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

NCT03597594 | Active Not Recruiting Phase 1 FDA Device

• 1 other identifier: SCIDBMT
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

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. 1.To evaluate the safety of a TCRα/β/CD19-depleted graft with CD45RA-depleted DLI in infants with SCID
2. 2.To estimate overall survival at 1 year post transplantation
3. 3.To evaluate the significant donor T cell reconstitution of a TCRα/β/CD19 depleted graft with CD45RA-depleted DLI at 1 year (+/-2 weeks).
4. 4.To evaluate engraftment at day 30, 100, month 6, and years 1 to 10 post HCT.
5. 5.To evaluate B cell reconstitution at years 1 to 10 post HCT.
6. 6.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.
7. 7.To evaluate clinical outcomes, post HCT.
8. 8.To define the incidence and severity of acute (at day 100, month 6), and chronic (month 6, 12, 24) GVHD following HCT.

Conditions

Severe Combined Immunodeficiency

Keywords

Severe Combined Immunodeficiency; SCID; TCRα/β/CD19-depleted graft; CD45RA-depleted DLI; Graft-Versus-Host-Disease; Transplant

Outcome Measures

Primary Outcomes (3)

• Number of treatment related deaths

  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.

  42 days post DLI

• Number of overall grade 3-4 acute Graft-Versus-Host-Disease (GVHD)

  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.

  42 days post DLI

• Overall Survival(OS)

  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.

  1 year post transplant

Study Arms (2)

TCRα/β/CD19-depleted SCT

ACTIVE COMPARATOR

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); Drug: Busulfan; Drug: Fludarabine; Drug: Thiotepa; Device: CliniMACS

Donor Lymphocyte Infusions

EXPERIMENTAL

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; Other: Donor Lymphocyte Infusion

Interventions

Anti-thymocyte globulin (rabbit) DRUG

given intravenously

Also known as: Thymoglobulin®, rabbit ATG

TCRα/β/CD19-depleted SCT

Busulfan DRUG

given intravenously

Also known as: Myleran, Busulfex

TCRα/β/CD19-depleted SCT

Fludarabine DRUG

given intravenously

Also known as: Fludara

TCRα/β/CD19-depleted SCT

Thiotepa DRUG

given intravenous infusion

Also known as: TESPA, TSPA

TCRα/β/CD19-depleted SCT

CliniMACS DEVICE

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.

Also known as: Cell Selection System

Donor Lymphocyte Infusions; TCRα/β/CD19-depleted SCT

Donor Lymphocyte Infusion OTHER

given intravenous infusion

Also known as: DLI

Donor Lymphocyte Infusions

Eligibility Criteria

• Age: 2 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Severe Combined Immunodeficiency; Graft vs Host Disease

Interventions

Antilymphocyte Serum; thymoglobulin; Busulfan; fludarabine; fludarabine phosphate; Thiotepa

Condition Hierarchy (Ancestors)

Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Ewelina Mamcarz, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients with SCID will receive TCRα/β-CD19 -depleted graft followed by CD45RA-depleted DLI.

Study Record Dates

• First Submitted: June 19, 2018
• First Posted: July 24, 2018
• Study Start: September 2, 2021
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2028
• Last Updated: July 1, 2025

Record last verified: 2025-06

Locations

US (1)