Cytokine-induced Memory-like NK Cells in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
NCT ID: NCT01898793
Last Updated: 2024-01-17
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE1/PHASE2
89 participants
INTERVENTIONAL
2014-08-11
2022-04-04
Brief Summary
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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.
With amendment 16, the decision was made to return to the use of rhIL-2 support instead of ALT-803.
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Phase I Dose Level 1: 0.5 x 10^6/kg CIML NK cells
* 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)
Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
IL-2
Peripheral blood for correlative studies
-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
Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Phase I Dose Level 2: 1.0 x 10^6/kg CIML NK cells
* 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)
Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
IL-2
Peripheral blood for correlative studies
-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
Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Phase I Dose Level 3: Maximum NK cell/number kg
* 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)
Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
IL-2
Peripheral blood for correlative studies
-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
Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Phase II (IL-2): Maximum NK cell/number kg
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.
Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
IL-2
Peripheral blood for correlative studies
-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
Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg
* 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).
Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
ALT-803
Peripheral blood for correlative studies
-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
Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Pediatric Cohort: Maximum NK cell/number kg
* 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
Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
IL-2
Peripheral blood for correlative studies
-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
Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Donors
-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.
No interventions assigned to this group
Interventions
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Fludarabine
Cyclophosphamide
Leukapheresis
Cytokine-induced killer cells
IL-2
ALT-803
Peripheral blood for correlative studies
-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
Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
2 Years
ALL
No
Sponsors
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American Society of Clinical Oncology
OTHER
American Society of Hematology
OTHER
Gabrielle's Angel Foundation
OTHER
The Leukemia and Lymphoma Society
OTHER
National Cancer Institute (NCI)
NIH
ImmunityBio, Inc.
INDUSTRY
Washington University School of Medicine
OTHER
Responsible Party
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Principal Investigators
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Amanda Cashen, M.D.
Role: PRINCIPAL_INVESTIGATOR
Washington University School of Medicine
Locations
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Washington University School of Medicine
St Louis, Missouri, United States
Countries
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References
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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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
Other Identifiers
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201401085
Identifier Type: -
Identifier Source: org_study_id
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