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Acute Myeloid LeukemiaPhase 2NCT02763475

NK Cells as Consolidation Therapy of Acute Myeloid Leukemia in Children/Adolescents

A Phase 2 study testing cyclophosphamide, Fludarabine and NK cell infusion in people with Acute Myeloid Leukemia and Leukemia, run by Instituto de Investigación Hospital Universitario La Paz at 6 sites in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The main goal of this study is to evaluate the anti-relapse prophylactic activity of inoculating Natural Killer (NK) cells as consolidation therapy of acute myeloid leukemia in paediatric patients with cytologic remission. Read more about this study

Who is it for?
Ages Up to 21 years
Conditions the study is for
Acute Myeloid Leukemia, Leukemia, Myeloid Leukemia
What is being tested?
cyclophosphamide, Fludarabine and NK cell infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
7 participants
Where
6 sitesSpain
Study dates
May 2016to Aug 2020
Phase
Phase 2
Are there results?
None posted in the registry

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 Up to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Patients aged between 0 and 21 years, diagnosed with AML in first cytological remission who have completed the induction and consolidation chemotherapy phases and no criteria for allogeneic hematopoietic stem cell transplantation (HSCT), ie patients who have responded well to induction lacking donor HLA identical relative and do not have high-risk cytogenetic abnormalities.
  • Karnofsky or Lansky Performance Scale (PS) > 60%
  • Mild-moderate (<4) organ functional impairment (liver, kidney, respiratory) according to the criteria of the National Cancer Institute (NCI CTCAE v4).
  • Left ventricular ejection fraction> 39%
  • Adult subjects who have voluntarily signed informed consent before the first study intervention.
  • Minor subjects whose representative / legal guardian has voluntarily signed informed consent before the first study intervention.
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  • For mature minors (12 to 17 years old), in addition to the consent signed by the legal guardian, the assent of the child will be obtained.
  • Women of childbearing potential must have a negative pregnancy test at the time inclusion and must agree to use highly effective contraceptive methods (diaphragms plus spermicide or male condom plus spermicide, combined oral contraceptive with a second method of contraceptive implant, injectable contraceptive, permanent intrauterine device, sexual abstinence or partner with vasectomy) while participating in the study and 30 days after the last visit.
  • Presence of a haploidentical donor

Who cannot join

  • Patients with a history of poor treatment compliance
  • Patients who after a psycho-social assessment are censored as unfit for procedure:
  • Socio-familiar situation that precludes proper participation in the study.
  • Patients with emotional or psychological problems secondary to the illness such as PTSD, phobias, delusions, psychosis, requiring assistance by specialists.
  • Evaluation of the involvement of the family in the patient's health.
  • Inability to understand the information about the trial.
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  • Severe (4) organ functional impairment (liver, kidney, respiratory) according to the criteria of the National Cancer Institute (NCI CTCAE v4).
  • They should be considered contraindications, interactions, precautions for use and dose reductions indicated in the respective data sheets.
  • Subjects who have been administered other investigational drugs within 90 days prior to inclusion

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

Spain6 sites

  • Hospital Materno Infantil de Badajoz

    Badajoz, 06010

  • Hospital Universitario de Cruces

    Barakaldo, Vizcaya, 48903

  • Hospital Universitario 12 de Octubre

    Madrid, 28041

  • Hospital Universitario La Paz

    Madrid, 28046

  • Hospital Materno-Infantil de Málaga

    Málaga, 29011

  • Hospital de la Arrixaca

    Murcia, 30120

Other trials in Spain

About this study

Official title: NK Cells Infusion as Consolidation Treatment of Acute Myeloid Leukemia in Children and Adolescents

The main goal of this study is to evaluate the anti-relapse prophylactic activity of inoculating Natural Killer (NK) cells as consolidation therapy of acute myeloid leukemia in paediatric patients with cytologic remission. The patients included have intermediate risk of relapse and no indication for allogeneic hematopoietic stem cell transplantation.

After the standard induction and consolidation chemotherapy treatment, patients will receive five days of fludarabine to try to kill any minimal residual disease and prevent NK cell rejection. Two different NK cells infusions will be performed within one week (day 0 and 7). Interleukin 2 (IL-2) will be administrated to increase the cytotoxic activity of NK cells.

Read the detailed description

Hypothesis:

NK cells are the natural defence against cancer cells. Thus, supplementing compatible NK cells from a related donor might increase the probability to eliminate any residual chemotherapy resistant cell in Acute myelogenous leukemia patients.

Description:

NK cells will be donated from a compatible family member who has a certain genetic code in their blood, called HLA, which partly matches patient genetic code, reducing any potential rejection. Interleukin-2 is co administrated during NK cell treatment to improve effectiveness.

Methodology:

The day that patient receive first NK cell infusion is called day 0. The days before are called minus days (-D). Conversely, the days after NK cell infusion are called plus days (+D).

Study administration

  • After standard chemotherapy treatment against acute myeloid leukemia (AML) and restoration of haematologic normal levels, patients will receive a 60mg/kg of cyclophosphamide (day -6) and five daily intravenous cycles 25 mg/m2 of the chemotherapic fludarabine every day (day -5, -4, -3, -2, -1).
  • Day 0 will be settled from 24h to 48h after fludarabine treatment completion. NK cells will be intravenous administered twice (day 0 and day 7). The first dose of NK cells (day 0) will contain up to 5x10^7 cells/kg with immunophenotype NK (CD3-CD56+). The second dose might be higher (up to 5x10^8 cells/kg) in case of no treatment related toxicity after first NK injection. In any case, no more than 1x10^6 cells/kg with an immunophenotype T (CD56-CD3+) will be administrated.
  • From day 0, IL-2 1x10^6 UI/m2 subcutaneous will be administrated three times a week during two weeks.

Study visits

Before and after the treatment a bone marrow aspirate will be analyzed in order to evaluate minimal residue disease (cytology, cytometry and/or molecular studies) at least one month after NK injection. objective response rate will be reevaluated at least once a year.

Before treatment starts:

  • Birthday, gender and personal medical history will be recorded
  • physical examination, including measurement of the vital signs (temperature, heart and breathing rate, etc…)
  • Blood and urine test
  • Bone marrow aspirate in order to evaluate the basal disease

On every visit

  • Physical examination and vital signs will be recorded
  • Adverse event form
  • Other concomitant drugs

After NK treatment

  • It will be 11 visits on days +30, +60, +90, +180, +270, +360, +480, +600, +720, +900, +1080 which included a blood and urine test and Lansky/karnofsky scale.
  • Additionally on days +30, +360, +720 and +1080 a bone marrow aspirate will be performed to evaluate relapse.

Length of the study:

Up to 35 AML patients will be included in the study during a 32 months recruitment period with a patient follow-up of thirty-six months. The maximum length of the study will be six years.

Being tested
cyclophosphamide, Fludarabine, NK cell infusion, IL-2
Keywords
Killer Cells, Natural, Consolidation treatment, cytologic remission, Haploidentical NK Cells, allogeneic, IL-2 Expanded NK Cells
Medical subject headings
Leukemia, Myeloid, Acute, Leukemia, Leukemia, Myeloid

What participants receive

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

  • cyclophosphamideDrug

    60mg/kg by vein on day -6

  • FludarabineDrug

    25mg/m2 iv daily on day -5 to -1

  • NK cell infusionProcedure or surgery

    • First allogeneic haploidentical NK cell iv. infusion: 5x10e7/kg, NK CD3-CD56+ immunophenotype, 24-48h after chemotherapy
    • Second allogeneic haploidentical NK cell iv. infusion: up to 5x10e8/kg, NK CD3-CD56+immunophenotype, 7 days after the first infusion.

  • IL-2Drug

    Also called Proleukin

    1x10^6 UI/m2 three times a week for two weeks from first NK infusion (day 0)

Study groups in NCT02763475
Study groupRoleWhat they receive
Natural Killer (NK) Cells + ChemotherapyExperimentalStarting on day -6, 60mg/Kg cyclophosphamide by vein will be administrated. Day -5 to -1 fludarabine administrated by vein at 25 mg/m2. 24-48 hours after chemotherapy completion, NK cell infusion will be injected (day 0). On day 7 a second NK cell infusion will be administrated. First infusion consist of 5x10^7/kg NK CD3-CD56+ NK cells. The second NK cell infusion will include up to 5x10^8 CD3-CD56+ cells if no treatment related toxicity occurred. Subcutaneous IL-2 (1x10^6 UI/m2) three times a week for two weeks will be administrated after first NK infusion.
Receives: Drug: cyclophosphamide; Drug: Fludarabine; Procedure: NK cell infusion; Drug: IL-2

What is being measured

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

  1. Relapse-free rate after allogeneic haploidentical NK cell infusion

    Relapse-free rate according to the clinical guidelines. A bone narrow aspirate one month after NK cell infusion will be evaluated for cytomorphological criteria and minimal residue disease (cytometry or real time PCR). Relapse defined as myeloid blast bone marrow presence with the same diagnosis markers, new ones or mixed. From cytologic analysis 25% of blast or minimal residue disease by cytometry (0,01%) and/or molecular level (0,0001%) present at diagnosis with or without cytogenetic alterations.

    Measured: Relapse-free rate at 1 month

  2. Relapse-free rate after allogeneic haploidentical NK cell infusion

    Relapse-free rate according to the clinical guidelines. A bone narrow aspirate one month after NK cell infusion and at least once a year during the three-year follow-up will be evaluated for cytomorphological criteria and minimal residue disease (cytometry or real time PCR). Relapse defined as myeloid blast bone marrow presence with the same diagnosis markers, new ones or mixed. From cytologic analysis 25% of blast or minimal residue disease by cytometry (0,01%) and/or molecular level (0,0001%) present at diagnosis with or without cytogenetic alterations.

    Measured: Relapse-free rate at one year

  3. Relapse-free rate after allogeneic haploidentical NK cell infusion

    Relapse-free rate according to the clinical guidelines. A bone narrow aspirate one month after NK cell infusion and at least once a year during the three-year follow-up will be evaluated for cytomorphological criteria and minimal residue disease (cytometry or real time PCR). Relapse defined as myeloid blast bone marrow presence with the same diagnosis markers, new ones or mixed. From cytologic analysis 25% of blast or minimal residue disease by cytometry (0,01%) and/or molecular level (0,0001%) present at diagnosis with or without cytogenetic alterations.

    Measured: Relapse-free rate at two years

  4. Relapse-free rate after allogeneic haploidentical NK cell infusion

    Relapse-free rate according to the clinical guidelines. A bone narrow aspirate one month after NK cell infusion and at least once a year during the three-year follow-up will be evaluated for cytomorphological criteria and minimal residue disease (cytometry or real time PCR). Relapse defined as myeloid blast bone marrow presence with the same diagnosis markers, new ones or mixed. From cytologic analysis 25% of blast or minimal residue disease by cytometry (0,01%) and/or molecular level (0,0001%) present at diagnosis with or without cytogenetic alterations.

    Measured: Relapse-free rate at three years

Secondary outcomes (7)

  1. Adverse events of special interest: administration issues, infections, immunological/allergic/toxic reactions and concomitant drug interactions.

    All adverse events (AE) will be monitorized. AE of special interest: administration issues, infections, immunological/allergic/toxic reactions and concomitant drug interactions. AE will be classified according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTC) v4.0 criteria or MedDRA classification (mild, moderate, severe or life threatening ).

    Measured: three years

  2. Evaluation of donor phenotype by SS-PCR

    Donor HLA phenotype will be determined by SS-PCR. The aim is identify KIR ligand mismatch between donor and recipient to achieve better response. Ideally we will choose KIR ligand mismatch recipient donor pair (http://www.ncbi.nlm.nih.gov/pubmed/26341478).

    Measured: Three years

  3. Evaluation of patient HLA phenotype by SS-PCR

    Patient HLA phenotype will be determined by SS-PCR. The aim is identify KIR ligand mismatch between donor and recipient to achieve better response. Ideally we will choose KIR ligand mismatch recipient donor pair (http://www.ncbi.nlm.nih.gov/pubmed/26341478).

    Measured: Three years

  4. Evaluation of donor KIR haplotype by PCR

    The objective is to identify activating KIRs and B haplotype (cen B), by PCR. Ideally we will choose B haplotype donors (http://www.ncbi.nlm.nih.gov/pubmed/20581313)

    Measured: Three years

  5. Analysis of Hematopoietic chimerism after NK infusion by PCR or flow cytometry

    Chimerism after NK cell infusion by PCR or flow cytometry: to correlate with NK survival and expansion and with clinical outcome (http://www.ncbi.nlm.nih.gov/pubmed/26772158).

    Measured: Three years

  6. Ligand expression of the activatory (MICA, MICB and ULBPs) or inhibitory (HLA-1) receptors of the NK cells

    Ligand expression of the activatory (MICA, MICB and ULBPs) or inhibitory (HLA-1) receptors of the NK cells will be determined by multiparametric flow cytometry in order to determine the main variables to predict treatment effectiveness and safety.

    Measured: Three years

  7. NK cytotoxic activity

    In vitro allogenic NK cytotoxic activity against leukemic blast will be performed by real time Eur-TDA fluorescence (Blomberg et al. J Immunol Methods 1986).

    Measured: Three years

Timeline

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

  1. First posted5 May 2016 (estimated)
  2. Study startMay 2016
  3. Primary completionAug 2020
  4. Study completionAug 2020

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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
7 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02763475
Sponsor's protocol ID
NKCell_LMA_2015
Other IDs
2015-001901-15, 2015
Status last verified
Sep 2020
First submitted
4 Apr 2016
Last updated
5 Oct 2020
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Blomberg K, Granberg C, Hemmila I, Lovgren T. Europium-labelled target cells in an assay of natural killer cell activity. II. A novel non-radioactive method based on time-resolved fluorescence. significance and specificity of the method. J Immunol Methods. 1986 Aug 21;92(1):117-23. doi: 10.1016/0022-1759(86)90511-9.

    PubMed 3745921

  • Gomez Garcia LM, Escudero A, Mestre C, Fuster Soler JL, Martinez AP, Vagace Valero JM, Vela M, Ruz B, Navarro A, Fernandez L, Fernandez A, Leivas A, Martinez-Lopez J, Ferreras C, De Paz R, Blanquer M, Galan V, Gonzalez B, Corral D, Sisinni L, Mirones I, Balas A, Vicario JL, Valle P, Borobia AM, Perez-Martinez A. Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL-Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia. Clin Lymphoma Myeloma Leuk. 2021 May;21(5):328-337.e1. doi: 10.1016/j.clml.2021.01.013. Epub 2021 Jan 25.

    PubMed 33610500

  • Munoz Builes M, Vela Cuenca M, Fuster Soler JL, Astigarraga I, Pascual Martinez A, Vagace Valero JM, Tong HY, Valentin Quiroga J, Fernandez Casanova L, Escudero Lopez A, Sisinni L, Blanquer M, Mirones Aguilar I, Gonzalez Martinez B, Borobia AM, Perez-Martinez A. Study protocol for a phase II, multicentre, prospective, non-randomised clinical trial to assess the safety and efficacy of infusing allogeneic activated and expanded natural killer cells as consolidation therapy for paediatric acute myeloblastic leukaemia. BMJ Open. 2020 Jan 8;10(1):e029642. doi: 10.1136/bmjopen-2019-029642.

    PubMed 31919123

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing cyclophosphamide, Fludarabine and NK cell infusion in people with Acute Myeloid Leukemia and Leukemia, run by Instituto de Investigación Hospital Universitario La Paz at 6 sites in Spain.

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 9 inclusion and 9 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: finished, as of the sponsor's last update on 5 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Spain. 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 phase mean?

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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Relapse-free rate after allogeneic haploidentical NK cell infusion (time frame: Relapse-free rate at 1 month). The study lists 4 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 NCT02763475, which also lists 3 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 5 Oct 2020.

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