Transplantace krvetvorných kmenových buněk s vyčerpanými alfa/beta T-buňkami od příbuzných nebo nepříbuzných dárců pro krevní choroby u dětí a mladých dospělých
Transplantace hematopoetických kmenových buněk s vyčerpanými TCRαβ+ a CD19+ od úzce sladěných nepříbuzných dárců nebo haploidentických příbuzných dárců pro hematologická onemocnění u dětí a mladých dospělých
This study is being done to see if the investigators can take peripheral blood stem cells from either an adult family member or a closely matched unrelated donor, and run them through a special lab instrument to remove alpha/beta T cells and B cells and then give them to the patient to treat disease. This is an experimental way of doing a hematopoietic stem cell transplant (HSCT). The investigators want to see if the new stem cells will grow without bad graft vs. host disease (GVHD). This treatment approach is experimental in the United States.
Přehled studie
Postavení
Podmínky
Detailní popis
This single institution, phase I clinical trial will determine the safety and feasibility of employing T-cell receptor (TCR) αβ+ and CD19+ (Cluster of Differentiation) depleted hematopoietic stem cell transplantation (HSCT) using peripheral blood stem cells (PBMC) from closely matched unrelated donors or haploidentical donors to treat non-malignant hematologic diseases in children and young adults. Allogeneic hematopoietic stem cell transplantation has become a curative option for children and adolescents with a variety of otherwise fatal conditions. To reduce the incidence and severity of graft-versus-host disease (GVHD) associated with allogeneic hematopoietic stem cell transplantation, donor grafts are depleted of T cells, either using CD34+ selection or CD3+/CD19+ depletion of grafts. However, these selection processes also deplete the graft of protective cell subsets, such as γδ T cells, natural killer (NK) cells, monocytes and dendritic cells, which play important roles in the immune response to infectious agents. Moreover, the presence of NK cells and γδ T cells in donor grafts is associated with more rapid immune reconstitution after HSCT transplantation. In order to retain these protective immune cell subsets, this trial will use a novel, highly selective graft engineering process using the Miltenyi CliniMACS system that selectively depletes αβ-T cells and B cells that are responsible for GVHD and Epstein Barr Virus (EBV)-related post-transplantation lymphoproliferative disorder, respectively. Prior to transplantation, patients will be treated with a conditioning regimen, specific for the original disorder.
The primary objective of this study is evaluation of the safety and feasibility of HSCT using TCRαβ+/CD19+ depleted hematopoietic stem cells to treat non-malignant hematologic diseases. This will be assessed by evaluating the incidence of graft failure, grade III-IV acute GVHD and chronic GVHD and TRM.
Secondary objectives include the evaluation of immune reconstitution and incidence of post-transplant infections, adverse events, serious adverse events, overall and disease-free survival and the efficiency of graft processing by the CliniMACS System.
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 1
Kontakty a umístění
Studijní kontakt
- Jméno: Celeste Matsushima
- Telefonní číslo: 608-890-8069
Studijní záloha kontaktů
- Jméno: Jenny Weiland
- Telefonní číslo: 608-890-8070
- E-mail: PedsHemOncResearch@lists.wisc.edu
Studijní místa
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Wisconsin
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Madison, Wisconsin, Spojené státy, 53792
- Nábor
- American Family Children's Hospital
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
Inclusion Criteria:
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No Human leukocyte antigen (HLA) identical sibling available AND
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NO HLA matched unrelated donor available OR urgent need of HSCT precludes time necessary to search for suitable HLA matched unrelated donor AND
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Haploidentical donor OR closely matched unrelated donor available and willing to undergo mobilization and apheresis
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If subject has genetically confirmed inherited bone marrow failure, related donor must be evaluated for this disorder and testing must be negative.
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If subject has sickle cell disease, donor must be unaffected or have only sickle cell trait
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Patient must be diagnosed with one of the following diseases or disorders:
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Hemoglobinopathies
- Sickle Cell Disease for patients ≤ 21 years of age for whom hydroxyurea has been trialed for at least six months, and failed
- Thalassemia Major for patients ≤ 21 years of age
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Acquired Bone Marrow Failure Syndromes
- Paroxysmal Nocturnal Hemoglobinuria with bone marrow failure
- Myelodysplastic Syndromes (lower risk)
- Severe acquired aplastic anemia
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Inherited Bone Marrow Failure Syndromes
- Fanconi Anemia
- Diamond Blackfan Anemia
- Dyskeratosis Congenita and related telomere disorders
- Congenital Thrombocytopenia Syndromes
- Severe Congenital Neutropenia
- Shwachman-Diamond Syndrome
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Inborn Errors of Immunity (IEI) or Primary Immune Regulatory Disorders (PIRD)
- Wiskott-Aldrich syndrome (WAS)
- Chronic granulomatous disease (CGD)
- Severe combined immunodeficiency (SCID)
- Primary hemophagocytic lymphohistiocytosis (HLH)
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Age ≤ 25 years (except patients with hemoglobinopathies)
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Life Expectancy ≥ 3 months
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Karnofsky (patients > 16 years)/Lansky (patients ≤ 16 years) index ≥ 60
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Organ Function Requirements
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Renal Function
- Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) greater than or equal to 60 ml/min/1.73m^2
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Liver Function
- Total bilirubin < 3 mg/dL
- Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase; synonymous with ALT (SCPT) ≤ 3 x Upper Limit of Normal (ULN) for age
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Cardiac Function
- Ejection fraction of > 40% by Multiple gated acquisition scan (MUGA) or echocardiogram
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Pulmonary Function
- No evidence of dyspnea at rest
- No supplemental oxygen requirement
- If measured, carbon monoxide diffusion capacity (DLCO) > 50%
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Willing to use effective birth control method if patient is of reproductive potential
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Informed consent obtained (patient or legal representative)
Exclusion Criteria:
- Pregnant
- HIV infection
- Uncontrolled, serious active infection at screening
- Significant serious intercurrent illnesses
- Enrollment in any other treatment study that would interfere with the endpoints of this study according to judgement of Principal Investigator (or PI designee).
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: N/A
- Intervenční model: Přiřazení jedné skupiny
- Maskování: Žádné (otevřený štítek)
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
|---|---|
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Experimentální: Treatment arm
Participants will undergo a conditioning regimen, specific for the original disease, After that peripheral blood stem cell transplant from a haploidentical donor or closely matched unrelated donor, depleted of TCRαβ+ and CD19+ cells using the CliniMACS TCR α/β-biotin and CD19 Systems will be administered intravenously on Day 0 to all participants. |
After undergoing a disease specific conditioning regimen (standard of care), participants will receive peripheral blood stem cell transplant from a haploidentical donor or closely matched unrelated donor, depleted of TCR αβ+ and CD19+ cells using the CliniMACS TCR α/β-biotin and CD19 Systems. The CliniMACS Cell Selection System is based on magnetic-activated cell sorting mechanism. The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures. |
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Incidence of grade III-IV acute graft-versus-host disease (GVHD)
Časové okno: 100 days post transplantation
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Acute GVHD will be assessed and graded according to the Keystone Consensus Criteria for staging and grading of acute graft-versus-host disease. |
100 days post transplantation
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Incidence of extensive chronic GVHD
Časové okno: up to 2 years
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Chronic GVHD will be assessed according to the current CIBMTR (Center for International Blood and Marrow Transplant Research) manual reflecting a grading system published by Sullivan KM (Sullivan 1981). |
up to 2 years
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Incidence of graft failure
Časové okno: up to 2 years after graft
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Graft failure - defined as failure to achieve ANC > 500 /µL at Day +28 or initial neutrophil engraftment followed by a decline in ANC < 500 /µL that is unresponsive to growth factor therapy (secondary graft failure). |
up to 2 years after graft
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Incidence of Treatment Related Mortality (TRM)
Časové okno: Day +100 post-HSCT
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TRM - defined as death from any cause other than disease progression. |
Day +100 post-HSCT
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Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Celkové přežití (OS)
Časové okno: do 2 let
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do 2 let
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Účinnost systému CliniMACS: Procento životaschopných buněk CD34+ získaných po postupu vyčerpání TCRαβ+ a CD19+
Časové okno: až 12 měsíců po HSCT
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až 12 měsíců po HSCT
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Korelace mezi výskytem GVHD a obsahem haplotypu dárcovských zabijáckých buněk imunoglobulinového receptoru (KIR)
Časové okno: do 2 let
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do 2 let
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Korelace mezi výskytem GVHD a nesouladem mezi dárcem a příjemcem imunoglobulinu podobný receptor (KIR)/KIR-ligand.
Časové okno: do 2 let
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do 2 let
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Počet účastníků s nežádoucími účinky souvisejícími s infuzí štěpu HSC
Časové okno: Den 0
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Den 0
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Výskyt závažných nežádoucích příhod
Časové okno: do 2 let
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do 2 let
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CliniMACS system efficiency: log depletion value for CD19/CD20+ B cells after the TCRαβ+ and CD19+ depletion procedure
Časové okno: Day 0
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Day 0
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CliniMACS system efficiency: log depletion value of TCRαβ+ T cells after the TCRαβ+ and CD19+ depletion procedure
Časové okno: Day 0
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Day 0
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Time to neutrophil engraftment
Časové okno: up to 28 days following HSCT
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The time to neutrophil engraftment is defined as the post-transplant day that is the first of 3 consecutive days with an absolute neutrophil count (ANC) of >500/µL as assessed by CBC. |
up to 28 days following HSCT
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Time to platelet engraftment
Časové okno: up to 28 days following HSCT
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The time to platelet engraftment is defined as the post-transplant day that is the first of 3 consecutive days with a platelet count ≥ 20,000/µL as assessed by complete blood count (CBC), without platelet support (transfusion) for 7 days. |
up to 28 days following HSCT
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Percentage donor chimerism using Short Tandem Repeat (STR)
Časové okno: up to 12 months following HSCT
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Short tandem repeat (STR) analysis will provide the percentage donor chimerism at specific time points post-transplant. |
up to 12 months following HSCT
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Kinetics of lymphocyte reconstitution via immunophenotyping using flow cytometry
Časové okno: up to 12 months following HSCT
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Lymphocyte reconstitution will be assessed at specific time points post-HSCT, expressed as the percentage of white blood cells comprised of T, B and NK cell subsets. |
up to 12 months following HSCT
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CliniMACS system efficiency: number of viable blood cell subsets after the TCRαβ+ and CD19+ depletion procedure
Časové okno: Day 0
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Number of viable CD34+ blood stem cells, CD20+ B cells, CD3-CD56+ NK cells, TCRαβ+ T cells, and TCRγδ+ T cells in the HSC graft after the TCRαβ+ and CD19+ depletion procedure |
Day 0
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Event free survival
Časové okno: up to 1 years
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An event is defined as death, graft failure or stable mixed chimerism with disease recurrence. |
up to 1 years
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Incidence of symptomatic bacterial/fungal and viral reactivation requiring therapy
Časové okno: up to 1 year
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The incidence of infections (symptomatic bacterial/fungal and viral reactivation requiring therapy) will be used as an additional safety measure |
up to 1 year
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Spolupracovníci a vyšetřovatelé
Sponzor
Vyšetřovatelé
- Vrchní vyšetřovatel: Christian Capitini, MD, University of Wisconsin, Madison
- Ředitel studie: Jacques Galipeau, MD, University of Wisconsin, Madison
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Odhadovaný)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Další relevantní podmínky MeSH
Další identifikační čísla studie
- 2020-1251
- A536755 (Jiný identifikátor: UW Madison)
- UW19113 (Jiný identifikátor: OnCore ID)
- 2020-1251 (Jiný identifikátor: HS IRB UW Madison)
- NCI-2021-02128 (Identifikátor registru: NCI CTRP)
- Protocol Version 6 (Jiný identifikátor: HS-IRB UW Madison)
Plán pro data jednotlivých účastníků (IPD)
Plánujete sdílet data jednotlivých účastníků (IPD)?
Popis plánu IPD
The Principal Investigator, Sponsor and funding institutions (if applicable) will ensure that all mechanisms used to share data include proper plans and safeguards to protect the rights and privacy of participants who participate in this research.
Typ podpůrných informací pro sdílení IPD
- PROTOKOL STUDY
- MÍZA
Informace o lécích a zařízeních, studijní dokumenty
Studuje lékový produkt regulovaný americkým FDA
Studuje produkt zařízení regulovaný americkým úřadem FDA
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