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Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells for Patients With Primary Immunodeficiencies

Primary Purpose

Immunodeficiencies, Immune Dysregulation Syndromes

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Apha/beta T and CD19+ cell depletion using CliniMACS device
Sponsored by
Children's Hospital of Philadelphia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Immunodeficiencies focused on measuring Immunodeficiencies, Immune dysregulation syndromes

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Ages 0-25 years at time of enrollment

  2. Diseases:

    • Immunodeficiencies for which allogeneic hematopoietic stem cell transplant is indicated, including severe combined immunodeficiencies, immunodeficiency polyendocrinopathy X-linked syndrome (IPEX), X-linked lymphoproliferative disease, chronic granulomatous disease, Wiskott-Aldrich syndrome (WAS), hyperIgM, and other life-threatening immunodeficiencies.
    • Immune dysregulation syndromes, including refractory or recurrent hemophagocytic lymphohistiocytosis, hemophagocytic lymphohistiocytosis (HLH) with genetic mutations, refractory multisystemic Langerhans cell histiocytosis, other macrophage activating syndrome (MAS) refractory to standard therapy.

  3. Clinical status

    • Lansky or Karnofsky performance >=60

    • Organ Function:

      1. Serum creatinine <1.5 x upper limit of normal for age Hepatic: ALT <=250; AST <=350
      2. Cardiac shortening fraction >=27%
      3. Bilirubin <2.5x normal (unless elevation due to Gilberts disease).
      4. No active untreated infection
  4. Signed informed consent
  5. No HLA matched related donor available.
  6. Females of childbearing potential must have negative pregnancy test.

Exclusion Criteria:

  • Uncontrolled bacterial, viral or fungal infections
  • HLA matched related or unrelated donor able to donate mobilized peripheral stem cells.
  • Pregnant Females
  • Matched related donor available for bone marrow donation

Donors Selection Criteria:

  • Donor selection will comply with 21 CFR 1271
  • Unrelated donor matched or up to one antigen mismatch as per National Marrow Donor Program (NMDP).
  • Haploidentical parent or sibling able to undergo mobilization for peripheral stem cell collection. Maternal donor preferred over paternal donor if both equally haploidentical.
  • Children's Hospital of Philadelphia (CHOP) Blood and Marrow Transplant (BMT) procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases.
  • Unrelated donor identified through the National Marrow Donor Program (NMDP) and fulfills the NMDP criteria for donation. Unrelated donor willing and able to undergo mobilization of peripheral stem cells and apheresis

Sites / Locations

  • Children's Hospital of PhiladelphiaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Other

Other

Arm Label

Reduced intensity regimen

Myeloablative regimen

Immunotherapy

Arm Description

Conditioning regimen is dependent on patient diagnosis and age. Reduced intensity conditioning with chemotherapy followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Standard of care reduced intensity conditioning will include Busulfan, Fludarabine, Thiotepa followed by stem cell infusion.

Conditioning regimen is dependent on patient diagnosis and age. Patients with chronic granulomatous disease or Wiskott-Aldrich syndrome will receive cyclophosphamide in lieu of thiotepa to ensure engraftment. Myeloablative regimen with chemotherapy followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Standard of care myeloablative regimen will include Busulfan, Fludarabine, Thiotepa, or Cyclophosphamide followed by stem cell infusion.

Conditioning regimen is dependent on patient diagnosis and age. Severe combined immunodeficiency (SCID) patients will be conditioned with immunotherapy only followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Immunotherapy regimen will include anti-thymocyte globulin followed by stem cell infusion.

Outcomes

Primary Outcome Measures

Event free survival
Event free survival in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted
Stable engraftment
Stable engraftment in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted

Secondary Outcome Measures

Severity of graft vs. host disease (GVHD)
Severity of acute and chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years
Incidence of graft vs. host disease (GVHD)
Evaluation of incidence of chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years

Full Information

First Posted
December 5, 2016
Last Updated
July 14, 2023
Sponsor
Children's Hospital of Philadelphia
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1. Study Identification

Unique Protocol Identification Number
NCT02990819
Brief Title
Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells for Patients With Primary Immunodeficiencies
Official Title
Phase II Study for Patients With Primary Immunodeficiencies Using and Cd19+ Depleted Unrelated Donor or Partially Matched Related Donor Peripheral Stem Cells
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 2016 (undefined)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Children's Hospital of Philadelphia

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase II trial to determine the ability of a reduced intensity conditioning regimen to allow successful engraftment with alpha/beta T and CD19+ depleted peripheral stem cell grafts from unrelated or partially matched related donors. There are two conditioning regimens depending upon patient diagnosis and age.
Detailed Description
This is a Phase II trial to determine the ability of a reduced intensity conditioning regimen to allow successful engraftment with alpha/beta T and CD19+ depleted peripheral stem cell grafts from unrelated or partially matched related donors. There are two conditioning regimens depending upon patient diagnosis and age. The study will include patients 0-25 years with PID, including immune dysregulation syndromes for which hematopoietic stem cell transplant is indicated. Treatment: Either conditioning regimen (listed below) followed by alpha/beta T and CD19+ depleted donor peripheral stem cells Reduced intensity conditioning with busulfan x 8 doses, fludarabine 40 mg/m2 x 4, thiotepa 5 mg/kg x 2, anti-thymocyte globulin (ATG) 3 mg/kg x 3. OR Myeloablative regimen with busulfan x 16 doses or Daily for four days, fludarabine 30 mg/m2 x 5, thiotepa 5 mg/kg x 2, ATG 3 mg/kg x 2. OR Immunotherapy regimen on days -9, 8, 7 with anti-thymocyte globulin 3 mg/kg/day (for severe combined immunodeficiency patients only). Infusion of alpha/beta T and CD19+ depleted donor peripheral stem cells. Follow up, including evaluation of chimerism and immune reconstitution.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Immunodeficiencies, Immune Dysregulation Syndromes
Keywords
Immunodeficiencies, Immune dysregulation syndromes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
T-depleted stem cell infusion
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Reduced intensity regimen
Arm Type
Other
Arm Description
Conditioning regimen is dependent on patient diagnosis and age. Reduced intensity conditioning with chemotherapy followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Standard of care reduced intensity conditioning will include Busulfan, Fludarabine, Thiotepa followed by stem cell infusion.
Arm Title
Myeloablative regimen
Arm Type
Other
Arm Description
Conditioning regimen is dependent on patient diagnosis and age. Patients with chronic granulomatous disease or Wiskott-Aldrich syndrome will receive cyclophosphamide in lieu of thiotepa to ensure engraftment. Myeloablative regimen with chemotherapy followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Standard of care myeloablative regimen will include Busulfan, Fludarabine, Thiotepa, or Cyclophosphamide followed by stem cell infusion.
Arm Title
Immunotherapy
Arm Type
Other
Arm Description
Conditioning regimen is dependent on patient diagnosis and age. Severe combined immunodeficiency (SCID) patients will be conditioned with immunotherapy only followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Immunotherapy regimen will include anti-thymocyte globulin followed by stem cell infusion.
Intervention Type
Device
Intervention Name(s)
Apha/beta T and CD19+ cell depletion using CliniMACS device
Intervention Description
Stem cells will be processed using the CliniMACS device for alpha/beta and CD19+ T cell depletion. Processing of cells using the CliniMACS will occur in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique.
Primary Outcome Measure Information:
Title
Event free survival
Description
Event free survival in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted
Time Frame
One year
Title
Stable engraftment
Description
Stable engraftment in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted
Time Frame
One year
Secondary Outcome Measure Information:
Title
Severity of graft vs. host disease (GVHD)
Description
Severity of acute and chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years
Time Frame
One and two years
Title
Incidence of graft vs. host disease (GVHD)
Description
Evaluation of incidence of chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years
Time Frame
One and two years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ages 0-25 years at time of enrollment Diseases: Immunodeficiencies for which allogeneic hematopoietic stem cell transplant is indicated, including severe combined immunodeficiencies, immunodeficiency polyendocrinopathy X-linked syndrome (IPEX), X-linked lymphoproliferative disease, chronic granulomatous disease, Wiskott-Aldrich syndrome (WAS), hyperIgM, and other life-threatening immunodeficiencies. Immune dysregulation syndromes, including refractory or recurrent hemophagocytic lymphohistiocytosis, hemophagocytic lymphohistiocytosis (HLH) with genetic mutations, refractory multisystemic Langerhans cell histiocytosis, other macrophage activating syndrome (MAS) refractory to standard therapy. Clinical status Lansky or Karnofsky performance >=60 Organ Function: Serum creatinine <1.5 x upper limit of normal for age Hepatic: ALT <=250; AST <=350 Cardiac shortening fraction >=27% Bilirubin <2.5x normal (unless elevation due to Gilberts disease). No active untreated infection Signed informed consent No HLA matched related donor available. Females of childbearing potential must have negative pregnancy test. Exclusion Criteria: Uncontrolled bacterial, viral or fungal infections HLA matched related or unrelated donor able to donate mobilized peripheral stem cells. Pregnant Females Matched related donor available for bone marrow donation Donors Selection Criteria: Donor selection will comply with 21 CFR 1271 Unrelated donor matched or up to one antigen mismatch as per National Marrow Donor Program (NMDP). Haploidentical parent or sibling able to undergo mobilization for peripheral stem cell collection. Maternal donor preferred over paternal donor if both equally haploidentical. Children's Hospital of Philadelphia (CHOP) Blood and Marrow Transplant (BMT) procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases. Unrelated donor identified through the National Marrow Donor Program (NMDP) and fulfills the NMDP criteria for donation. Unrelated donor willing and able to undergo mobilization of peripheral stem cells and apheresis
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Barbara McGlynn, RN, BSN
Email
MCGLYNN@chop.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy Bunin, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Barbara McGlynn, RN, BSN
Email
MCGLYNN@chop.edu

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells for Patients With Primary Immunodeficiencies

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