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

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ClinicalTrials.gov Identifier: NCT03597594
Recruitment Status : Not yet recruiting
First Posted : July 24, 2018
Last Update Posted : August 7, 2019
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Tracking Information
First Submitted Date  ICMJE June 19, 2018
First Posted Date  ICMJE July 24, 2018
Last Update Posted Date August 7, 2019
Estimated Study Start Date  ICMJE August 2019
Estimated Primary Completion Date July 1, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2018)
  • Number of treatment related deaths [ Time Frame: 42 days post DLI ]
    Treatment related deaths will be considered as one of the primary measures to evaluate the safety of a TCRα/β/CD19-depleted graft with CD45RA-depleted DLI in infants with SCID. Number of patients with treatment related deaths will be provided.
  • Number of overall grade 3-4 acute Graft-Versus-Host-Disease (GVHD) [ Time Frame: 42 days post DLI ]
    Overall grade 3-4 acute GVHD events will be considered as one of the primary measures to evaluate the safety of a TCRα/β/CD19-depleted graft with CD45RA-depleted DLI in infants with SCID. Acute 3-4 GVHD events will be evaluated using established staging/grading criteria and expert consensus guidelines. Number of patients with overall grade 3-4 acute GVHD will be provided.
  • Overall Survival(OS) [ Time Frame: 1 year post transplant ]
    To estimate OS at 1 year post transplantation. OS is defined as time from transplantation to death due to any cause. Patients who are alive at the time of analysis will be censored. Based on sample size, either binomial proportion or Kaplan-Meier analysis will be performed.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03597594 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
Official Title  ICMJE 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Patients with SCID will receive TCRα/β-CD19 -depleted graft followed by CD45RA-depleted DLI.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Severe Combined Immunodeficiency
Intervention  ICMJE
  • Drug: Anti-thymocyte globulin (rabbit)
    given intravenously
    Other Names:
    • Thymoglobulin®
    • rabbit ATG
  • Drug: Busulfan
    given intravenously
    Other Names:
    • Myleran
    • Busulfex
  • Drug: Fludarabine
    given intravenously
    Other Name: Fludara
  • Drug: Thiotepa
    given intravenous infusion
    Other Names:
    • TESPA
    • TSPA
  • Device: CliniMACS
    The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
    Other Name: Cell Selection System
  • Other: Donor Lymphocyte Infusion
    given intravenous infusion
    Other Name: DLI
Study Arms  ICMJE
  • Active Comparator: TCRα/β/CD19-depleted SCT

    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

    Interventions:
    • Drug: Anti-thymocyte globulin (rabbit)
    • Drug: Busulfan
    • Drug: Fludarabine
    • Drug: Thiotepa
    • Device: CliniMACS
  • Experimental: Donor Lymphocyte Infusions

    Phase I:

    On the Phase I portion of the study, up to 4 different dose levels will be evaluated: Dose level -1, Dose ≥0.1 to ≤0.3; Dose level 1, Dose >0.3 to ≤0.56; Dose level 2, Dose >0.56 to ≤1.8; Dose level 3, Dose >1.80 to ≤3.0

    Dosing is determined based on the number of CD3+CD45RA-cells/kg and the patient weight in kilograms.

    Phase II:

    Participants will receive the Phase I determined maximum tolerated dose (MTD) of DLI.

    Cells for infusion are prepared using the CliniMACS System.

    Interventions:
    • Device: CliniMACS
    • Other: Donor Lymphocyte Infusion
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 20, 2018)
42
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2028
Estimated Primary Completion Date July 1, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Months and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ewelina Mamcarz, MD 866-278-5833 referralinfo@stjude.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03597594
Other Study ID Numbers  ICMJE SCIDBMT
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Pediatric Postmarket Surveillance of a Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party St. Jude Children's Research Hospital
Study Sponsor  ICMJE St. Jude Children's Research Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ewelina Mamcarz, MD St. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP