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

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ClinicalTrials.gov Identifier: NCT02990819
Recruitment Status : Recruiting
First Posted : December 13, 2016
Last Update Posted : June 18, 2018
Sponsor:
Collaborator:
University of California, San Francisco
Information provided by (Responsible Party):
Nancy Bunin, Children's Hospital of Philadelphia

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.

Condition or disease Intervention/treatment Phase
Immunodeficiencies Immune Dysregulation Syndromes Device: Apha/beta T and CD19+ cell depletion using CliniMACS device Phase 2

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 0-22 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

  1. Reduced intensity conditioning with busulfan x 8 doses, fludarabine 40 mg/m2 x 4, thiotepa 5 mg/kg x 2, ATG 3 mg/kg x 3.

    OR

  2. 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

  3. Immunotherapy regimen on days -9, 8, 7 with anti-thymocyte globulin 3 mg/kg/day (for severe combined immunodeficiency patients only).
  4. Infusion of alpha/beta T and CD19+ depleted donor peripheral stem cells.
  5. Follow up, including evaluation of chimerism and immune reconstitution.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : December 2016
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Reduced intensity regimen
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, Fludarbine, Thiotepa followed by stem cell infusion.
Device: Apha/beta T and CD19+ cell depletion using CliniMACS device
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 SOPs and using aseptic technique.

Myeloablative regimen

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, Fludarbine, Thiotepa, or Cyclophosamide followed by stem cell infusion.

Device: Apha/beta T and CD19+ cell depletion using CliniMACS device
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 SOPs and using aseptic technique.

Immunotherapy
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.
Device: Apha/beta T and CD19+ cell depletion using CliniMACS device
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 SOPs and using aseptic technique.




Primary Outcome Measures :
  1. Event free survival [ Time Frame: One year ]
    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

  2. Stable engraftment [ Time Frame: One year ]
    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 :
  1. Severity of graft vs. host disease (GVHD) [ Time Frame: One and two years ]
    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

  2. Incidence of graft vs. host disease (GVHD) [ Time Frame: One and two years ]
    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



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Ages Eligible for Study:   up to 22 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Ages 0-22 years at time of enrollment
  2. Diseases:

    • Immunodeficiencies for which allogeneic hematopoietic stem cell transplant is indicated, including severe combined immunodeficiencies, IPEX syndrome, X-linked lymphoproliferative disease, chronic granulomatous disease, WAS, hyperIgM, and other life-threatening immunodeficiencies.
    • Immune dysregulation syndromes, including refractory or recurrent hemophagocytic lymphohistiocytosis, HLH with genetic mutations, refractory multisystemic Langerhans cell histiocytosis, other 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.
  • CHOP 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02990819


Contacts
Contact: Barbara McGlynn, RN, BSN MCGLYNN@email.chop.edu

Locations
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Barbara McGlynn, RN, BSN       MCGLYNN@email.chop.edu   
Sponsors and Collaborators
Children's Hospital of Philadelphia
University of California, San Francisco
Investigators
Principal Investigator: Nancy Bunin, MD Children's Hospital of Philadelphia

Responsible Party: Nancy Bunin, Director, Blood and Marrow Transplant, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT02990819     History of Changes
Other Study ID Numbers: 15-011733
15BT022 ( Other Identifier: CHOP )
First Posted: December 13, 2016    Key Record Dates
Last Update Posted: June 18, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Nancy Bunin, Children's Hospital of Philadelphia:
Immunodeficiencies
Immune dysregulation syndromes

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Immune System Diseases