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

Primary Purpose

Severe Combined Immunodeficiency

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Anti-thymocyte globulin (rabbit)

Busulfan

Fludarabine

Thiotepa

CliniMACS

Donor Lymphocyte Infusion

About this trial

This is an interventional treatment trial for Severe Combined Immunodeficiency focused on measuring Severe Combined Immunodeficiency, SCID, TCRα/β/CD19-depleted graft, CD45RA-depleted DLI, Graft-Versus-Host-Disease, Transplant

Eligibility Criteria

2 Months - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

TCRα/β/CD19-depleted SCT

Donor Lymphocyte Infusions

Arm 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

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT03597594

First Posted

June 19, 2018

Last Updated

June 7, 2023

Sponsor

St. Jude Children's Research Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03597594

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)

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

September 2, 2021 (Actual)

Primary Completion Date

July 1, 2027 (Anticipated)

Study Completion Date

July 1, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

St. Jude Children's Research Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Data Monitoring Committee

5. Study Description

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 To evaluate the safety of a TCRα/β/CD19-depleted graft with CD45RA-depleted DLI in infants with SCID To estimate overall survival at 1 year post transplantation Exploratory Objectives To evaluate the significant donor T cell reconstitution of a TCRα/β/CD19 depleted graft with CD45RA-depleted DLI at 1 year (+/-2 weeks). To evaluate engraftment at day 30, 100, month 6, and years 1 to 10 post HCT. To evaluate B cell reconstitution at years 1 to 10 post HCT. 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. To evaluate clinical outcomes, post HCT. 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. 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). 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Combined Immunodeficiency

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

4 (Actual)

8. Arms, Groups, and Interventions

Arm Title

TCRα/β/CD19-depleted SCT

Arm Type

Active Comparator

Arm Description

Arm Title

Donor Lymphocyte Infusions

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Anti-thymocyte globulin (rabbit)

Other Intervention Name(s)

Thymoglobulin®, rabbit ATG

Intervention Description

given intravenously

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Myleran, Busulfex

Intervention Description

given intravenously

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara

Intervention Description

given intravenously

Intervention Type

Drug

Intervention Name(s)

Thiotepa

Other Intervention Name(s)

TESPA, TSPA

Intervention Description

given intravenous infusion

Intervention Type

Device

Intervention Name(s)

CliniMACS

Other Intervention Name(s)

Cell Selection System

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Donor Lymphocyte Infusion

Other Intervention Name(s)

DLI

Intervention Description

given intravenous infusion

Primary Outcome Measure Information:

Title

Number of treatment related deaths

Description

Time Frame

42 days post DLI

Title

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

Description

Time Frame

42 days post DLI

Title

Overall Survival(OS)

Description

Time Frame

1 year post transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Months

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ewelina Mamcarz, MD

Organizational Affiliation

St. Jude Children's Research Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

St. Jude Children's Research Hospital

City

Memphis

State/Province

Tennessee

ZIP/Postal Code

38105

Country

United States

12. IPD Sharing Statement

Links:

URL

http://www.stjude.org

Description

St. Jude Children's Research Hospital

URL

http://www.stjude.org/protocols

Description

Clinical Trials Open at St. Jude

Learn more about this trial

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

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