Conditioning SCID Infants Diagnosed Early

• Register: ClinicalTrials.gov
• Last refreshed on: 26 September 2023
• Main ID: NCT03619551
• Date of registration: 16/07/2018
• Prospective Registration: Yes
• Primary sponsor: Michael Pulsipher, MD
• Public title: Conditioning SCID Infants Diagnosed Early CSIDE
• Scientific title: A Randomized Trial of Low Versus Moderate Exposure Busulfan for Infants With Severe Combined Immunodeficiency (SCID) Receiving TCRaß+/CD19+ Depleted Transplantation: A Phase II Study by the Primary Immune Deficiency Treatment Consortium (PIDTC) and Pediatric Blood and Marrow Transplant Consortium (PBMTC)
• Date of first enrolment: October 22, 2018
• Target sample size: 64
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03619551
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

Canada, United States

Contacts

• Name: Sung-Yun Pai, MD
• Affiliation: National Institutes of Health (NIH)

• Name: Janelle Olson, Ph.D.

• Name: Michael Pulsipher, MD
• Affiliation: Children's Hospital Los Angeles

Key inclusion & exclusion 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.



Age minimum: 0 Years
Age maximum: 2 Years
Gender: All

Health Condition(s) or Problem(s) studied

SCID

Intervention(s)

Device: Cell processing for TCRaß+/CD19+ depletion

Drug: Busulfan

Primary Outcome(s)

Vaccine specific antibody response [Time Frame: 2 years]

Secondary Outcome(s)

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

Chronic graft-versus-host disease (cGVHD) [Time Frame: 2 years post HCT]

Immune Reconstitution [Time Frame: Up to 3 years]

Busulfan Pharmacokinetics [Time Frame: Pre-HCT]

Post-HCT Complications [Time Frame: Up to 2 years post-HCT]

Overall Survival [Time Frame: 3 years]

Acute graft-versus-host disease (aGVHD) [Time Frame: day 100 and 6 months post HCT]

Event Free Survival [Time Frame: 3 years]

Secondary ID(s)

PBMTC NMD1801

Source(s) of Monetary Support

Please refer to primary and secondary sponsors