Conditioning SCID Infants Diagnosed Early

  • STATUS
    Recruiting
  • End date
    Aug 1, 2026
  • participants needed
    64
  • sponsor
    Michael Pulsipher, MD
Updated on 23 September 2021

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.

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 TCR+/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 mgh/L or 55-65 mgh/L with Thymoglobulin. Patients with RAG1/2 would be randomized to receive busulfan targeted to cumulative exposure of 25-35 mgh/L or 55-65 mgh/L, in conjunction with fludarabine, thiotepa and Thymoglobulin. Safety/feasibility of the novel TCR +/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.

Details
Condition Severe Combined Immunodeficiency, scid
Treatment busulfan, Cell processing for TCRαβ+/CD19+ depletion
Clinical Study IdentifierNCT03619551
SponsorMichael Pulsipher, MD
Last Modified on23 September 2021

Eligibility

Yes No Not Sure

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 <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 <
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
Elevated IgE
Elevated absolute eosinophil count
Oligoclonal T cells measured by CDR3 length or flow cytometry (upload report)
Proliferation to PHA is reduced to < 50% of lower limit of normal (LLN) or SI < 30
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
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 < 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
\. 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
-hour creatinine clearance or nuclear GFR, and must be > 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
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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