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

March 30, 2022 updated by: Instituto de Investigación Hospital Universitario La Paz

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

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

18

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Spain
      • Barcelona, Spain, 08041
        • Recruiting
        • Hospital de la Santa Creu i Sant Pau
        • Contact:
        • Principal Investigator:
          • Isabel Badell Serra, Doctor
        • Sub-Investigator:
          • María Trabazo del Castillo, Doctor
      • Madrid, Spain, 28046
        • Recruiting
        • Hospital Universitario La Paz
        • Contact:
        • Principal Investigator:
          • Antonio Pérez Martínez, Doctor
        • Sub-Investigator:
          • David Bueno Sánchez, Doctor
        • Sub-Investigator:
          • Pilar Guerra García, Doctor
      • Madrid, Spain, 28007
        • Recruiting
        • Hospital General Universitario Gregorio Maranon
        • Contact:
        • Principal Investigator:
          • Cristina Beléndez Bieler, Doctor
      • Madrid, Spain, 28009
        • Recruiting
        • Hospital Infantil Universitario Niño Jeús
        • Contact:
        • Principal Investigator:
          • Marta González Vicent, Doctor
      • Murcia, Spain, 30120
        • Not yet recruiting
        • Hospital Clínico Universitario Virgen de la Arrixaca
        • Contact:
        • Principal Investigator:
          • José L Fuster Soler, Doctor
      • Málaga, Spain, 29010
        • Not yet recruiting
        • Hospital Regional Universitario de Malaga (Carlos de Haya)
        • Contact:
        • Principal Investigator:
          • Antonia I Pascual Martínez, Doctor
      • Sevilla, Spain, 41013
        • Recruiting
        • Hospital Universitario Virgen del Rocío
        • Contact:
        • Principal Investigator:
          • José M Pérez Hurtado, Doctor
      • Valencia, Spain, 46026
        • Not yet recruiting
        • Hospital Universitario La Fe
        • Contact:
    • A Coruña
      • Santiago De Compostela, A Coruña, Spain, 15706
        • Recruiting
        • Hospital Clínico Universitario de Santiago
        • Contact:
        • Principal Investigator:
          • Alexandra Regueiro García, Doctor
    • Asturias
      • Oviedo, Asturias, Spain, 33011
        • Recruiting
        • Hospital Universitario Central de Asturias
        • Contact:
        • Principal Investigator:
          • Pilar M Palomo Moraleda, Doctor

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 21 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: KIR mismatch aloreactive NK donor cells
Three patients from each cohort will receive NK aloreactive cells from a KIR mismatch donor
Biological: Alloreactive NK cells
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
EXPERIMENTAL: NK cells stimulated ex vivo with IL-15 from KIR match donor
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
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose-limiting toxicity (TLD)
Time Frame: 52 weeks
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)
Time Frame: 52 weeks
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
Time Frame: Week 52
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
Time Frame: Week 52
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
Time Frame: Week 52
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Instituto de Investigación Hospital Universitario La Paz

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

November 30, 2020

Primary Completion (ANTICIPATED)

June 1, 2022

Study Completion (ANTICIPATED)

May 1, 2023

Study Registration Dates

First Submitted

January 12, 2022

First Submitted That Met QC Criteria

March 30, 2022

First Posted (ACTUAL)

March 31, 2022

Study Record Updates

Last Update Posted (ACTUAL)

March 31, 2022

Last Update Submitted That Met QC Criteria

March 30, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Other Study ID Numbers

  • PHINK -01/2019
  • 2019-000911-10 (EUDRACT_NUMBER)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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