Clinical Trials /

Cytokine-induced Memory-like NK Cells in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

NCT01898793

Description:

This phase I/2 trial studies the side effects and best dose of activated natural killer cells in treating patients with relapsed or refractory acute myeloid leukemia and myeloid dysplastic syndromes. Giving chemotherapy before a donor natural killer cell infusion helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's natural killer cells. Modified natural killer cells may help the body build an immune response to kill cancer cells. Aldesleukin (interleukin-2) may stimulate the white blood cells (including natural killer cells) to kill leukemia cells. In the phase II and pediatric portion of the study, the investigators intend to use maximal tolerated or tested (MT/TD) CIML NK cell dose as determined from the phase I part of this study. The phase II portion of the study also replaces IL-2 with ALT-803. The rationale for this change is to support the donor derived NK cells in vivo after adoptive transfer.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cytokine-induced Memory-like NK Cells in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
  • Official Title: A Phase 1/2 Study of Cytokine-Induced Memory-Like NK Cells in Patients With AML or MDS

Clinical Trial IDs

  • ORG STUDY ID: 201401085
  • SECONDARY ID: 5F32CA200253-02
  • NCT ID: NCT01898793

Conditions

  • Leukemia, Myeloid, Acute

Interventions

DrugSynonymsArms
Fludarabine2-F-ara-AMP, 75607-67-9, 9H-purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl), Beneflur, Fludara, fludarabine-5'-monophosphateLead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg
CyclophosphamideCytoxan®, CPMLead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg
Cytokine-induced killer cellsCIK cellsLead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg
IL-2Proleukin, recombinant human interleukin-2, recombinant interleukin-2, Ro-236019, T-cell growth factor, TCGF, TCGF,, interleukin, AldesleukinPediatric Cohort: Maximum NK cell/number kg
ALT-803Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg

Purpose

This phase I/2 trial studies the side effects and best dose of activated natural killer cells in treating patients with relapsed or refractory acute myeloid leukemia and myeloid dysplastic syndromes. Giving chemotherapy before a donor natural killer cell infusion helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's natural killer cells. Modified natural killer cells may help the body build an immune response to kill cancer cells. Aldesleukin (interleukin-2) may stimulate the white blood cells (including natural killer cells) to kill leukemia cells. In the phase II and pediatric portion of the study, the investigators intend to use maximal tolerated or tested (MT/TD) CIML NK cell dose as determined from the phase I part of this study. The phase II portion of the study also replaces IL-2 with ALT-803. The rationale for this change is to support the donor derived NK cells in vivo after adoptive transfer.

Detailed Description

      Amendment 16: Based on the data indicating that ALT-803/IL-15 result in more modulation of
      the NK cells in vivo, the investigators performed a lead in cohort with ALT-803 replacing
      IL-2 at a dose of 10 mcg/kg SQ administered q5 days starting on the date of NK cell infusion.
      The first two patients treated in the ALT-803 lead in cohort experienced a set of symptoms
      consistent with cytokine release syndrome (CRS) including fevers, elevated markers of
      inflammation between days 10-14 after ML NK cell infusion.

      Based on the evidence of increased CD8 T cell activation, the in vitro data indicating that
      ALT-803 promoted recipient CD8 T cell expansion and killing of donor ML NK cells, and the
      lack of clinical responses using ALT-803, the lead in cohort was closed, and a decision was
      made to return to rhIL-2 support, mimicking the cytokine support utilized in the phase 2
      portion of the trial.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I: 0.5 x 10^6/kg CIML NK cells (Dose Levels 1-3)ExperimentalLymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors over 5 hours on day -1. CIML NK Cells: Patients undergo CIML NK cell infusion over 15-60 minutes on day 0. Interleukin-2: Patients receive aldesleukin SC every other day for 2 weeks starting on day 1 (total of 7 doses)
  • Fludarabine
  • Cyclophosphamide
  • Cytokine-induced killer cells
  • IL-2
Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kgExperimentalLymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors on Day -1. CIML NK Cells: Patients undergo CIML NK cell infusion on Day 0. Subcutaneous ALT-803 will begin approximately 4 hours after the infusion and will continue for a total of 2 doses (Days 0 and 5).
  • Fludarabine
  • Cyclophosphamide
  • Cytokine-induced killer cells
  • ALT-803
Pediatric Cohort: Maximum NK cell/number kgExperimentalLymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors on Day -1 CIML NK Cells: Patients undergo CIML NK cell infusion on Day 0 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
  • Fludarabine
  • Cyclophosphamide
  • Cytokine-induced killer cells
  • IL-2
Phase II (IL-2): Maximum NK cell/number kgExperimentalThe recipient will begin a lymphodepleting preparative regimen of fludarabine and cyclophosphamide on Day -6. 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. 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.
  • Fludarabine
  • Cyclophosphamide
  • Cytokine-induced killer cells
  • IL-2

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis requirement for phase I patients:

               -  Refractory AML without complete remission (CR) after induction therapy (primary
                  induction failure) or relapsed AML after obtaining a CR.

               -  OR High-risk AML (by ELN criteria; See Appendix C) in complete remission (CR) and
                  has either refused hematopoietic stem cell transplantation OR is currently not
                  eligible for hematopoietic stem cell transplantation OR for whom hematopoietic
                  stem cell transplantation is being reserved for later relapse. This is inclusive
                  of patients with minimal residual disease evidenced by cytogenetics, molecular
                  testing, and/or flow cytometry.

               -  OR Myelodysplastic syndrome (MDS) with excess blasts (>5%) and progressive
                  disease at any time after initiation of DNA hypomethylator treatment during the
                  past 2 years, OR failure to achieve complete or partial response or hematological
                  improvement (see section 12.4) after at least six cycles of azacytidine or four
                  cycles of decitabine administered during the past 2 years, OR intolerance to
                  azacytidine or decitabine. MDS patients with isolated 5q- abnormalities that meet
                  these criteria after lenalidomide therapy and DNA hypomethylator therapy are also
                  eligible.

          -  Diagnosis requirement for phase II patients:

             *Refractory AML without CR after induction therapy (primary induction failure) or
             relapsed AML after obtaining a CR. Favorable-risk core binding factor (CBF) mutated
             AML and acute promyelocytic leukemia (APL) will be excluded.

          -  Diagnosis requirement for pediatric cohort patients:

             *Refractory AML without complete remission (CR) after induction therapy (primary
             induction failure) or relapsed AML after obtaining a CR.

          -  Age requirement for phase I and phase II patients: At least 18 years of age.

          -  Age requirement for pediatric cohort: 2-17 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 IULN

               -  Creatinine within normal institutional limits OR creatinine clearance ≥ 50
                  mL/min/1.73 m2 by Cockcroft-Gault Formula (adults) or Schwartz formula (pediatric
                  cohort)

               -  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 (phase II only).

          -  More than one course of salvage chemotherapy for primary induction failure or AML
             relapsing after CR1 (phase II only).

          -  Circulating blast count ≥30,000/µL by morphology or flow cytometry (cytoreductive
             therapies including leukapheresis or hydroxyurea are allowed).

          -  Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection.

          -  Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of
             acute ischemia or active conduction system abnormalities.

          -  New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that
             have not been evaluated with bronchoscopy. Infiltrates attributed to infection must be
             stable/ improving after 1 week of appropriate therapy (4 weeks for presumed or proven
             fungal infections).

          -  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 and/or breastfeeding.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximal tolerated or tested dose (MT/TD) of CIML-NK cells (Phase I)
Time Frame:35 days
Safety Issue:
Description:Defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity (DLT) or the maximum dose if less than or equal to 1 patient suffers a DLT at the maximum dose. Summary statistics including proportions and their 95% confidence interval will be calculated.

Secondary Outcome Measures

Measure:Response assessed according to IWG criteria (Phase 1, Phase II, and Pediatric)
Time Frame:35 days
Safety Issue:
Description:Reported with 95% confidence intervals.
Measure:Duration of remission (DOR) (Phase I, Phase II, and Pediatric)
Time Frame:Up to 3 years
Safety Issue:
Description:DOR is defined only for patients who achieve a CR or PR, and is measured from the first date of attaining CR or PR until the date of disease progression or death.
Measure:Time to progression (Phase I, Phase II, and Pediatric)
Time Frame:Up to 3 years
Safety Issue:
Description:TTP is defined as the time from date of first dose of fludarabine until evidence of disease progression.
Measure:Disease free survival (DFS) (Phase I, Phase II, and Pediatric)
Time Frame:Up to 3 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) (Phase I, Phase II, and Pediatric)
Time Frame:Up to 3 years
Safety Issue:
Description:OS is defined from the date of first dose of fludarabine on this study until death.
Measure:Toxicity as measured by the frequency and incidence of serious adverse events (Phase I and Phase II)
Time Frame:Through Day 100
Safety Issue:
Description:Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 AEs will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC < 500/uL/µL) and AEs of GVHD involving the liver, skin, or GI tract will be recorded to Day 100.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

June 12, 2020