Clinical trial NCT03619551: Conditioning SCID Infants Diagnosed Early
Official 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: SCID
Lead sponsor: Center for International Blood and Marrow Transplant Research
Sponsor class: NETWORK
First posted: 2018-08-08
Enrollment: 56
Sex: ALL
Minimum age (years): 0
Maximum age (years): 2
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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).
Primary purpose: TREATMENT

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.

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

Eligibility 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.

Primary outcomes:
measure: Vaccine specific antibody response
timeFrame: 2 years
Secondary outcomes:
measure: Immune Reconstitution
timeFrame: Up to 3 years
measure: Engraftment
timeFrame: Neutrophil Engraftment: 42 days post-HCT. Donor cell chimerism up to 2 years post-HCT.
measure: Overall Survival
timeFrame: 3 years
measure: Event Free Survival
timeFrame: 3 years
measure: Acute graft-versus-host disease (aGVHD)
timeFrame: day 100 and 6 months post HCT
measure: Chronic graft-versus-host disease (cGVHD)
timeFrame: 2 years post HCT
measure: Post-HCT Complications
timeFrame: Up to 2 years post-HCT
measure: Busulfan Pharmacokinetics
timeFrame: Pre-HCT
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univeristy of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona and Phoenix Children's Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA Center for Health Sciences
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital, San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center - Peds
state: California
city: Stanford
country: United States
facility: Lucile Packard Children's Hospital / Stanford Children's Health
state: California
city: Aurora
country: United States
facility: University of Colorado - Children's Hospital
state: Colorado
city: Wilmington
country: United States
facility: Nemours Alfred I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: Shands HealthCare & University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami/Jackson Memorial Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Egleston
state: Georgia
city: Chicago
country: United States
facility: Comer Children's Hospital/University of Chicago Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Hospital/Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: New Orleans
country: United States
facility: Children's Hospital / LSUHSC
state: Louisiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute - Peds
state: Massachusetts
city: Ann Arbor
country: United States
facility: The University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Helen DeVos Children's
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Blood and Marrow Transplant Program - Pediatrics
state: Minnesota
city: Kansas City
country: United States
facility: The Children's Mercy Hospitals and Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Washington University/St. Louis Children's Hospital
state: Missouri
city: Omaha
country: United States
facility: Nebraska Medicine
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Morgan Stanley Children's Hospital of New York-Presbyterian - Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Peds
state: New York
city: Queens
country: United States
facility: Cohen Children's Medical Center
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Charlotte
country: United States
facility: Levine Children's Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center; Pediatric Blood and Marrow Transplant
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Houston
country: United States
facility: M.D. Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Utah Blood and Marrow Transplant Program-Peds
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: TheHospital fo Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba/University of Manitoba
Study officials:
affiliation: National Institutes of Health (NIH)
name: Sung-Yun Pai, MD
role: STUDY_CHAIR
affiliation: Children's Hospital Los Angeles
name: Michael Pulsipher, MD
role: STUDY_CHAIR
References: