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

Primary Purpose

Leukemia, Myeloid, Acute

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
IL-2
ALT-803
Peripheral blood for correlative studies
Bone marrow for correlative studies
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute

Eligibility Criteria

2 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Washington University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

No Intervention

Arm Label

Phase I Dose Level 1: 0.5 x 10^6/kg CIML NK cells

Phase I Dose Level 2: 1.0 x 10^6/kg CIML NK cells

Phase I Dose Level 3: Maximum NK cell/number kg

Phase II (IL-2): Maximum NK cell/number kg

Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg

Pediatric Cohort: Maximum NK cell/number kg

Donors

Arm Description

Lymphodepleting 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)

Lymphodepleting 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)

Lymphodepleting 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)

The 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.

Lymphodepleting 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).

Lymphodepleting 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

-The haploidentical donor identified by HLA matching of the immediate family members (parents, siblings, and children) will undergo non-mobilized leukapheresis on Day -1. Peripheral blood mononuclear cells (PBMCs) will be collected using standard collection techniques.

Outcomes

Primary Outcome Measures

Maximal Tolerated or Tested Dose (MT/TD) of CIML-NK Cells (Phase I)
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.
Complete Remission Rate (CR/CRi) in Participants With Relapsed or Refractory AML Following CIML NK Therapy (Phase II)
Complete remission rate (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 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.
Safety of CIML NK Cells as Measured by the Number of Participants With Treatment Related Adverse Events (Pediatric Cohort)
Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Related indicates possibly, probably, or definitely related to study treatment. Adverse events 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.

Secondary Outcome Measures

Response Assessed According to IWG Criteria (Phase 1, Phase II, and Pediatric)
Duration of Remission (DOR) (Phase I, Phase II, and Pediatric)
DOR is defined only for patients who achieve a complete remission (CR), complete remission with incomplete blood count recovery (CRi), marrow complete response (mCR), or partial remission (PR), and is measured from the first date of attaining CR or PR until the date of disease progression or death.
Time to Progression (Phase I, Phase II, and Pediatric)
TTP is defined as the time from date of first dose of fludarabine until evidence of disease progression.
Disease Free Survival (DFS) (Phase I, Phase II, and Pediatric)
DFS is defined as the time from the day CR, mCR, or CRi is documented until disease progression or death.
Overall Survival (OS) (Phase I, Phase II, and Pediatric)
OS is defined from the date of first dose of fludarabine on this study until death.
Toxicity as Measured by the Number of Participants With Treatment Related Adverse Events (Phase I and Phase II)
Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Related indicates possibly, probably, or definitely related to study treatment. 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.

Full Information

First Posted
July 9, 2013
Last Updated
January 4, 2023
Sponsor
Washington University School of Medicine
Collaborators
American Society of Clinical Oncology, American Society of Hematology, Gabrielle's Angel Foundation, The Leukemia and Lymphoma Society, National Cancer Institute (NCI), ImmunityBio, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01898793
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Terminated
Why Stopped
Insufficient funding/staff
Study Start Date
August 11, 2014 (Actual)
Primary Completion Date
December 28, 2021 (Actual)
Study Completion Date
April 4, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
American Society of Clinical Oncology, American Society of Hematology, Gabrielle's Angel Foundation, The Leukemia and Lymphoma Society, National Cancer Institute (NCI), ImmunityBio, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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 myelodysplastic syndromes. Giving chemotherapy before a donor natural killer cell infusion helps stop the growth of cancer cells and stops 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. Update with Amendment 16: The first two patients treated in the Phase II ALT-803 lead in cohort experienced a set of symptoms consistent with cytokine release syndrome (CRS).The Phase II ALT-803 lead in cohort was closed and a decision was made to return to rhIL-2 support for the remainder of enrollments in the Phase II portion of the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
89 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase I Dose Level 1: 0.5 x 10^6/kg CIML NK cells
Arm Type
Experimental
Arm Description
Lymphodepleting 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)
Arm Title
Phase I Dose Level 2: 1.0 x 10^6/kg CIML NK cells
Arm Type
Experimental
Arm Description
Lymphodepleting 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)
Arm Title
Phase I Dose Level 3: Maximum NK cell/number kg
Arm Type
Experimental
Arm Description
Lymphodepleting 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)
Arm Title
Phase II (IL-2): Maximum NK cell/number kg
Arm Type
Experimental
Arm Description
The 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.
Arm Title
Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg
Arm Type
Experimental
Arm Description
Lymphodepleting 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).
Arm Title
Pediatric Cohort: Maximum NK cell/number kg
Arm Type
Experimental
Arm Description
Lymphodepleting 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
Arm Title
Donors
Arm Type
No Intervention
Arm Description
-The haploidentical donor identified by HLA matching of the immediate family members (parents, siblings, and children) will undergo non-mobilized leukapheresis on Day -1. Peripheral blood mononuclear cells (PBMCs) will be collected using standard collection techniques.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
2-F-ara-AMP, 75607-67-9, 9H-purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl), Beneflur, Fludara, fludarabine-5'-monophosphate
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan®, CPM
Intervention Type
Procedure
Intervention Name(s)
Leukapheresis
Intervention Type
Biological
Intervention Name(s)
Cytokine-induced killer cells
Other Intervention Name(s)
CIK cells
Intervention Type
Biological
Intervention Name(s)
IL-2
Other Intervention Name(s)
Proleukin, recombinant human interleukin-2, recombinant interleukin-2, Ro-236019, T-cell growth factor, TCGF, TCGF,, interleukin, Aldesleukin
Intervention Type
Drug
Intervention Name(s)
ALT-803
Intervention Type
Procedure
Intervention Name(s)
Peripheral blood for correlative studies
Intervention Description
-Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse
Intervention Type
Procedure
Intervention Name(s)
Bone marrow for correlative studies
Intervention Description
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Primary Outcome Measure Information:
Title
Maximal Tolerated or Tested Dose (MT/TD) of CIML-NK Cells (Phase I)
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.
Time Frame
35 days
Title
Complete Remission Rate (CR/CRi) in Participants With Relapsed or Refractory AML Following CIML NK Therapy (Phase II)
Description
Complete remission rate (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 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.
Time Frame
Up to 3 years
Title
Safety of CIML NK Cells as Measured by the Number of Participants With Treatment Related Adverse Events (Pediatric Cohort)
Description
Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Related indicates possibly, probably, or definitely related to study treatment. Adverse events 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.
Time Frame
Through Day 100
Secondary Outcome Measure Information:
Title
Response Assessed According to IWG Criteria (Phase 1, Phase II, and Pediatric)
Time Frame
35 days
Title
Duration of Remission (DOR) (Phase I, Phase II, and Pediatric)
Description
DOR is defined only for patients who achieve a complete remission (CR), complete remission with incomplete blood count recovery (CRi), marrow complete response (mCR), or partial remission (PR), and is measured from the first date of attaining CR or PR until the date of disease progression or death.
Time Frame
Up to 3 years
Title
Time to Progression (Phase I, Phase II, and Pediatric)
Description
TTP is defined as the time from date of first dose of fludarabine until evidence of disease progression.
Time Frame
Up to 3 years
Title
Disease Free Survival (DFS) (Phase I, Phase II, and Pediatric)
Description
DFS is defined as the time from the day CR, mCR, or CRi is documented until disease progression or death.
Time Frame
Up to 3 years
Title
Overall Survival (OS) (Phase I, Phase II, and Pediatric)
Description
OS is defined from the date of first dose of fludarabine on this study until death.
Time Frame
Up to 3 years
Title
Toxicity as Measured by the Number of Participants With Treatment Related Adverse Events (Phase I and Phase II)
Description
Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Related indicates possibly, probably, or definitely related to study treatment. 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.
Time Frame
Through Day 100

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amanda Cashen, M.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19181844
Citation
Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM. Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1915-9. doi: 10.1073/pnas.0813192106. Epub 2009 Jan 30.
Results Reference
background
PubMed Identifier
22983442
Citation
Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA. Cytokine activation induces human memory-like NK cells. Blood. 2012 Dec 6;120(24):4751-60. doi: 10.1182/blood-2012-04-419283. Epub 2012 Sep 14.
Results Reference
background
PubMed Identifier
23209317
Citation
Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med. 2012 Dec 17;209(13):2351-65. doi: 10.1084/jem.20120944. Epub 2012 Dec 3.
Results Reference
background
PubMed Identifier
34797911
Citation
Berrien-Elliott MM, Becker-Hapak M, Cashen AF, Jacobs M, Wong P, Foster M, McClain E, Desai S, Pence P, Cooley S, Brunstein C, Gao F, Abboud CN, Uy GL, Westervelt P, Jacoby MA, Pusic I, Stockerl-Goldstein KE, Schroeder MA, DiPersio JF, Soon-Shiong P, Miller JS, Fehniger TA. Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy. Blood. 2022 Feb 24;139(8):1177-1183. doi: 10.1182/blood.2021011532.
Results Reference
derived
Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Learn more about this trial

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

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