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Leukemia, Myeloid, AcutePhase 1/2NCT01898793

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

A Phase 1/2 study testing Fludarabine, Cyclophosphamide and Leukapheresis in people with Leukemia, Myeloid, Acute, run by Washington University School of Medicine at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 2 years and older
Conditions the study is for
Leukemia, Myeloid, Acute
What is being tested?
Fludarabine, Cyclophosphamide and Leukapheresis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
89 participants
Where
1 siteUnited States
Study dates
11 Aug 2014to 4 Apr 2022
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
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  • 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).

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: A Phase 1/2 Study of Cytokine-Induced Memory-Like NK Cells in Patients With AML or MDS

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.

With amendment 16, the decision was made to return to the use of rhIL-2 support instead of ALT-803.

Being tested
Fludarabine, Cyclophosphamide, Leukapheresis, Cytokine-induced killer cells, IL-2
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FludarabineDrug

    Also called 2-F-ara-AMP, 75607-67-9, 9H-purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)

  • CyclophosphamideDrug

    Also called Cytoxan®, CPM

  • LeukapheresisProcedure or surgery

  • Cytokine-induced killer cellsBiological

    Also called CIK cells

  • IL-2Biological

    Also called Proleukin, recombinant human interleukin-2, recombinant interleukin-2, Ro-236019

  • ALT-803Drug

  • Peripheral blood for correlative studiesProcedure or surgery

    -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 studiesProcedure or surgery

    -Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse

Study groups in NCT01898793
Study groupRoleWhat they receive
Phase I Dose Level 1: 0.5 x 10^6/kg CIML NK cellsExperimental* 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)
Receives: Drug: Fludarabine; Drug: Cyclophosphamide; Procedure: Leukapheresis; Biological: Cytokine-induced killer cells; Biological: IL-2; Procedure: Peripheral blood for correlative studies; Procedure: Bone marrow for correlative studies
Phase I Dose Level 2: 1.0 x 10^6/kg CIML NK cellsExperimental* 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)
Receives: Drug: Fludarabine; Drug: Cyclophosphamide; Procedure: Leukapheresis; Biological: Cytokine-induced killer cells; Biological: IL-2; Procedure: Peripheral blood for correlative studies; Procedure: Bone marrow for correlative studies
Phase I Dose Level 3: Maximum NK cell/number kgExperimental* 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)
Receives: Drug: Fludarabine; Drug: Cyclophosphamide; Procedure: Leukapheresis; Biological: Cytokine-induced killer cells; Biological: IL-2; Procedure: Peripheral blood for correlative studies; Procedure: Bone marrow for correlative studies
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.
Receives: Drug: Fludarabine; Drug: Cyclophosphamide; Procedure: Leukapheresis; Biological: Cytokine-induced killer cells; Biological: IL-2; Procedure: Peripheral blood for correlative studies; Procedure: Bone marrow for correlative studies
Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kgExperimental* 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).
Receives: Drug: Fludarabine; Drug: Cyclophosphamide; Procedure: Leukapheresis; Biological: Cytokine-induced killer cells; Drug: ALT-803; Procedure: Peripheral blood for correlative studies; Procedure: Bone marrow for correlative studies
Pediatric Cohort: Maximum NK cell/number kgExperimental* 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
Receives: Drug: Fludarabine; Drug: Cyclophosphamide; Procedure: Leukapheresis; Biological: Cytokine-induced killer cells; Biological: IL-2; Procedure: Peripheral blood for correlative studies; Procedure: Bone marrow for correlative studies
DonorsNo intervention-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.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 35 days

  2. 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.

    Measured: Up to 3 years

  3. 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.

    Measured: Through Day 100

Secondary outcomes (6)

  1. Response Assessed According to IWG Criteria (Phase 1, Phase II, and Pediatric)

    Measured: 35 days

  2. 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.

    Measured: Up to 3 years

  3. 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.

    Measured: Up to 3 years

  4. 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.

    Measured: Up to 3 years

  5. 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.

    Measured: Up to 3 years

  6. 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.

    Measured: Through Day 100

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jul 2013 (estimated)
  2. Study start11 Aug 2014
  3. Primary completion28 Dec 2021
  4. Study completion4 Apr 2022

Why it stopped: Insufficient funding/staff

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
89 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01898793
Sponsor's protocol ID
201401085
Other IDs
5F32CA200253-02
Status last verified
Dec 2023
First submitted
9 Jul 2013
Last updated
17 Jan 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 19181844

  • 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.

    PubMed 22983442

  • 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.

    PubMed 23209317

  • 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.

    PubMed 34797911

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Fludarabine, Cyclophosphamide and Leukapheresis in people with Leukemia, Myeloid, Acute, run by Washington University School of Medicine at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 17 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximal Tolerated or Tested Dose (MT/TD) of CIML-NK Cells (Phase I) (time frame: 35 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01898793, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jan 2024.

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