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

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ClinicalTrials.gov Identifier: NCT01898793
Recruitment Status : Recruiting
First Posted : July 12, 2013
Last Update Posted : May 17, 2019
Sponsor:
Collaborators:
American Society of Clinical Oncology
American Society of Hematology
Gabrielle's Angel Foundation
The Leukemia and Lymphoma Society
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Washington University School of Medicine

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 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.


Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: Fludarabine Drug: Cyclophosphamide Procedure: Leukapheresis Biological: Cytokine-induced killer cells Biological: IL-2 Drug: ALT-803 Procedure: Peripheral blood for correlative studies Procedure: Bone marrow for correlative studies Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 133 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of Cytokine-Induced Memory-Like NK Cells in Patients With AML or MDS
Actual Study Start Date : August 11, 2014
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: Phase I: 0.5 x 10^6/kg CIML NK cells (Dose Levels 1-3)
  • 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)
Drug: Fludarabine
Other Names:
  • 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

Drug: Cyclophosphamide
Other Names:
  • Cytoxan®
  • CPM

Procedure: Leukapheresis
Biological: Cytokine-induced killer cells
Other Name: CIK cells

Biological: IL-2
Other Names:
  • Proleukin
  • recombinant human interleukin-2
  • recombinant interleukin-2
  • Ro-236019
  • T-cell growth factor
  • TCGF
  • TCGF,
  • interleukin
  • Aldesleukin

Procedure: 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

Procedure: Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse

Experimental: 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).
Drug: Fludarabine
Other Names:
  • 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

Drug: Cyclophosphamide
Other Names:
  • Cytoxan®
  • CPM

Procedure: Leukapheresis
Biological: Cytokine-induced killer cells
Other Name: CIK cells

Drug: ALT-803
Procedure: 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

Procedure: Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse

Experimental: Pediatric Cohort: Maximum NK cell/number kg
  • Lymphodepleting Preparative Regimen: Patients receive fludarabine and cyclophosphamide on Day -6, Day -5, fludarabine only Day -4 and Day -3
  • 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
Drug: Fludarabine
Other Names:
  • 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

Drug: Cyclophosphamide
Other Names:
  • Cytoxan®
  • CPM

Procedure: Leukapheresis
Biological: Cytokine-induced killer cells
Other Name: CIK cells

Biological: IL-2
Other Names:
  • Proleukin
  • recombinant human interleukin-2
  • recombinant interleukin-2
  • Ro-236019
  • T-cell growth factor
  • TCGF
  • TCGF,
  • interleukin
  • Aldesleukin

Procedure: 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

Procedure: Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse

Experimental: 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.
Drug: Fludarabine
Other Names:
  • 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

Drug: Cyclophosphamide
Other Names:
  • Cytoxan®
  • CPM

Procedure: Leukapheresis
Biological: Cytokine-induced killer cells
Other Name: CIK cells

Biological: IL-2
Other Names:
  • Proleukin
  • recombinant human interleukin-2
  • recombinant interleukin-2
  • Ro-236019
  • T-cell growth factor
  • TCGF
  • TCGF,
  • interleukin
  • Aldesleukin

Procedure: 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

Procedure: Bone marrow for correlative studies
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse




Primary Outcome Measures :
  1. Maximal tolerated or tested dose (MT/TD) of CIML-NK cells (Phase I) [ Time Frame: 35 days ]
    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.

  2. Complete remission rate (CR/CRi) in participants with relapsed or refractory AML following CIML NK therapy (Phase II) [ Time Frame: Up to 3 years ]
    • 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.

  3. Safety of CIML NK cells (Pediatric) as measured by the frequency and incidence of adverse events [ Time Frame: Through Day 100 ]

    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.



Secondary Outcome Measures :
  1. Response assessed according to IWG criteria (Phase 1, Phase II, and Pediatric) [ Time Frame: 35 days ]
    Reported with 95% confidence intervals.

  2. Duration of remission (DOR) (Phase I, Phase II, and Pediatric) [ Time Frame: Up to 3 years ]
    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.

  3. Time to progression (Phase I, Phase II, and Pediatric) [ Time Frame: Up to 3 years ]
    TTP is defined as the time from date of first dose of fludarabine until evidence of disease progression.

  4. Disease free survival (DFS) (Phase I, Phase II, and Pediatric) [ Time Frame: Up to 3 years ]
    DFS is defined as the time from the day CR or CRi is documented until disease progression or death.

  5. Overall survival (OS) (Phase I, Phase II, and Pediatric) [ Time Frame: Up to 3 years ]
    OS is defined from the date of first dose of fludarabine on this study until death.

  6. Toxicity as measured by the frequency and incidence of serious adverse events (Phase I and Phase II) [ Time Frame: Through Day 100 ]
    • 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01898793


Contacts
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Contact: Amanda Cashen, M.D. 314-434-8323 acashen@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Amanda Cashen, M.D.    314-434-8323    acashen@wustl.edu   
Principal Investigator: Amanda Cashen, M.D.         
Sub-Investigator: Camille Abboud, M.D.         
Sub-Investigator: Todd Fehniger, M.D., Ph.D.         
Sub-Investigator: John DiPersio, M.D., Ph.D.         
Sub-Investigator: Meagan Jacoby, M.D., Ph.D.         
Sub-Investigator: Iskra Pusic, M.D.         
Sub-Investigator: Mark Schroeder, M.D.         
Sub-Investigator: Keith Stockerl-Goldstein, M.D.         
Sub-Investigator: Geoffrey Uy, M.D.         
Sub-Investigator: Ravi Vij, M.D.         
Sub-Investigator: Lukas Wartman, M.D.         
Sub-Investigator: John Welch, M.D.,Ph.D.         
Sub-Investigator: Peter Westervelt, M.D., Ph.D.         
Sub-Investigator: Armin Ghobadi, M.D.         
Sub-Investigator: Michael Tomasson, M.D.         
Sub-Investigator: Matthew Walter, M.D.         
Sub-Investigator: Tanya Wildes, M.D.         
Sub-Investigator: Brad Kahl, M.D.         
Sub-Investigator: Terrence Wong, M.D. Ph.D.         
Sub-Investigator: Jeffery Bednarski, M.D., Ph.D.         
Sub-Investigator: Shalini Shenoy, M.D.         
Sub-Investigator: Robert Hayashi, M.D.         
Sub-Investigator: Sima Bhatt, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
American Society of Clinical Oncology
American Society of Hematology
Gabrielle's Angel Foundation
The Leukemia and Lymphoma Society
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Amanda Cashen, M.D. Washington University School of Medicine

Additional Information:
Publications:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01898793     History of Changes
Other Study ID Numbers: 201401085
5F32CA200253-02 ( U.S. NIH Grant/Contract )
First Posted: July 12, 2013    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Interleukin-2
Aldesleukin
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-HIV Agents
Anti-Retroviral Agents