Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)

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Brief Title

Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)

Official Title

Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)

Brief Summary

      Infants with severe combined immunodeficiency (SCID) have a profound decrease in number and
      function of immune cells, and therefore remain highly vulnerable to infection. If not
      corrected this often leads to death. Hematopoietic cell transplantation (HCT) from matched
      sibling donor is the standard treatment for these patients, unfortunately though; most SCID
      patients lack a sibling donor. Building upon experience and existing data, the investigators
      are proposing a trial the goals of which are: to provide a conditioning regimen that is well
      tolerated, and provision of immune cells that altogether should establish rapid immune
      recovery providing protection from life threatening infections without increasing the risk of
      dangerous Graft-Versus-Host-Disease.

      Primary Objectives

        1. To evaluate the safety of a TCRα/β/CD19-depleted graft with CD45RA-depleted DLI in
           infants with SCID

        2. To estimate overall survival at 1 year post transplantation

      Exploratory Objectives

        1. To evaluate the significant donor T cell reconstitution of a TCRα/β/CD19 depleted graft
           with CD45RA-depleted DLI at 1 year (+/-2 weeks).

        2. To evaluate engraftment at day 30, 100, month 6, and years 1 to 10 post HCT.

        3. To evaluate B cell reconstitution at years 1 to 10 post HCT.

        4. To evaluate biomarkers of immune reconstitution at day 30, 60 100, month 6 and years 1
           to 10; e.g. immunophenotype (including epigenetic profiling) of T, B, and NK cells, and
           assays to determine their function.

        5. To evaluate clinical outcomes, post HCT.

        6. To define the incidence and severity of acute (at day 100, month 6), and chronic (month
           6, 12, 24) GVHD following HCT.
    

Detailed Description

      In this study, the investigators propose to investigate T and B cell recovery using
      peripheral blood manipulation that removes potentially Graft-Versus-Host-Disease (GVHD)
      inducing α/β and CD45RA+ T cells, while still providing potentially beneficial donor γδ and
      memory T cells.

      Donors will undergo a standard hematopoietic progenitor cell (HPC) mobilization regimen
      consisting of 5 days of G-CSF given subcutaneously at 10 micrograms/kilogram. The graft will
      be collected by leukapheresis on days 5 and if needed 6 of G-CSF. The HPC product(s) will be
      T-cell depleted (TCD) using the investigational CliniMACS device.

      The initial HPC product(s) will be split into two portions; one portion will be used for TCR
      TCRαβ/CD19 depletion and the second portion for CD45depleted DLI product.

        1. TCRα/β/CD19-depleted stem cell transplant: All participants will undergo a preparative
           regimen based on the type of Severe Combined Immunodeficiency (SCID) they have. This is
           followed by infusion of TCRα/β/CD19-depleted donor cells (with the exception of
           participants who undergo matched sibling donor HCT).

        2. Donor Lymphocyte Infusion (CD45depleted DLI product): Participants, other than those who
           undergo matched sibling HCT transplant, will receive one dose of CD45RA depleted DLI
           infusion post TCRα/β/CD19-depleted graft infusion.

      During the Phase I portion of the study, up to 4 different dose levels of CD45depleted DLI
      product will be evaluated.

      On the Phase II portion of the study, all participants will receive the Phase I determined
      maximum tolerated dose (MTD) of DLI.

      Participants on both the Phase I and Phase II portions of the study that are unable to
      receive protocol defined dosing of DLI due to insufficient dose generated will be eligible to
      receive the entirety of the generated product.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Number of treatment related deaths


Condition

Severe Combined Immunodeficiency

Intervention

Anti-thymocyte globulin (rabbit)

Study Arms / Comparison Groups

 TCRα/β/CD19-depleted SCT
Description:  A preparative regimen based on the type of SCID will be given followed by infusion of donor cells. Cells for infusion are prepared using the CliniMACS System
Regimen 1 - IL2RG, JAK 3 (Haplocompatible) and all MSD
ATG (rabbit) IV Days -9 -8 and -7, Rest Days -6 and -5, Busulfan IV Days -4, -3, and -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0
Regimen 2 - RAG1, RAG2 (Haplocompatible)
ATG (rabbit) IV Days -9 -8 and -7, Fludarabine IV Days -7, -6, -5 and -4, Busulfan IV Days -5, -4 and -3, Thiotepa IV twice daily, Day -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0
Regimen 3 - ADA, IL7R, CD45 deficiency, CD3 subunits (Haplocompatible)
ATG (rabbit) IV Days -9 -8 and -7, Fludarabine IV Days -7, -6, -5 and -4, Busulfan: IV Days -4, -3 and -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

42

Start Date

July 2020

Completion Date

July 1, 2028

Primary Completion Date

July 1, 2027

Eligibility Criteria

        Inclusion Criteria - Transplant Recipient

          -  Age ≥2 months old at the time of chemotherapy administration

          -  A proven mutation as defined by direct sequencing of patient DNA

          -  Has a suitable matched sibling donor or matched unrelated donor (8/8) or single
             haplotype matched (≥3 of 6) family member donor

          -  Patient must fulfill pre-transplant evaluation:

          -  Left ventricular ejection fraction >40% and no evidence of uncorrected congenital
             malformation with clinical symptomatology

          -  Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2 or
             serum Creatinine ≤1.2mg/dL

          -  Resting pulse oximetry ≥90% on room or ≥95% on oxygen supplementation

          -  Lansky (age-dependent) performance score ≥50

          -  Bilirubin ≤3 times the upper limit of normal for age

          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper
             limit of normal for age

        Exclusion Criteria - Transplant Recipient

          -  Positive for HIV infection by genome PCR

          -  Presence of active malignancy

          -  A social situation indicating that the family may not be able to comply with protocol
             procedures and recommended medical care

          -  Presence of a medical condition indicating that survival will be dismal such as the
             requirement for mechanical ventilation, severe failure of a major organ system, or
             evidence of a serious, progressive infection that is refractory to medical therapy

        Inclusion Criteria - Matched Sibling Donor and Haplocompatible Donor

          -  Fully matched sibling donor (8/8), or matched unrelated donor (8/8), or at least
             single haplotype matched (≥3 of 6) family member

          -  At least 1 year old (MSD) and at least 18 years of age (Haplocompatible)

          -  HIV negative

          -  Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days
             prior to enrollment (if female)

          -  Not breast feeding

          -  Regarding donation eligibility, is identified as either:

               -  Completed the process of donor eligibility determination as outlined in 21 CFR
                  1271 and agency guidance; OR

               -  Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of
                  urgent medical need completed by the principal investigator or physician
                  sub-investigator per 21 CFR 1271
      

Gender

All

Ages

2 Months - N/A

Accepts Healthy Volunteers

No

Contacts

Ewelina Mamcarz, MD, 866-278-5833, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03597594

Organization ID

SCIDBMT


Responsible Party

Sponsor

Study Sponsor

St. Jude Children's Research Hospital


Study Sponsor

Ewelina Mamcarz, MD, Principal Investigator, St. Jude Children's Research Hospital


Verification Date

June 2020