Clinical trial NCT02763475: NK Cells as Consolidation Therapy of Acute Myeloid Leukemia in Children/Adolescents
Official title: NK Cells Infusion as Consolidation Treatment of Acute Myeloid Leukemia in Children and Adolescents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Leukemia
Myeloid Leukemia
Keywords: Killer Cells, Natural
Consolidation treatment
cytologic remission
Haploidentical NK Cells
allogeneic
IL-2 Expanded NK Cells
Lead sponsor: Instituto de Investigación Hospital Universitario La Paz
Sponsor class: OTHER
Collaborators: name: Hospital Infantil Universitario Niño Jesús, Madrid, Spain
name: Fundación Mutua Madrileña
First posted: 2016-05-05
Enrollment: 7
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. Karnofsky or Lansky Performance Scale (PS) \> 60%
3. Mild-moderate (\<4) organ functional impairment (liver, kidney, respiratory) according to the criteria of the National Cancer Institute (NCI CTCAE v4).
4. Left ventricular ejection fraction\> 39%
5. Adult subjects who have voluntarily signed informed consent before the first study intervention.
6. Minor subjects whose representative / legal guardian has voluntarily signed informed consent before the first study intervention.
7. 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.
8. 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.
9. Presence of a haploidentical donor

Exclusion Criteria:

1. Patients with a history of poor treatment compliance
2. 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.
3. Severe (4) organ functional impairment (liver, kidney, respiratory) according to the criteria of the National Cancer Institute (NCI CTCAE v4).
4. They should be considered contraindications, interactions, precautions for use and dose reductions indicated in the respective data sheets.
5. Subjects who have been administered other investigational drugs within 90 days prior to inclusion

Primary outcomes:
measure: Relapse-free rate after allogeneic haploidentical NK cell infusion
timeFrame: Relapse-free rate at 1 month
measure: Relapse-free rate after allogeneic haploidentical NK cell infusion
timeFrame: Relapse-free rate at one year
measure: Relapse-free rate after allogeneic haploidentical NK cell infusion
timeFrame: Relapse-free rate at two years
measure: Relapse-free rate after allogeneic haploidentical NK cell infusion
timeFrame: Relapse-free rate at three years
Secondary outcomes:
measure: Adverse events of special interest: administration issues, infections, immunological/allergic/toxic reactions and concomitant drug interactions.
timeFrame: three years
measure: Evaluation of donor phenotype by SS-PCR
timeFrame: Three years
measure: Evaluation of patient HLA phenotype by SS-PCR
timeFrame: Three years
measure: Evaluation of donor KIR haplotype by PCR
timeFrame: Three years
measure: Analysis of Hematopoietic chimerism after NK infusion by PCR or flow cytometry
timeFrame: Three years
measure: Ligand expression of the activatory (MICA, MICB and ULBPs) or inhibitory (HLA-1) receptors of the NK cells
timeFrame: Three years
measure: NK cytotoxic activity
timeFrame: Three years
Other outcomes:
Locations:
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces
state: Vizcaya
city: Badajoz
country: Spain
facility: Hospital Materno Infantil de Badajoz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Murcia
country: Spain
facility: Hospital de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Materno-Infantil de Málaga
Study officials:
affiliation: aperezmartinez@salud.madrid.org
name: Antonio Pérez Martínez, MD, PhD.
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.