Phase I / II Study on Infusion of Natural Killer Cells After Haploidentical Transplantation in Pediatric Patients

Study Overview
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Brief Summary
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Phase I / II study on infusion of alloreactive or stimulated Natural Killer cells with IL-15 ex vivo after haploidentical transplantation of hematopoietic progenitors in pediatric patients with hematologic malignancies (PHINK

Detailed Description
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Haploidentical hematopoietic stem cell transplantation (haploTPH) constitutes a highly complex but effective procedure for some hematologic malignancies high-risk pediatric patients in the absence of an identical HLA donor. Relapse Post-transplant leukemia is the main problem for survival. Just like reported different expert groups on haploTPH in adults and children, there is a determining role of Natural Killer (NK) cells in haploTPH as inducers powerful graft-versus-leukemia (EIcL) effect. The presence of NK cells allo-reactive is correlated with a lower relapse rate, in addition to favoring the graft, decrease graft versus recipient disease (GVHD) and decrease viral infections. This only occurs in half of the donor-recipient pairs, so that, in its absence, it is necessary to develop other strategies for activating the NK cells. In this sense, the investigational group has extensive experience in research translational with NK cells and is a pioneer in infusing ex vivo activated NK cells with IL-15. The investigators propose a phase I / II clinical trial with dose escalation, multicenter, framed in the Spanish Group of Hematopoietic Transplantation / Marrow Transplant Bone in Children (GETH / GETMON), to determine the safety and efficacy of a post-haploTPH IL-15 alloreactive / stimulated NK cell infusion in children with malignant blood diseases. The investigators will monitor immune reconstitution, chimerism, Post-transplantation NK cell expansion, phenotype, and function. Secondarily evaluate the effectiveness of therapy on the incidence of graft failure; EICR; viral reactivations; transplant-related mortality; and relapse of leukemia.

Official Title
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Phase I / II Study on Infusion of Alloreactive or Stimulated Natural Killer Cells With IL-15 ex Vivo After Haploidentical Transplantation of Hematopoietic Progenitors in Pediatric Patients With Hematological Neoplasms

Conditions
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High-risk Leukemias

Intervention / Treatment
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* Biological: NK cells stimulated ex vivo with IL-15
* Biological: Alloreactive NK cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of both sexes with age ≤ 21 years. Not having an identical HLA donor (family or non-family) available in the time needed for the donation of hematopoietic parents. Having a haploidenic donor available Diagnosis of high-risk hematological malignancy. This includes: i. High risk ALL in first complete remission (RC1); ii. ALL in second complete remission (RC2); iii. ALL in third complete remission (RC3) or later; iv. High risk AML in RC1; v. AML in RC2 or later; vi. Relapsed AML with <25% blasts in bone marrow; vii. AML related to previous treatments in CR> 12 months; viii. Primary or secondary myelodysplastic syndrome ix. NK cell leukemia, biphenotypic or undifferentiated in RC1 or later, x. Chronic myeloid leukemia (CML) in accelerated phase, in chronic phase with persistent molecular positivity, or with intolerance to tyrosine kinase inhibitors xi. Hodgkin's lymphoma in RC2 or later after failure of autologous TPH, or unable to mobilize hematopoietic progenitors for autologous TPH xii. Non-Hodgkin's lymphoma in RC2 or later after failure of autologous TPH, or unable to mobilize hematopoietic progenitors for autologous TPH xiii. Myelomonocytic juvenile leukemia. Positive pre-transplant evaluation i. Left ventricular ejection fraction > 40% or shortening fraction ≥ 25%; ii. Creatinine clearance (ACr) or glomerular filtration rate (TFG) ≥ 50 ml/min/1.73 m2 iii. Forced Vital Capacity (FVC) ≥ 50% of predicted value or pulse-oximetry ≥ 92% if the patient cannot perform the pulmonary function tests; iv. Karnofsky or Lansky Index (depending on the patient's age) ≥ 50; v. Bilirubin ≤ 3 times the upper limit of normal for age vi. Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal for age vii. Women who are not breastfeeding. viii. No uncontrolled bacterial, fungal, or viral infections at the time of inclusion. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 14 days prior to trial inclusion and must agree to use highly effective contraceptive methods (diaphragms plus spermicide or male condom plus spermicide, oral contraceptive combined with a second method of contraceptive implant, injectable contraceptive, permanent intrauterine device, sexual abstinence, or partner with vasectomy) during study participation and for six months after the last trial visit. In the case of male patients with reproductive capacity, they must commit to using an appropriate barrier method for the duration of the study and for up to 6 months thereafter Exclusion Criteria: Patients with an active infectious process or other serious underlying medical condition Patients who, according to the investigator's criteria, have a history of poor compliance with therapy. Patients who after a psycho-social evaluation are advised as not suitable for the procedure: i. Social-family situation that makes correct participation in the study impossible. ii. Patients with emotional or psychological problems secondary to the illness such as post-traumatic stress disorder, phobias, delusions, psychosis, with the need for support from specialists. iii. Evaluation of the involvement of family members in the health of the patient Inability to understand the information about the trial Received an investigational drug within 30 days prior to the start of therapy or within 5 half-lives of receiving an investigational drug, whichever is longer.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: KIR mismatch aloreactive NK donor cells<br>Three patients from each cohort will receive NK aloreactive cells from a KIR mismatch donor | Biological: Alloreactive NK cells<br>* When the patient lacks the HLA class I molecule and his donor has this molecule and also the donor NK cells have the KIR receptor that recognizes the absence of the corresponding HLA class I ligand<br>|
| Experimental: NK cells stimulated ex vivo with IL-15 from KIR match donor<br>Three patients in each cohort will receive ex vivo stimulated NK cells with IL-15 from a KIR match donor. | Biological: NK cells stimulated ex vivo with IL-15<br>* When patient and donor are KIR-HLA match, the patient submits all HLA class I molecules, or in the absence of any, your donor does not have this molecule, or having it lacks the corresponding KIR receiver. For more information detailed information on the product under investigation, reference is made to the Dossier of the Research Product (IMPD): PEI 09-008<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (TLD) | To determine dose-limiting toxicity (TLD) of a single infusion of aloreactive NK cells or ex vivo IL-15-stimulated NK cells after haploTPH in pediatric patients with high-risk leukemias. | 52 weeks | 
| Maximum tolerated dose (MTD) | To determine maximum tolerated dose (MTD) of a single infusion of aloreactive NK cells or ex vivo IL-15-stimulated NK cells after haploTPH in pediatric patients with high-risk leukemias. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of post haploTPH NK cell therapy | The efficacy of post haploTPH NK cell therapy will be determined, comparing it with the historical cohort recently reported by GETH/GETMON in the incidence of graft failure, acute/chronic GVHD, viral reactivations (CMV, EBV, HHV-6, adenovirus, BKV), transplant-related mortality (TRM), and leukemia relapse. | Week 52 | 
| Clinical evolution of patients | The clinical course of patients will be compared based on the dose of infused NK cells, KIR match vs. KIR mismatch NK cells, expansion, chimerism, and phenotypic and functional characteristics of the infused NK cells, and the speed and characteristics of immune reconstitution post haploTPH. | Week 52 | 
| Monitor immune reconstitution and characterize NK cells | Immune reconstitution will be monitored by quantifying immunoglobulins at different times, and characterizing NK cells in patients, at a phenotypic and functional level, for 1 year after haploTPH | Week 52 |