Conditioning SCID Infants Diagnosed Early

NCT03619551 | Active Not Recruiting Phase 2 DMC FDA Device

• 1 other identifier: PBMTC NMD1801
• Study Type: interventional
• Target: 56
• Locations: 2 countries
• Sites: 44

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.

Conditions

SCID

Outcome Measures

Primary Outcomes (1)

• Vaccine specific antibody response

  Humoral immune reconstitution by 2 years post HCT, defined by specific antibody response to tetanus toxoid. Criteria for evaluation of humoral immune response are the following: * Donor T cell chimerism ≥50% * B cell count ≥50 cells/microliter * IVIG independent for ≥12 weeks Subjects meeting the criteria receive 3 doses of tetanus toxoid at least 4 weeks apart, followed by measurement of tetanus titer at least 4-6 weeks after the 3rd dose. Those who achieve tetanus titer of ≥0.15 IU/ml after vaccination will meet the primary endpoint. Patients who have documented humoral immune response at a time prior to 2 years will be considered a success for the primary endpoint, while patients who do not have humoral immune response evaluated by 2 years will be considered failures for the primary endpoint.

  2 years

Secondary Outcomes (8)

• Immune Reconstitution

  Up to 3 years

• Engraftment

  Neutrophil Engraftment: 42 days post-HCT. Donor cell chimerism up to 2 years post-HCT.

• Overall Survival

  3 years

• Event Free Survival

  3 years

• Acute graft-versus-host disease (aGVHD)

  day 100 and 6 months post HCT

Study Arms (2)

Low Dose Busulfan

EXPERIMENTAL

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.

Drug: Busulfan; Device: Cell processing for TCRαβ+/CD19+ depletion

Medium Dose Busulfan

EXPERIMENTAL

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.

Drug: Busulfan; Device: Cell processing for TCRαβ+/CD19+ depletion

Interventions

Busulfan DRUG

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

Low Dose Busulfan; Medium Dose Busulfan

Cell processing for TCRαβ+/CD19+ depletion 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.

Also known as: CliniMACS

Low Dose Busulfan; Medium Dose Busulfan

Eligibility Criteria

• Age: 0 Years - 2 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \. Infants with SCID, either typical or leaky or Omenn syndrome.
• 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
• 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.
• 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.
• Hepatomegaly
• Splenomegaly
• Lymphadenopathy

You may not qualify if:

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

Sponsors & Collaborators

• Center for International Blood and Marrow Transplant Research: lead

Study Sites (44)

Univeristy of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Mayo Clinic Arizona and Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

UCLA Center for Health Sciences

Los Angeles, California, 90095, United States

Location

Rady Children's Hospital, San Diego

San Diego, California, 92123, United States

Location

University of California San Francisco Medical Center - Peds

San Francisco, California, 94143, United States

Location

University of Colorado - Children's Hospital

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Shands HealthCare & University of Florida

Gainesville, Florida, 32610, United States

Location

University of Miami/Jackson Memorial Hospital

Miami, Florida, 33136, United States

Location

All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, 30329, United States

Location

Comer Children's Hospital/University of Chicago Medicine

Chicago, Illinois, 60637, United States

Location

Indiana University Hospital/Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

University of Iowa Hospitals & Clinics

Iowa City, Iowa, 52242, United States

Location

Children's Hospital / LSUHSC

New Orleans, Louisiana, 70118, United States

Location

Dana Farber Cancer Institute - Peds

Boston, Massachusetts, 02115, United States

Location

The University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Helen DeVos Children's

Grand Rapids, Michigan, 49503, United States

Location

University of Minnesota Blood and Marrow Transplant Program - Pediatrics

Minneapolis, Minnesota, 55455, United States

Location

The Children's Mercy Hospitals and Clinics

Kansas City, Missouri, 64108, United States

Location

Cardinal Glennon Children's Medical Center

St Louis, Missouri, 63104, United States

Location

Nebraska Medicine

Omaha, Nebraska, 68198, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

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

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center - Peds

New York, New York, 10065, United States

Location

Cohen Children's Medical Center

Queens, New York, 11040, United States

Location

Westchester Medical Center

Valhalla, New York, 10595, United States

Location

Levine Children's Hospital

Charlotte, North Carolina, 28203, United States

Location

Duke University Medical Center; Pediatric Blood and Marrow Transplant

Durham, North Carolina, 27705, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239-3098, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Children's Medical Center Dallas

Dallas, Texas, 75235, United States

Location

Utah Blood and Marrow Transplant Program-Peds

Salt Lake City, Utah, 84112, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Montreal, QC, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1E8, Canada

Location

Cancer Care Manitoba/University of Manitoba

Winnipeg, Winnipeg, MB, Canada

Location

MeSH Terms

Interventions

Busulfan

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Sung-Yun Pai, MD

  National Institutes of Health (NIH)

  STUDY CHAIR

• Michael Pulsipher, MD

  University of Utah

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Randomization will be performed after eligibility is confirmed. Randomization between the two busulfan dose levels will be done separately in each genotype stratum, using permuted blocks. Randomization will be stratified further by donor type (Haploidentical related vs. Matched Unrelated Donor).

Study Record Dates

• First Submitted: July 16, 2018
• First Posted: August 8, 2018
• Study Start: October 22, 2018
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: February 17, 2026

Record last verified: 2026-01

Locations

US (41); CA (3)