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

Blood Disease Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04806347
• Other study ID #: UW19113
• Secondary ID: 2020-1251A536755
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: June 2024
• Est. completion date: March 2029

Study information

• Verified date: December 2023
• Source: University of Wisconsin, Madison
• Contact: Jenny Weiland
• Phone: 608-890-8070
• Email: PedsHemOncResearch[@]lists.wisc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 12
• Est. completion date: March 2029
• Est. primary completion date: March 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 40 Years

Eligibility

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).

Related Conditions & MeSH terms

• Blood Disease
• Hematologic Diseases

Intervention

Biological:
• TCRaß+/CD19+ depleted Hematopoietic stem cell (HSC) graft
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 aß+ and CD19+ cells using the CliniMACS TCR a/ß-biotin and CD19 Systems.

Device:
• CliniMACS® System
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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University of Wisconsin, Madison	University of Wisconsin Carbone Cancer Center (UWCCC)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	100 days post transplantation
Primary	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).	up to 2 years
Primary	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).	up to 2 years after graft
Primary	Incidence of Treatment related mortality(TRM)	TRM - defined as death from any cause other than disease progression.	Day +100 post-HSCT
Secondary	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.	up to 28 days following HSCT
Secondary	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.	up to 28 days following HSCT
Secondary	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.	up to 12 months following HSCT
Secondary	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.	up to 12 months following HSCT
Secondary	CliniMACS system efficiency: Percentage of viable CD34+ cells recovered after the TCRaß+ and CD19+ depletion procedure		up to 12 months following HSCT
Secondary	CliniMACS system efficiency: log depletion value for CD19+ cells after the TCRaß+ and CD19+ depletion procedure		Day 0
Secondary	CliniMACS system efficiency: log depletion value of TCRaß+ cells after the TCRaß+ and CD19+ depletion procedure		Day 0
Secondary	CliniMACS system efficiency: number of viable blood cell subsets after the TCRaß+ and CD19+ depletion procedure	Number of viable CD34+ blood stem cells, CD20+ B cells, CD3-CD56+ NK cells, TCRaß+ T cells, and TCR?d+ T cells in the HSC graft after the TCRaß+ and CD19+ depletion procedure	Day 0
Secondary	Correlation between GVHD incidence and donor killer-cell immunoglobulin-like receptor (KIR) haplotype content		up to 2 years
Secondary	Correlation between GVHD incidence and killer-cell immunoglobulin-like receptor (KIR)/KIR-ligand mismatch between donor and recipient.		up to 2 years
Secondary	Event free survival	An event is defined as death, graft failure or stable mixed chimerism with disease recurrence.	up to 1 years
Secondary	Overall survival (OS)		up to 2 years
Secondary	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	up to 1 year
Secondary	Number of participants with adverse events related to infusion of the HSC graft		Day 0
Secondary	Incidence of serious adverse events		up to 2 years