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Clinical Trials Search at Vanderbilt-Ingram Cancer Center

Conditioning SCID Infants Diagnosed Early

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.
Hematologic, Pediatrics
Phase II
Children
Chemotherapy - cytotoxic, Mol. targeted/Immunotherapy/Biologics
Busulfan, Fludarabine (Fludara), Thiotepa, Thymoglobulin
Connelly, James
National
Vanderbilt University
10-22-2018
Treatment
VICCNCPED18122
NCT03619551

Eligibility

0 Years
BOTH
NO
Inclusion Criteria:

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
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) 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
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 (
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

Elevated IgE

Elevated absolute eosinophil count

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

*Proliferation to PHA is reduced to
*Low TRECs and/or percentage of CD4+/RA+ CD31+ or CD4+/RA+ CD62L+ cells below the lower level of normal

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

Haploidentical related mobilized peripheral blood cells

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

Adequate organ function defined as:

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

Hepatic: Total bilirubin
Renal: GFR estimated by the updated Schwartz formula 90 mL/min/1.73 m2. If the estimated GFR is 50 mL/min/1.73 m2.

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:

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.

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