0 x upper limit of normal (ULN)
    
                   -  Creatinine within normal institutional limits OR creatinine clearance > 50
                      mL/min/1.73 m2 by Schwartz formula or GFR (See Appendix B)
    
                   -  Oxygen saturation ≥90% on room air
    
                   -  Ejection fraction ≥35%
    
              -  Able to be off corticosteroids and any other immune suppressive medications beginning
                 on Day -3 and continuing until 30 days after the infusion of the CIML NK cells.
                 However, use of low-level corticosteroids is permitted if deemed medically necessary.
                 Low-level corticosteroid use is defined as 10mg or less of prednisone (or equivalent
                 for other steroids) per day.
    
              -  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 and throughout the DLT evaluation
                 period.
    
              -  Ability to understand and willingness to sign an IRB approved written informed consent
                 document (or that of legally authorized representative, if applicable).
    
            Exclusion Criteria:
    
              -  Relapsed after allogeneic transplantation.
    
              -  Isolated extramedullary relapse
    
              -  Circulating blast count >30,000/µL by morphology or flow cytometry (cytoreductive
                 therapies including leukapheresis or hydroxyurea are allowed).
    
              -  Patients with any of the following diagnoses:
    
                   -  Down's syndrome
    
                   -  Acute promyelocytic leukemia (APL)
    
                   -  Juvenile myelomonocytic leukemia (JMML)
    
              -  Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection.
    
              -  Known hypersensitivity to one or more of the study agents.
    
              -  Received any investigational drugs within the 14 days prior to the first dose of
                 fludarabine.
    
              -  Pregnant
          
    Maximum Eligible Age:21 Years
    Minimum Eligible Age:1 Year
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Response rate (complete remission (CR) plus complete remission with incomplete blood count recovery (CRi))
    Time Frame:Day 28
    Safety Issue:
    Description:Complete remission (CR) requires all of the following: Bone marrow: Morphologically leukemia free state (≤ 5% myeloblasts) with normal maturation of all cell lines. Persistent dysplasia may be noted Peripheral blood: Platelets ≥ 100,000/uL Neutrophils ≥ 1000/uL Complete remission with incomplete blood count recovery (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.

    Secondary Outcome Measures

    Measure:Disease-free survival (DFS)
    Time Frame:Up to 2 years
    Safety Issue:
    Description:-DFS is defined as the time from the day CR or CRi is documented until disease progression or death.
    Measure:Overall survival (OS)
    Time Frame:Up to 2 years
    Safety Issue:
    Description:-OS is defined from the date of first dose of fludarabine on this study until death.
    Measure:Percentage of patients who achieve minimum residual disease (MRD)-negative status
    Time Frame:Day 28
    Safety Issue:
    Description:
    Measure:Safety of regimen as measured by number of adverse events
    Time Frame:From Day 0 to Day 100
    Safety Issue:
    Description:-Adverse events will be collected from Day 0 to Day 35; however, bone marrow suppression (ANC ≤ 500/mcL) and adverse events of GVHD involving the liver, skin, or gastrointestinal tract will be recorded to Day 100
    Measure:Duration of remission
    Time Frame:Up to 2 years
    Safety Issue:
    Description:
    Measure:Time to progression
    Time Frame:Up to 2 years
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Washington University School of Medicine

    Last Updated

    April 16, 2020