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

NCT02763475 | Completed Phase 2

• 2 other identifiers: NKCell_LMA_20152015-001901-15
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 6

Brief 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. 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.

Conditions

Acute Myeloid Leukemia; Leukemia; Myeloid Leukemia

Keywords

Killer Cells, Natural; Consolidation treatment; cytologic remission; Haploidentical NK Cells; allogeneic; IL-2 Expanded NK Cells

Outcome Measures

Primary Outcomes (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 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.

  Relapse-free rate at 1 month

• 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.

  Relapse-free rate at one year

• 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.

  Relapse-free rate at two years

• 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.

  Relapse-free rate at three years

Secondary Outcomes (7)

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

  three years

• Evaluation of donor phenotype by SS-PCR

  Three years

• Evaluation of patient HLA phenotype by SS-PCR

  Three years

• Evaluation of donor KIR haplotype by PCR

  Three years

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

  Three years

Study Arms (1)

Natural Killer (NK) Cells + Chemotherapy

EXPERIMENTAL

Starting 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.

Drug: cyclophosphamide; Drug: Fludarabine; Procedure: NK cell infusion; Drug: IL-2

Interventions

cyclophosphamide DRUG

60mg/kg by vein on day -6

Natural Killer (NK) Cells + Chemotherapy

Fludarabine DRUG

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

Natural Killer (NK) Cells + Chemotherapy

NK cell infusion PROCEDURE

* 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.

Natural Killer (NK) Cells + Chemotherapy

IL-2 DRUG

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

Also known as: Proleukin

Natural Killer (NK) Cells + Chemotherapy

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.
• Presence of a haploidentical donor

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Instituto de Investigación Hospital Universitario La Paz: lead
• Hospital Infantil Universitario Niño Jesús, Madrid, Spain: collaborator
• Fundación Mutua Madrileña: collaborator

Study Sites (6)

Hospital Universitario de Cruces

Barakaldo, Vizcaya, 48903, Spain

Location

Hospital Materno Infantil de Badajoz

Badajoz, 06010, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Materno-Infantil de Málaga

Málaga, 29011, Spain

Location

Hospital de la Arrixaca

Murcia, 30120, Spain

Location

Related Publications (3)

• 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.

  PMID: 3745921 BACKGROUND

• 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.

  PMID: 33610500 DERIVED

• 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.

  PMID: 31919123 DERIVED

Related Links

• Genetics Home Reference
• Acute Myeloid Leukemia MedlinePlus

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia; Leukemia, Myeloid

Interventions

Cyclophosphamide; fludarabine; Interleukin-2; aldesleukin

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Antonio Pérez Martínez, MD, PhD.

  aperezmartinez@salud.madrid.org

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2016
• First Posted: May 5, 2016
• Study Start: May 1, 2016
• Primary Completion: August 1, 2020
• Study Completion: August 1, 2020
• Last Updated: October 5, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

ES (6)