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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 : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

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.

Condition or disease Intervention/treatment Phase
Severe Combined Immunodeficiency Drug: Anti-thymocyte globulin (rabbit) Drug: Busulfan Drug: Fludarabine Drug: Thiotepa Device: CliniMACS Other: Donor Lymphocyte Infusion Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
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
Official Title: Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : July 1, 2027
Estimated Study Completion Date : July 1, 2028


Arm Intervention/treatment
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

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

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.

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




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.



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Ages Eligible for Study:   2 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT03597594


Contacts
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Contact: Ewelina Mamcarz, MD 866-278-5833 referralinfo@stjude.org

Locations
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United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Ewelina Mamcarz, MD    866-278-5833    referralinfo@stjude.org   
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Ewelina Mamcarz, MD St. Jude Children's Research Hospital

Additional Information:
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT03597594     History of Changes
Other Study ID Numbers: SCIDBMT
First Posted: July 24, 2018    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019

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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

Keywords provided by St. Jude Children's Research Hospital:
Severe Combined Immunodeficiency
SCID
TCRα/β/CD19-depleted graft
CD45RA-depleted DLI
Graft-Versus-Host-Disease
Transplant

Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Severe Combined Immunodeficiency
Immune System Diseases
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Fludarabine
Fludarabine phosphate
Busulfan
Thiotepa
Thymoglobulin
Antilymphocyte Serum
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Alkylating Agents
Antineoplastic Agents, Alkylating
Myeloablative Agonists