SCID Clinical Trial
— CSIDEOfficial title:
A Randomized Trial of Low Versus Moderate Exposure Busulfan for Infants With Severe Combined Immunodeficiency (SCID) Receiving TCRαβ+/CD19+ Depleted Transplantation: A Phase II Study by the Primary Immune Deficiency Treatment Consortium (PIDTC) and Pediatric Blood and Marrow Transplant Consortium (PBMTC)
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.
Status | Recruiting |
Enrollment | 64 |
Est. completion date | August 1, 2026 |
Est. primary completion date | August 1, 2026 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 0 Years to 2 Years |
Eligibility | 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. |
Country | Name | City | State |
---|---|---|---|
Canada | Centre Hospitalier Universitaire Sainte-Justine | Montreal | |
Canada | TheHospital fo Sick Children | Toronto | Ontario |
Canada | Cancer Care Manitoba/University of Manitoba | Winnipeg | |
United States | The University of Michigan | Ann Arbor | Michigan |
United States | Children's Healthcare of Atlanta at Egleston | Atlanta | Georgia |
United States | University of Colorado - Children's Hospital | Aurora | Colorado |
United States | Univeristy of Alabama at Birmingham | Birmingham | Alabama |
United States | Dana Farber Cancer Institute - Peds | Boston | Massachusetts |
United States | Medical University of South Carolina | Charleston | South Carolina |
United States | Levine Children's Hospital | Charlotte | North Carolina |
United States | Comer Children's Hospital/University of Chicago Medicine | Chicago | Illinois |
United States | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio |
United States | Cleveland Clinic Foundation | Cleveland | Ohio |
United States | Nationwide Children's Hospital | Columbus | Ohio |
United States | Children's Medical Center Dallas | Dallas | Texas |
United States | Duke University Medical Center; Pediatric Blood and Marrow Transplant | Durham | North Carolina |
United States | Shands HealthCare & University of Florida | Gainesville | Florida |
United States | Helen DeVos Children's | Grand Rapids | Michigan |
United States | Hackensack University Medical Center | Hackensack | New Jersey |
United States | M.D. Anderson Cancer Center | Houston | Texas |
United States | Indiana University Hospital/Riley Hospital for Children | Indianapolis | Indiana |
United States | University of Iowa Hospitals & Clinics | Iowa City | Iowa |
United States | The Children's Mercy Hospitals and Clinics | Kansas City | Missouri |
United States | Children's Hospital Los Angeles | Los Angeles | California |
United States | UCLA Center for Health Sciences | Los Angeles | California |
United States | University of Wisconsin Hospital and Clinics | Madison | Wisconsin |
United States | University of Miami/Jackson Memorial Hospital | Miami | Florida |
United States | Children's Hospital of Wisconsin | Milwaukee | Wisconsin |
United States | University of Minnesota Blood and Marrow Transplant Program - Pediatrics | Minneapolis | Minnesota |
United States | Vanderbilt University Medical Center | Nashville | Tennessee |
United States | Children's Hospital / LSUHSC | New Orleans | Louisiana |
United States | Memorial Sloan Kettering Cancer Center - Peds | New York | New York |
United States | Morgan Stanley Children's Hospital of New York-Presbyterian - Columbia University Medical Center | New York | New York |
United States | Nebraska Medicine | Omaha | Nebraska |
United States | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania |
United States | Mayo Clinic Arizona and Phoenix Children's Hospital | Phoenix | Arizona |
United States | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania |
United States | Oregon Health and Science University | Portland | Oregon |
United States | Cohen Children's Medical Center | Queens | New York |
United States | Virginia Commonwealth University Massey Cancer Center | Richmond | Virginia |
United States | Cardinal Glennon Children's Medical Center | Saint Louis | Missouri |
United States | Washington University/St. Louis Children's Hospital | Saint Louis | Missouri |
United States | All Children's Hospital | Saint Petersburg | Florida |
United States | Utah Blood and Marrow Transplant Program-Peds | Salt Lake City | Utah |
United States | Methodist Children's Hospital | San Antonio | Texas |
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 | Fred Hutchinson Cancer Research Center | Seattle | Washington |
United States | Lucile Packard Children's Hospital / Stanford Children's Health | Stanford | California |
United States | Westchester Medical Center | Valhalla | New York |
United States | Children's National Medical Center | Washington | District of Columbia |
United States | Nemours Alfred I. duPont Hospital for Children | Wilmington | Delaware |
Lead Sponsor | Collaborator |
---|---|
Michael Pulsipher, MD |
United States, Canada,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | Immune Reconstitution | T cell immune reconstitution at 30 days, 60 days, 3 months, 6 months, 12 months, and 2 years post-HCT.
Naïve T cell generation and thymic output at 3 months, 6 months, 12 months and 2 years post-HCT. Freedom from immunoglobulin substitution will be assessed on all patients at 9 months, 12 months, 2 years and 3 years post-HCT. Patients who have not received IVIG for at least 12 weeks at the time of assessment will be considered free from immunoglobulin substitution. Tetanus responses on all patients who complete a trial of vaccination by additional timepoints of 12 months, 18 months and 3 years post-HCT. Live vaccine responses on all patients who undergo trial of vaccination by 3 years post-HCT |
Up to 3 years | |
Secondary | Engraftment | Neutrophil engraftment will be assessed on all patients and defined as achieving an absolute neutrophil count of >500 cells/microliter for 3 consecutive days by day 42 post-HCT
Donor cell chimerism (whole blood, sorted CD3 (T-cell), CD19 (B-cell) and CD56 (NK cell) and granulocyte (CD15)) at 42 days, 3 months, 6 months, 12 months, and 2 years post-HCT. Absolute B cell, NK cell and granulocyte counts will be measured. |
Neutrophil Engraftment: 42 days post-HCT. Donor cell chimerism up to 2 years post-HCT. | |
Secondary | Overall Survival | Data to track overall survival will be collected at 1, 2 and 3 years post-HCT. | 3 years | |
Secondary | Event Free Survival | Data to track event free survival will be collected at 1, 2 and 3 years post-HCT. Events will be defined as 1) death from any cause, 2) rejection of the graft (T-cell and/or whole blood chimerism <5% donor), 3) graft failure necessitating a second HCT procedure from the same donor or a different donor, with or without conditioning, 4) DLI given for treatment of falling chimerism. | 3 years | |
Secondary | Acute graft-versus-host disease (aGVHD) | Occurrence of acute (grade II-IV and grade III-IV) GVHD. | day 100 and 6 months post HCT | |
Secondary | Chronic graft-versus-host disease (cGVHD) | Occurrence of chronic GVHD by 6 months, 12 months and 24 months post-HCT. | 2 years post HCT | |
Secondary | Post-HCT Complications | Infections
Targeted regimen related toxicity (severe veno-occlusive disease of the liver, idiopathic pneumonitis syndrome) Autoimmunity |
Up to 2 years post-HCT | |
Secondary | Busulfan Pharmacokinetics | Blood samples will be collected on busulfan dosing days 1 and 3 at 2.35, 4, 6 and 8 hours from the time of the start of the infusion. The results will be used to estimate individual exposure (AUC and cAUC). | Pre-HCT |
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT01652092 -
Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
|
N/A | |
Completed |
NCT01953016 -
Participation in a Research Registry for Immune Disorders
|
||
Enrolling by invitation |
NCT01346150 -
Patients Treated for SCID (1968-Present)
|
||
Recruiting |
NCT02963064 -
JSP191 Antibody Targeting Conditioning in SCID Patients
|
Phase 1/Phase 2 |