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Alpha/Beta T-cell Depleted Blood-forming Stem Cell Transplant From Related or Unrelated Donors for Blood Diseases in Children and Young Adults

Primary Purpose

Blood Disease

Status

Not yet recruiting

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

TCRαβ+/CD19+ depleted Hematopoietic stem cell (HSC) graft

CliniMACS® System

About this trial

This is an interventional treatment trial for Blood Disease

Eligibility Criteria

3 Months - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

No Human leukocyte antigen (HLA) identical sibling available AND
NO HLA matched unrelated donor available OR urgent need of HSCT precludes time necessary to search for suitable HLA matched unrelated donor AND
Haploidentical donor OR closely matched unrelated donor available and willing to undergo mobilization and apheresis
If subject has genetically confirmed inherited bone marrow failure, related donor must be evaluated for this disorder and testing must be negative.
If subject has sickle cell disease, donor may have only sickle cell trait
Patient must be diagnosed with one of the following diseases or disorders:

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

Acquired Bone Marrow Failure Syndromes

Paroxysmal Nocturnal Hemoglobinuria with bone marrow failure
Myelodysplastic Syndromes (lower risk)

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
Age ≤ 40 years (except patients with hemoglobinopathies)
Life Expectancy ≥ 3 months
Karnofsky (patients > 16 years)/Lansky (patients ≤ 16 years) index ≥ 60
Organ Function Requirements

Renal Function

Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) greater than or equal to 60 ml/min/1.73m^2

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

Cardiac Function

Ejection fraction of > 40% by Multiple gated acquisition scan (MUGA) or echocardiogram

Pulmonary Function

No evidence of dyspnea at rest
No supplemental oxygen requirement
If measured, carbon monoxide diffusion capacity (DLCO) > 50%
Willing to use effective birth control method if patient is of reproductive potential
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).

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

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.

Outcomes

Primary Outcome Measures

Incidence of grade III-IV acute graft-versus-host disease (GVHD)

Acute GVHD will be assessed and graded according to the Keystone Consensus Criteria for staging and grading of acute graft-versus-host disease.

Incidence of extensive chronic GVHD

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).

Incidence of graft failure

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).

Incidence of Treatment related mortality(TRM)

TRM - defined as death from any cause other than disease progression.

Secondary Outcome Measures

Time to neutrophil engraftment

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.

Time to platelet engraftment

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.

Percentage donor chimerism using Short tandem repeat (STR)

Short tandem repeat (STR) analysis will provide the percentage donor chimerism at specific time points post-transplant.

Kinetics of lymphocyte reconstitution via immunophenotyping using flow cytometry

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.

CliniMACS system efficiency: Percentage of viable CD34+ cells recovered after the TCRαβ+ and CD19+ depletion procedure

CliniMACS system efficiency: log depletion value for CD19+ cells after the TCRαβ+ and CD19+ depletion procedure

CliniMACS system efficiency: log depletion value of TCRαβ+ cells after the TCRαβ+ and CD19+ depletion procedure

CliniMACS system efficiency: number of viable blood cell subsets after the TCRαβ+ and CD19+ depletion procedure

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

Correlation between GVHD incidence and donor killer-cell immunoglobulin-like receptor (KIR) haplotype content

Correlation between GVHD incidence and killer-cell immunoglobulin-like receptor (KIR)/KIR-ligand mismatch between donor and recipient.

Event free survival

An event is defined as death, graft failure or stable mixed chimerism with disease recurrence.

Overall survival (OS)

Incidence of symptomatic bacterial/fungal and viral reactivation requiring therapy

The incidence of infections (symptomatic bacterial/fungal and viral reactivation requiring therapy) will be used as an additional safety measure

Number of participants with adverse events related to infusion of the HSC graft

Incidence of serious adverse events

Full Information

NCT ID

NCT04806347

First Posted

March 2, 2021

Last Updated

September 27, 2023

Sponsor

University of Wisconsin, Madison

Collaborators

University of Wisconsin Carbone Cancer Center (UWCCC)

1. Study Identification

Unique Protocol Identification Number

NCT04806347

Brief Title

Alpha/Beta T-cell Depleted Blood-forming Stem Cell Transplant From Related or Unrelated Donors for Blood Diseases in Children and Young Adults

Official Title

TCRαβ+ and CD19+ Depleted Hematopoietic Stem Cell Transplant From Closely Matched Unrelated Donors or Haploidentical Related Donors for Hematologic Diseases in Children and Young Adults

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

October 2023 (Anticipated)

Primary Completion Date

March 2028 (Anticipated)

Study Completion Date

March 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Wisconsin, Madison

Collaborators

University of Wisconsin Carbone Cancer Center (UWCCC)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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 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 which 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Blood Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment arm

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

TCRαβ+/CD19+ depleted Hematopoietic stem cell (HSC) graft

Intervention Description

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.

Intervention Type

Device

Intervention Name(s)

CliniMACS® System

Intervention Description

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.

Primary Outcome Measure Information:

Title

Incidence of grade III-IV acute graft-versus-host disease (GVHD)

Description

Acute GVHD will be assessed and graded according to the Keystone Consensus Criteria for staging and grading of acute graft-versus-host disease.

Time Frame

100 days post transplantation

Title

Incidence of extensive chronic GVHD

Description

Time Frame

up to 2 years

Title

Incidence of graft failure

Description

Time Frame

up to 2 years after graft

Title

Incidence of Treatment related mortality(TRM)

Description

TRM - defined as death from any cause other than disease progression.

Time Frame

Day +100 post-HSCT

Secondary Outcome Measure Information:

Title

Time to neutrophil engraftment

Description

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.

Time Frame

up to 28 days following HSCT

Title

Time to platelet engraftment

Description

Time Frame

up to 28 days following HSCT

Title

Percentage donor chimerism using Short tandem repeat (STR)

Description

Short tandem repeat (STR) analysis will provide the percentage donor chimerism at specific time points post-transplant.

Time Frame

up to 12 months following HSCT

Title

Kinetics of lymphocyte reconstitution via immunophenotyping using flow cytometry

Description

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.

Time Frame

up to 12 months following HSCT

Title

CliniMACS system efficiency: Percentage of viable CD34+ cells recovered after the TCRαβ+ and CD19+ depletion procedure

Time Frame

up to 12 months following HSCT

Title

CliniMACS system efficiency: log depletion value for CD19+ cells after the TCRαβ+ and CD19+ depletion procedure

Time Frame

Day 0

Title

CliniMACS system efficiency: log depletion value of TCRαβ+ cells after the TCRαβ+ and CD19+ depletion procedure

Time Frame

Day 0

Title

CliniMACS system efficiency: number of viable blood cell subsets after the TCRαβ+ and CD19+ depletion procedure

Description

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

Time Frame

Day 0

Title

Correlation between GVHD incidence and donor killer-cell immunoglobulin-like receptor (KIR) haplotype content

Time Frame

up to 2 years

Title

Correlation between GVHD incidence and killer-cell immunoglobulin-like receptor (KIR)/KIR-ligand mismatch between donor and recipient.

Time Frame

up to 2 years

Title

Event free survival

Description

An event is defined as death, graft failure or stable mixed chimerism with disease recurrence.

Time Frame

up to 1 years

Title

Overall survival (OS)

Time Frame

up to 2 years

Title

Incidence of symptomatic bacterial/fungal and viral reactivation requiring therapy

Description

The incidence of infections (symptomatic bacterial/fungal and viral reactivation requiring therapy) will be used as an additional safety measure

Time Frame

up to 1 year

Title

Number of participants with adverse events related to infusion of the HSC graft

Time Frame

Day 0

Title

Incidence of serious adverse events

Time Frame

up to 2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Months

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: No Human leukocyte antigen (HLA) identical sibling available AND NO HLA matched unrelated donor available OR urgent need of HSCT precludes time necessary to search for suitable HLA matched unrelated donor AND Haploidentical donor OR closely matched unrelated donor available and willing to undergo mobilization and apheresis If subject has genetically confirmed inherited bone marrow failure, related donor must be evaluated for this disorder and testing must be negative. If subject has sickle cell disease, donor may have only sickle cell trait Patient must be diagnosed with one of the following diseases or disorders: 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 Acquired Bone Marrow Failure Syndromes Paroxysmal Nocturnal Hemoglobinuria with bone marrow failure Myelodysplastic Syndromes (lower risk) 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 Age ≤ 40 years (except patients with hemoglobinopathies) Life Expectancy ≥ 3 months Karnofsky (patients > 16 years)/Lansky (patients ≤ 16 years) index ≥ 60 Organ Function Requirements Renal Function Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) greater than or equal to 60 ml/min/1.73m^2 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 Cardiac Function Ejection fraction of > 40% by Multiple gated acquisition scan (MUGA) or echocardiogram Pulmonary Function No evidence of dyspnea at rest No supplemental oxygen requirement If measured, carbon monoxide diffusion capacity (DLCO) > 50% Willing to use effective birth control method if patient is of reproductive potential 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).

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jenny Weiland

Phone

608-890-8070

PedsHemOncResearch@lists.wisc.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Celeste Matsushima

Phone

608-890-8069

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kenneth DeSantes, MD

Organizational Affiliation

University of Wisconsin, Madison

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Jacques Galipeau, MD

Organizational Affiliation

University of Wisconsin, Madison

Official's Role

Study Director

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Alpha/Beta T-cell Depleted Blood-forming Stem Cell Transplant From Related or Unrelated Donors for Blood Diseases in Children and Young Adults

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