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TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children

Primary Purpose

Primary Immune Deficiency Disorders, Metabolic Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Haploidentical Hematopoietic Cell Transplantation
Sponsored by
Johns Hopkins All Children's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Immune Deficiency Disorders

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patient with any form of primary immune deficiency/dysregulatory disorders characterized by aberrant immune function, abnormal hematopoiesis, systemic or organ specific autoimmunity and/or non-malignant lymphoproliferation. This includes, but not limited to:

    I. Disorders of phagocytes: Chronic granulomatous disease, Leukocyte adhesion deficiency, defects of IL-10 pathway, MonoMac syndrome

    II. Defects of cellular and humoral immunity: Severe Combined Immunodeficiency Disorder (infants with classic SCID up to 2 years of age will be excluded due to other open protocol), X-linked hyper-IgM syndrome, DOCK8 deficiency, ZAP70 deficiency, common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, NEMO deficiency.

    III. Disorder of immune dysregulation: Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, CTLA4 deficiency, LRBA deficiency, STAT1 GOF, STAT3 GOF, X-linked lymphoproliferative disease etc.

    IV. Other PIDs and immune dysregulatory disorders who can be benefitted by HCT as deemed appropriate by the PI and the treating immunologist.

  2. Histiocytic disorders including hemophagocytic lymphohistiocytosis (familial HLH (types 1-5), secondary HLH (refractory to therapy or with recurrent episodes of hyper inflammation) and multisystem refractory Langerhans cell histiocytosis.
  3. Metabolic disorders that could improve or stabilize after stem cell transplantation such as mucopolysaccharidoses, neurodegenerative disorders, osteopetrosis, etc.

Inclusion Criteria:

  1. Patient has a suitable genotypic identical match of 5/10. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1.
  2. Patients must have adequate organ function measured by:

    1. Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26%
    2. Pulmonary: asymptomatic or if symptomatic DLCO ≥ 40% of predicted (corrected for hemoglobin) or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing.
    3. Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2.
    4. Hepatic: Serum conjugated (direct) bilirubin < 2.0 x ULN for age; AST and ALT < 5.0 x ULN for age.
    5. Karnofsky or Lansky (age-dependent) performance score ≥ 50
  3. Signed written informed consent

Exclusion Criteria:

  1. Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donors are not excluded.
  2. Pregnant or breastfeeding females.
  3. Patient has HIV or uncontrolled fungal, bacterial or viral infections.
  4. Patient has received prior solid organ transplant.
  5. Patient has active GVHD (> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.

Sites / Locations

  • Johns Hopkins All Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

TCR alpha beta T cell depletion

Arm Description

The leukapheresis product will undergo TCR alpha beta negative selection following a standardized protocol

Outcomes

Primary Outcome Measures

Incidence of successful donor engraftment
The incidence of engraftment at day 100 will be described based on donor chimerism in the whole blood and or fractions sorted for T-cell and myeloid subsets. The donor chimerism will be scored as autologous reconstitution (< 5% donor), mixed chimerism (5-49%=low mixed, 50-95%=high mixed), > 95%=full donor chimerism.

Secondary Outcome Measures

Overall survival and Event-free survival
Overall survival is defined as the time of enrollment to death from any cause or last follow up. Event-free survival is defined as the time of enrollment to death, primary or secondary graft failure, graft failure necessitating a second HCT procedure, DLI or stem cell boost given for treatment of falling chimerism, or disease recurrence
Kinetics of neutrophil engraftment
Neutrophil engraftment defined as absolute neutrophil count ≥500/μL for 3 consecutive measurements on different days
Kinetics of platelet engraftment
Platelet engraftment defined as sustained platelet count >20,000/μL and >50,000//μL with no platelet transfusions in the preceding seven days.
Transplant-related mortality
Rate of transplant-related mortality
Acute grade II-IV GvHD
Incidence and severity of acute graft versus host disease
Chronic GvHD
Incidence and severity of chronic graft versus host disease
Primary graft failure
Rates of primary graft failure
Secondary graft failure
Rates of secondary graft failure
Transplant-related complications
Frequency of transplant-related complications following transplantation
Transplant-related infections
Frequency of transplant-related infections following transplantation
Cellular and Immunological reconstitution by laboratory evaluations
The recovery of different lymphocyte subpopulation (CD3+; CD4+; CD8+; CD3+CD45RA+and CD45RO; TCR alpha beta; TCR gamma delta; CD19+)

Full Information

First Posted
May 24, 2020
Last Updated
September 8, 2023
Sponsor
Johns Hopkins All Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04414046
Brief Title
TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children
Official Title
Study of TCR Alpha Beta T-Cell and CD19 B-Cell Depletion for Hematopoietic Cell Transplantation From Haploidentical Donors in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 22, 2020 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins All Children's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This research is being done to learn if a new type of haploidentical transplantation using TCR alpha beta and CD19 depleted stem cell graft from the donor is safe and effective to treat the patient's underlying condition. This study will use stem cells obtained via peripheral blood or bone marrow from parent or other half-matched family member donor. These will be processed through a special device called CliniMACS, which is considered investigational.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Immune Deficiency Disorders, Metabolic Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
17 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
TCR alpha beta T cell depletion
Arm Type
Experimental
Arm Description
The leukapheresis product will undergo TCR alpha beta negative selection following a standardized protocol
Intervention Type
Biological
Intervention Name(s)
Haploidentical Hematopoietic Cell Transplantation
Intervention Description
TCR alpha beta T-cell and CD19 B-cell depleted haploidentical transplantation
Primary Outcome Measure Information:
Title
Incidence of successful donor engraftment
Description
The incidence of engraftment at day 100 will be described based on donor chimerism in the whole blood and or fractions sorted for T-cell and myeloid subsets. The donor chimerism will be scored as autologous reconstitution (< 5% donor), mixed chimerism (5-49%=low mixed, 50-95%=high mixed), > 95%=full donor chimerism.
Time Frame
Day 100 after transplantation
Secondary Outcome Measure Information:
Title
Overall survival and Event-free survival
Description
Overall survival is defined as the time of enrollment to death from any cause or last follow up. Event-free survival is defined as the time of enrollment to death, primary or secondary graft failure, graft failure necessitating a second HCT procedure, DLI or stem cell boost given for treatment of falling chimerism, or disease recurrence
Time Frame
Up to 2 years post transplant
Title
Kinetics of neutrophil engraftment
Description
Neutrophil engraftment defined as absolute neutrophil count ≥500/μL for 3 consecutive measurements on different days
Time Frame
Up to 42 days post transplant
Title
Kinetics of platelet engraftment
Description
Platelet engraftment defined as sustained platelet count >20,000/μL and >50,000//μL with no platelet transfusions in the preceding seven days.
Time Frame
Up to 42 days post transplant
Title
Transplant-related mortality
Description
Rate of transplant-related mortality
Time Frame
Up to 100 days post transplant
Title
Acute grade II-IV GvHD
Description
Incidence and severity of acute graft versus host disease
Time Frame
Up to 2 years post transplant
Title
Chronic GvHD
Description
Incidence and severity of chronic graft versus host disease
Time Frame
Up to 2 years post transplant
Title
Primary graft failure
Description
Rates of primary graft failure
Time Frame
Up to 2 years post transplant
Title
Secondary graft failure
Description
Rates of secondary graft failure
Time Frame
Up to 2 years post transplant
Title
Transplant-related complications
Description
Frequency of transplant-related complications following transplantation
Time Frame
Up to 2 years post transplant
Title
Transplant-related infections
Description
Frequency of transplant-related infections following transplantation
Time Frame
Up to 2 years post transplant
Title
Cellular and Immunological reconstitution by laboratory evaluations
Description
The recovery of different lymphocyte subpopulation (CD3+; CD4+; CD8+; CD3+CD45RA+and CD45RO; TCR alpha beta; TCR gamma delta; CD19+)
Time Frame
Up to 2 years post transplant

10. Eligibility

Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient with any form of primary immune deficiency/dysregulatory disorders characterized by aberrant immune function, abnormal hematopoiesis, systemic or organ specific autoimmunity and/or non-malignant lymphoproliferation. This includes, but not limited to: I. Disorders of phagocytes: Chronic granulomatous disease, Leukocyte adhesion deficiency, defects of IL-10 pathway, MonoMac syndrome II. Defects of cellular and humoral immunity: Severe Combined Immunodeficiency Disorder (infants with classic SCID up to 2 years of age will be excluded due to other open protocol), X-linked hyper-IgM syndrome, DOCK8 deficiency, ZAP70 deficiency, common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, NEMO deficiency. III. Disorder of immune dysregulation: Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, CTLA4 deficiency, LRBA deficiency, STAT1 GOF, STAT3 GOF, X-linked lymphoproliferative disease etc. IV. Other PIDs and immune dysregulatory disorders who can be benefitted by HCT as deemed appropriate by the PI and the treating immunologist. Histiocytic disorders including hemophagocytic lymphohistiocytosis (familial HLH (types 1-5), secondary HLH (refractory to therapy or with recurrent episodes of hyper inflammation) and multisystem refractory Langerhans cell histiocytosis. Metabolic disorders that could improve or stabilize after stem cell transplantation such as mucopolysaccharidoses, neurodegenerative disorders, osteopetrosis, etc. Inclusion Criteria: Patient has a suitable genotypic identical match of 5/10. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1. Patients must have adequate organ function measured by: Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26% Pulmonary: asymptomatic or if symptomatic DLCO ≥ 40% of predicted (corrected for hemoglobin) or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing. Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2. Hepatic: Serum conjugated (direct) bilirubin < 2.0 x ULN for age; AST and ALT < 5.0 x ULN for age. Karnofsky or Lansky (age-dependent) performance score ≥ 50 Signed written informed consent Exclusion Criteria: Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donors are not excluded. Pregnant or breastfeeding females. Patient has HIV or uncontrolled fungal, bacterial or viral infections. Patient has received prior solid organ transplant. Patient has active GVHD (> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jade Hanson, MSN
Phone
7277676468
Email
jade.hanson@jhmi.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Deepak Chellapandian, MD
Organizational Affiliation
Johns Hopkins All Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ian Snyder
Email
isnyder5@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Deepak Chellapandian, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children

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