Alfa/beta-T-cellutarmade Blodbildande stamcellstransplantation från släkt eller obesläktade donatorer för blodsjukdomar hos barn och unga vuxna
TCRαβ+ och CD19+ utarmade hematopoetiska stamcellstransplantationer från nära matchade obesläktade givare eller haploidentiska relaterade givare för hematologiska sjukdomar hos barn och unga vuxna
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.
Studieöversikt
Status
Betingelser
Intervention / Behandling
Detaljerad beskrivning
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.
Studietyp
Inskrivning (Beräknad)
Fas
- Fas 1
Kontakter och platser
Studiekontakt
- Namn: Celeste Matsushima
- Telefonnummer: 608-890-8069
Studera Kontakt Backup
- Namn: Jenny Weiland
- Telefonnummer: 608-890-8070
- E-post: PedsHemOncResearch@lists.wisc.edu
Studieorter
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-
Wisconsin
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Madison, Wisconsin, Förenta staterna, 53792
- Rekrytering
- American Family Children's Hospital
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-
Deltagandekriterier
Urvalskriterier
Åldrar som är berättigade till studier
Tar emot friska volontärer
Kön som är behöriga för studier
Beskrivning
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).
Studieplan
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Behandling
- Tilldelning: N/A
- Interventionsmodell: Enskild gruppuppgift
- Maskning: Ingen (Open Label)
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
|---|---|
|
Experimentell: 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. |
Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Incidence of grade III-IV acute graft-versus-host disease (GVHD)
Tidsram: 100 days post transplantation
|
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
Tidsram: up to 2 years
|
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
|
|
Incidence of graft failure
Tidsram: up to 2 years after graft
|
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
|
|
Incidence of Treatment Related Mortality (TRM)
Tidsram: Day +100 post-HSCT
|
TRM - defined as death from any cause other than disease progression. |
Day +100 post-HSCT
|
Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Total överlevnad (OS)
Tidsram: upp till 2 år
|
upp till 2 år
|
|
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CliniMACS-systemeffektivitet: Andel livskraftiga CD34+-celler som återvunnits efter TCRαβ+- och CD19+-utarmningsproceduren
Tidsram: upp till 12 månader efter HSCT
|
upp till 12 månader efter HSCT
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|
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Korrelation mellan GVHD-incidens och donatormördarcellsimmunoglobulinliknande receptor (KIR) haplotypinnehåll
Tidsram: upp till 2 år
|
upp till 2 år
|
|
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Korrelation mellan GVHD-incidens och mördarcellsimmunoglobulinliknande receptor (KIR)/KIR-ligandfelmatchning mellan givare och mottagare.
Tidsram: upp till 2 år
|
upp till 2 år
|
|
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Antal deltagare med biverkningar relaterade till infusion av HSC-transplantatet
Tidsram: Dag 0
|
Dag 0
|
|
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Förekomst av allvarliga biverkningar
Tidsram: upp till 2 år
|
upp till 2 år
|
|
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CliniMACS system efficiency: log depletion value for CD19/CD20+ B cells after the TCRαβ+ and CD19+ depletion procedure
Tidsram: Day 0
|
Day 0
|
|
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CliniMACS system efficiency: log depletion value of TCRαβ+ T cells after the TCRαβ+ and CD19+ depletion procedure
Tidsram: Day 0
|
Day 0
|
|
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Time to neutrophil engraftment
Tidsram: up to 28 days following HSCT
|
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
|
|
Time to platelet engraftment
Tidsram: up to 28 days following HSCT
|
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
|
|
Percentage donor chimerism using Short Tandem Repeat (STR)
Tidsram: up to 12 months following HSCT
|
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
Tidsram: 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
|
|
CliniMACS system efficiency: number of viable blood cell subsets after the TCRαβ+ and CD19+ depletion procedure
Tidsram: Day 0
|
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
|
|
Event free survival
Tidsram: up to 1 years
|
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
Tidsram: up to 1 year
|
The incidence of infections (symptomatic bacterial/fungal and viral reactivation requiring therapy) will be used as an additional safety measure |
up to 1 year
|
Samarbetspartners och utredare
Sponsor
Utredare
- Huvudutredare: Christian Capitini, MD, University of Wisconsin, Madison
- Studierektor: Jacques Galipeau, MD, University of Wisconsin, Madison
Studieavstämningsdatum
Studera stora datum
Studiestart (Beräknad)
Primärt slutförande (Beräknad)
Avslutad studie (Beräknad)
Studieregistreringsdatum
Först inskickad
Först inskickad som uppfyllde QC-kriterierna
Första postat (Faktisk)
Uppdateringar av studier
Senaste uppdatering publicerad (Faktisk)
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
Senast verifierad
Mer information
Termer relaterade till denna studie
Ytterligare relevanta MeSH-villkor
Andra studie-ID-nummer
- 2020-1251
- A536755 (Annan identifierare: UW Madison)
- UW19113 (Annan identifierare: OnCore ID)
- 2020-1251 (Annan identifierare: HS IRB UW Madison)
- NCI-2021-02128 (Registeridentifierare: NCI CTRP)
- Protocol Version 6 (Annan identifierare: HS-IRB UW Madison)
Plan för individuella deltagardata (IPD)
Planerar du att dela individuella deltagardata (IPD)?
IPD-planbeskrivning
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.
IPD-delning som stöder informationstyp
- STUDY_PROTOCOL
- SAV
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