Conditioning SCID Infants Diagnosed Early

NCT ID: NCT03619551

Last Updated: 2026-01-28

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-22
• Study Completion Date: 2028-12-01

Brief Summary

The investigators want to study if lower doses of chemotherapy will help babies with SCID to achieve good immunity with less short and long-term risks of complications after transplantation. This trial identifies babies with types of immune deficiencies that are most likely to succeed with this approach and offers them transplant early in life before they get severe infections or later if their infections are under control. It includes only patients receiving unrelated or mismatched related donor transplants.

The study will test if patients receiving transplant using either a low dose busulfan or a medium dose busulfan will have immune recovery of both T and B cells, measured by the ability to respond to immunizations after transplant. The exact regimen depends on the subtype of SCID the patient has. Donors used for transplant must be unrelated or half-matched related (haploidentical) donors, and peripheral blood stem cells must be used. To minimize the chance of graft-versus-host disease (GVHD), the stem cells will have most, but not all, of the T cells removed, using a newer, experimental approach of a well-established technology. Once the stem cell transplant is completed, patients will be followed for 3 years. Approximately 9-18 months after the transplant, vaccinations will be administered, and a blood test measuring whether your child's body has responded to the vaccine will be collected.

Detailed Description

This is a prospective, multicenter, phase II, open-label study of two reduced busulfan dose levels in newborns identified at birth with SCID of appropriate genotype/phenotype and clinical status, undergoing either haploidentical related or well-matched unrelated donor TCRαβ+/CD19+ depleted HCT. Subjects will be enrolled on either of 2 strata according to genotype (defects of cytokine receptor function i.e. IL2RG or JAK3 and defects of receptor recombination i.e. RAG1 or RAG2). Thus up to 32 subjects on each of 2 strata or 64 subjects total would be enrolled over 4 years with 3 years follow-up.

Patients with IL2RG/JAK3 would be randomized to receive busulfan targeted either to cumulative exposure of 25-35 mg*h/L or 55-65 mg*h/L with Thymoglobulin. Patients with RAG1/2 would be randomized to receive busulfan targeted to cumulative exposure of 25-35 mg*h/L or 55-65 mg*h/L, in conjunction with fludarabine, thiotepa and Thymoglobulin. Safety/feasibility of the novel TCR αβ+/CD19+ depleted allogeneic HCT strategy will be monitored on an ongoing basis using stopping rules for lack of neutrophil engraftment and other important short-term toxicities.

Donor selection would be determined clinically at the discretion of the treating clinicians at each site. Pharmacokinetic monitoring of busulfan exposure will be performed per local practices at CLIA-certified laboratories. Patients will receive busulfan and pharmacokinetic measurement to individualize dosing. Time-concentration data of the initial dose and subsequent doses will be reviewed centrally (Dr. Janel Long-Boyle) using a cloud-based application (InsightRx) to guide dose adjustment in real-time (Long-Boyle, Chan, Keizer, 2017, ASBMT Tandem abstract accepted). Clinical and laboratory data will be collected at defined time points over 3 years and entered in an electronic data capture system using study-specific case report forms. These data will be used to measure the outcomes including the primary outcome (cAUC of busulfan that promotes humoral immune reconstitution at 2 years post HCT with acceptable regimen-related toxicity at 42 days post HCT) and secondary outcomes (the quality of donor cell engraftment and immune function achieved in B and T cell compartments and survival). Mechanistic studies supporting the exploratory endpoints will be conducted centrally in designated laboratories.

Conditions

SCID

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low Dose Busulfan

Busulfan based preparative regimen targeted at area-under-the-curve (cAUC) exposure of 25-35 mg*h/L .

Randomization between the two dose levels will be done separately in each genotype stratum (RAG1/RAG2 and IL2RG/JAK3), using permuted blocks.

Group Type: EXPERIMENTAL

Busulfan

Intervention Type: DRUG

Randomization between low and medium doses of busulfan for TCR αβ+/CD19+ depleted haploidentical related and unrelated donor HCT.

Cell processing for TCRαβ+/CD19+ depletion

Intervention Type: DEVICE

T-cells and B-cells will be removed from the stem cells collected from the donor by an investigational process called alpha-beta CD3+/CD19+ t-cell depletion using a device called CliniMACS® prior to recipient infusion, hopefully minimizing the risk of significant graft vs. host disease (GVHD) or lymphoproliferative disorder.

Medium Dose Busulfan

Busulfan based preparative regimen targeted at area-under-the-curve (cAUC) exposure of 55-65 mg*h/L.

Randomization between the two dose levels will be done separately in each genotype stratum (RAG1/RAG2 and IL2RG/JAK3), using permuted blocks.

Group Type: EXPERIMENTAL

Busulfan

Intervention Type: DRUG

Randomization between low and medium doses of busulfan for TCR αβ+/CD19+ depleted haploidentical related and unrelated donor HCT.

Cell processing for TCRαβ+/CD19+ depletion

Intervention Type: DEVICE

T-cells and B-cells will be removed from the stem cells collected from the donor by an investigational process called alpha-beta CD3+/CD19+ t-cell depletion using a device called CliniMACS® prior to recipient infusion, hopefully minimizing the risk of significant graft vs. host disease (GVHD) or lymphoproliferative disorder.

Interventions

Busulfan

Randomization between low and medium doses of busulfan for TCR αβ+/CD19+ depleted haploidentical related and unrelated donor HCT.

Intervention Type: DRUG

Cell processing for TCRαβ+/CD19+ depletion

T-cells and B-cells will be removed from the stem cells collected from the donor by an investigational process called alpha-beta CD3+/CD19+ t-cell depletion using a device called CliniMACS® prior to recipient infusion, hopefully minimizing the risk of significant graft vs. host disease (GVHD) or lymphoproliferative disorder.

Intervention Type: DEVICE

Other Intervention Names

CliniMACS

Eligibility Criteria

Inclusion Criteria

1. Infants with SCID, either typical or leaky or Omenn syndrome.

1. Typical SCID is defined as either of the following

• Absence or very low number of T cells (CD3+ T cells <300/microliter AND no or very low T cell function (<10% of lower limit of normal) as measured by response to phytohemagglutinin OR
• Presence of maternally derived T cells

2. Leaky SCID is defined as the following

• Absence of maternally derived T cells

• AND either one or both of the following (i, ii): i) <50% of lower limit of normal T cell function as measured by response to PHA OR <30% of lower limit of normal T cell function as measured by response to CD3 ii) Absent or <10% of lower limit of normal proliferative responses to candida and tetanus toxoid antigens (must document post vaccination or exposure for this criterion to apply)

• AND at least two of the following (i through iii): i) CD3 T cells < 1500/microliter ii) >80% of CD3+ or CD4+ T cells are CD45RO+ AND/OR >80% of CD3+ or CD4+ T cells are CD62L negative AND/OR >50% of CD3+ or CD4+ T cells express HLA-DR (at < 4 years of age) AND/OR are oligoclonal T iii) Low TRECs and/or the percentage of CD4+/45RA+/CD31+ or CD4+/45RA+/CD62L+ cells is below the lower level of normal.

3. Omenn syndrome • Generalized skin rash

• Maternal lymphocytes tested for and not detected.
• >80% of CD3+ or CD4+ T cells are CD45RO+ AND/OR >80% of CD3+ or CD4+ T cells are CD62L negative AND/OR >50% of CD3+ or CD4+ T cells express HLA-DR (<2 years of age)
• Absent or low (up to 30% lower limit of normal (LLN)) T cell proliferation to antigens (Candida, tetanus) to which the patient has been exposed IF: Proliferation to antigen was not performed, but at least 4 of the following 8 supportive criteria, at least one of which must be among those marked with an asterisk (*) below are present, the patient is eligible as Omenn Syndrome.

1. Hepatomegaly

2. Splenomegaly

3. Lymphadenopathy

4. Elevated IgE

5. Elevated absolute eosinophil count

6. *Oligoclonal T cells measured by CDR3 length or flow cytometry (upload report)

7. *Proliferation to PHA is reduced to < 50% of lower limit of normal (LLN) or SI < 30

8. *Low TRECs and/or percentage of CD4+/RA+ CD31+ or CD4+/RA+ CD62L+ cells below the lower level of normal

2. Documented mutation in one of the following SCID-related genes

a. Cytokine receptor defects (IL2RG, JAK3) b. T cell receptor rearrangement defects (RAG1, RAG2) 3. No available genotypically matched related donor (sibling) 4. Availability of a suitable donor and graft source

1. Haploidentical related mobilized peripheral blood cells

2. 9/10 or 10/10 allele matched (HLA-A, -B, -C, -DRB1, -DQB1) volunteer unrelated donor mobilized peripheral blood cells 5. Age 0 to 2 years at enrollment

Note: to ensure appropriate hepatic metabolism, age at time of busulfan start:

For IL2RG/JAK3: 8 weeks For RAG1/RAG2: 12 weeks

6. Adequate organ function defined as:

1. Cardiac:

Left ventricular ejection fraction (LVEF) at rest ≥ 40% or, shortening fraction (SF) ≥ 26% by echocardiogram.

2. Hepatic:

Total bilirubin < 3.0 x the upper limit of normal (ULN) for age (patients who have been diagnosed with Gilbert's Disease are allowed to exceed this limit) and AST and ALT < 5.0 x ULN for age.

3. Renal:

GFR estimated by the updated Schwartz formula ≥ 90 mL/min/1.73 m2. If the estimated GFR is < 90 mL/min/1.73 m2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m2.

4. Pulmonary No need for supplemental oxygen and O2 saturation > 92% on room air at sea level (with lower levels allowed at higher elevations per established center standard of care).

Exclusion Criteria

1. Presence of any serious life-threatening or opportunistic infection at time of enrollment and prior to the initiation of the preparative regimen. Serious infections as defined below that occur after enrollment must be reported immediately to the Study Coordinating Center, and enrollment will be put on hold until the infection resolves. Ideally enrolled subjects will not have had any infection. If patients have experienced infections, these must have resolved by the following definitions:

a. Bacterial i. Positive culture from a sterile site (e.g. blood, CSF, etc.): Repeat culture(s) from same site must be negative and patient has completed appropriate course of antibacterial therapy (typically at least 10 days).

ii. Tissue-based clinical infection (e.g. cellulitis): Complete resolution of clinical signs (e.g. erythema, tenderness, etc.) and patient has completed appropriate course of antibacterial therapy (typically at least 10 days).

iii. Pneumonia, organism not identified by bronchoalveolar lavage: Complete resolution of clinical signs (e.g. tachypnea, oxygen requirement, etc.) and patient has completed appropriate course of antibacterial therapy (typically at least 10 days). If possible, radiographic resolution should also be demonstrated.

b. Fungal i. Positive culture from a sterile site (e.g. blood, CSF, etc.): Repeat culture(s) from same site is negative and patient has completed appropriate course of antifungal therapy (typically at least 14 days). The patient may be continued on antifungal prophylaxis following completion of the treatment course.

c. Pneumocystis i. Complete resolution of clinical signs (e.g. tachypnea, oxygen requirement, etc.) and patient has completed appropriate course of therapy (typically at least 21 days). If possible, radiographic resolution should also be demonstrated. The patient may be continued on prophylaxis following completion of the treatment course.

d. Viral i. Viral PCRs from previously documented sites (blood, nasopharynx, CSF) must be re-tested and are negative.

ii. If re-sampling a site is not clinically feasible (i.e. BAL fluid): Complete resolution of clinical signs (e.g. tachypnea, oxygen requirement, etc.). If possible, radiographic resolution should also be demonstrated.

2. Patients with HIV or HTLV I/II infection will be excluded.

• Minimum Eligible Age: 0 Years
• Maximum Eligible Age: 2 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Center for International Blood and Marrow Transplant Research

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sung-Yun Pai, MD

Role: STUDY_CHAIR

National Institutes of Health (NIH)

Michael Pulsipher, MD

Role: STUDY_CHAIR

University of Utah

Locations

Univeristy of Alabama at Birmingham

Birmingham, Alabama, United States

Mayo Clinic Arizona and Phoenix Children's Hospital

Phoenix, Arizona, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

UCLA Center for Health Sciences

Los Angeles, California, United States

Rady Children's Hospital, San Diego

San Diego, California, United States

University of California San Francisco Medical Center - Peds

San Francisco, California, United States

University of Colorado - Children's Hospital

Aurora, Colorado, United States

Nemours Alfred I. duPont Hospital for Children

Wilmington, Delaware, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Shands HealthCare & University of Florida

Gainesville, Florida, United States

University of Miami/Jackson Memorial Hospital

Miami, Florida, United States

All Children's Hospital

St. Petersburg, Florida, United States

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, United States

Comer Children's Hospital/University of Chicago Medicine

Chicago, Illinois, United States

Indiana University Hospital/Riley Hospital for Children

Indianapolis, Indiana, United States

University of Iowa Hospitals & Clinics

Iowa City, Iowa, United States

Children's Hospital / LSUHSC

New Orleans, Louisiana, United States

Dana Farber Cancer Institute - Peds

Boston, Massachusetts, United States

The University of Michigan

Ann Arbor, Michigan, United States

Helen DeVos Children's

Grand Rapids, Michigan, United States

University of Minnesota Blood and Marrow Transplant Program - Pediatrics

Minneapolis, Minnesota, United States

The Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States

Cardinal Glennon Children's Medical Center

St Louis, Missouri, United States

Nebraska Medicine

Omaha, Nebraska, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Morgan Stanley Children's Hospital of New York-Presbyterian - Columbia University Medical Center

New York, New York, United States

Memorial Sloan Kettering Cancer Center - Peds

New York, New York, United States

Cohen Children's Medical Center

Queens, New York, United States

Westchester Medical Center

Valhalla, New York, United States

Levine Children's Hospital

Charlotte, North Carolina, United States

Duke University Medical Center; Pediatric Blood and Marrow Transplant

Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Children's Medical Center Dallas

Dallas, Texas, United States

M.D. Anderson Cancer Center

Houston, Texas, United States

Utah Blood and Marrow Transplant Program-Peds

Salt Lake City, Utah, United States

Virginia Commonwealth University Massey Cancer Center

Richmond, Virginia, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Montreal, Canada

The Hospital for Sick Children

Toronto, Ontario, Canada

Cancer Care Manitoba/University of Manitoba

Winnipeg, Winnipeg, Canada

Countries

United States; Canada

Other Identifiers

PBMTC NMD1801

Identifier Type: -

Identifier Source: org_study_id