Clinical trial NCT05600426: A Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)
Official title: A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation With Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Severe Aplastic Anemia
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Center for International Blood and Marrow Transplant Research
name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
name: North American Pediatric Aplastic Anemia Consortium
name: Pediatric Transplantation and Cellular Therapy Consortium
name: Blood and Marrow Transplant Clinical Trials Network
First posted: 2022-10-31
Enrollment: 234
Sex: ALL
Minimum age (years): 0
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Unblinded, stratified, multi-center, phase 3, randomized controlled trial
Primary purpose: TREATMENT

Brief summary: Severe Aplastic Anemia (SAA) is a rare condition in which the body stops producing enough new blood cells. SAA can be cured with immune suppressive therapy or a bone marrow transplant. Regular treatment for patients with aplastic anemia who have a matched sibling (brother or sister), or family donor is a bone marrow transplant. Patients without a matched family donor normally are treated with immune suppressive therapy (IST). Match unrelated donor (URD) bone marrow transplant (BMT) is used as a secondary treatment in patients who did not get better with IST, had their disease come back, or a new worse disease replaced it (like leukemia).

This trial will compare time from randomization to failure of treatment or death from any cause of IST versus URD BMT when used as initial therapy to treat SAA.

The trial will also assess whether health-related quality of life and early markers of fertility differ between those randomized to URD BMT or IST, as well as assess the presence of marrow failure-related genes and presence of gene mutations associated with MDS or leukemia and the change in gene signatures after treatment in both study arms.

This study treatment does not include any investigational drugs. The medicines and procedures in this study are standard for treatment of SAA.

Detailed description: This study is a multi-center randomized phase III trial to compare the failure free survival between those randomized to IST vs 9-10/10 HLA matched URD BMT. The study will also address patient-reported outcomes and gonadal function in each arm and explore critical biological correlates including assessing germline genetic mutations associated with pediatric SAA that may lead to a predisposition to the disease and the risk of development of clonal hematopoiesis following IST vs BMT in pediatric and young adult SAA.

This clinical trial will randomize 234 children/AYA over 3.3-4.7 years at a 1:1 ratio between initial treatment with immune suppression therapy (IST) with horse ATG (hATG)/cyclosporine (CsA) versus well- matched (9-10/10 allele) unrelated donor (URD) bone marrow transplantation (BMT) using a regimen of rabbit ATG (rATG)/fludarabine/cyclophosphamide and 200 cGy TBI. Duration of subject participation for all study procedures in this study will be up to 2 years after treatment; a single later timepoint between 3 and 5 years will be collected to follow patients for specific protocol defined late effects and survival.

Eligibility criteria: Inclusion Criteria:

To be eligible to participate in the randomized trial, an individual must meet all the following criteria:

1. Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian.
2. Age ≤25 years old at time of randomized trial consent.
3. Confirmed diagnosis of idiopathic SAA, defined as:

   1. Bone marrow cellularity \<25%, or \<30% hematopoietic cells.
   2. Two of three of the following (in peripheral blood): neutrophils \<0.5 x 10\^9/L, platelets \<20 x 10\^9/L, absolute reticulocyte count \<60 x 10\^9/L or hemoglobin \<8 g/dL.
4. No suitable fully matched related donor available (minimum 6/6 match for HLA-A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing).
5. At least 2 unrelated donors noted on NMDP search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution).
6. In the treating physician's opinion, no obvious contraindications precluding them from BMT or IST.

Exclusion Criteria:

1. Presence of Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis Congenita (DC), but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder should be excluded by pancreatic isoamylase testing or gene mutation analysis (note: pancreatic isoamylase testing is not useful in children \<3). Other testing per center may be performed to exclude IBMFS.
2. Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination.
3. Known severe allergy to ATG.
4. Prior allogeneic or autologous stem cell transplant.
5. Prior solid organ transplant.
6. Infection with human immunodeficiency virus (HIV).
7. Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs).
8. Female patients who are pregnant or breast-feeding.
9. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ.
10. Disease modifying treatment prior to study enrollment, including but not limited to use of androgens, eltrombopag, romiplostim, or immune suppression. Note: Supportive care measures such as G-CSF, blood transfusion support and antibiotics are allowable

Primary outcomes:
measure: The primary endpoint of this trial is time from randomization to treatment failure or death from any cause.
timeFrame: Randomization to 2 years post-randomization
Secondary outcomes:
measure: Comparison of subjects with failure of IST or BMT before or at 2 years
timeFrame: Randomization to 2 years post-randomization
measure: Comparison of subjects with inadequate counts at 2 years among those who have not died or failed treatment.
timeFrame: Randomization to 2 years post-randomization
measure: Comparison of subjects on immune suppression therapy at 2 years among those who have not died or failed treatment.
timeFrame: Randomization to 2 years post-randomization
measure: Estimate the time from randomization to initiation of IST or BMT.
timeFrame: Randomization through Day 100
measure: Comparison of the frequency of failure to receive primary assigned therapy (IST or BMT) and reasons for the failure.
timeFrame: Randomization through Day 100
measure: Comparison of the incidence of bacteremia, viremia, and invasive fungal infection in the first two years after randomization in the IST and BMT arms.
timeFrame: Randomization through two years post randomization
measure: Estimate the median time to T- and B-cell immune reconstitution the first year for the URD BMT Arm
timeFrame: Initiation of therapy (Day 0) to 100 days, 180 days, 1 year and 2 years
measure: Comparison of overall survival at 1 and 2 years from randomization in both arms.
timeFrame: Randomization to one year, randomization to two years
measure: Comparison of treatment-related mortality (TRM) at 1 and 2 years from randomization in both arms.
timeFrame: Randomization to 1 year, randomization to 2 years
measure: Comparison of the median time from randomization to and rates of neutrophil recovery on both arms
timeFrame: Randomization to 100 days, 180 days, 1 year and 2 years
measure: Comparison of the median time from randomization to and rate of platelet recovery on both arms
timeFrame: Randomization to 100 days, 180 days, 1 year and 2 years
measure: Comparison of the median time from randomization to and rates of red blood cell recovery on both arms
timeFrame: Randomization to 100 days, 180 days, 1 year and 2 years
measure: Comparison of the median time from initiation of therapy to and rates of neutrophil recovery on both arms
timeFrame: Initiation of therapy to 100 days, 180 days, 1 year and 2 years
measure: Comparison of the median time from initiation of therapy to and rate of platelet recovery on both arms
timeFrame: Initiation of therapy to 100 days, 180 days, 1 year and 2 years
measure: Comparison of the median time from initiation of therapy to and rates of red blood cell recovery on both arms.
timeFrame: Randomization to 100 days, 180 days, 1 year and 2 years
measure: Estimate the rates of engraftment in patients who are randomized to URD BMT.
timeFrame: Randomization to 3-5 years
measure: Estimate the rates of primary graft failure in patients who are randomized to URD BMT .
timeFrame: Randomization to 3-5 years
measure: Estimate the rates of secondary graft failure in patients who are randomized to URD BMT .
timeFrame: Randomization to 3-5 years
measure: Estimate the rates of grade II-IV acute GVHD in patients who are randomized to URD BMT .
timeFrame: Randomization to 3-5 years
measure: Estimate the rates of grade III-IV acute GVHD in patients who are randomized to URD BMT.
timeFrame: Randomization to 3-5 years
measure: Estimate the rates of severe chronic GVHD in patients who are randomized to URD BMT.
timeFrame: Randomization to 3-5 years
measure: Estimate the rates of response of patients randomized to IST
timeFrame: Randomization to 100 days, 180 days, 1 year and 2 years
measure: Estimate the rates of failure of patients randomized to IST
timeFrame: Randomization to 100 days, 180 days, 1 year and 2 years
measure: Describe the secondary therapies given and outcomes achieved for patients failing initial therapy
timeFrame: Randomization to 3-5 years
measure: Comparison of rates of secondary MDS, AML, other subsequent neoplasms, and development of Paroxysmal Nocturnal Hemoglobinuria in both treatment arms for the duration of the trial.
timeFrame: Randomization to 3-5 years
measure: Comparison of HR-QoL score between patients randomized to both arms
timeFrame: Randomization to 2 years post-randomization, randomization to up to 5 years post-randomization
measure: Comparison of gonadal function values between patients randomized to both arms
timeFrame: Randomization to 1 year post-randomization, randomization to 2 years post-randomization, and randomization to up to 5 years post-randomization
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas
state: Arkansas
city: Loma Linda
country: United States
facility: Loma Linda
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Oakland
country: United States
facility: Children's Hospital & Research Center Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Stanford
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
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Wilmington
country: United States
facility: Nemours Children's Hospital, Delaware
state: Delaware
city: Washington
country: United States
facility: Children's National Hospital
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Hospital of Atlanta/Emory
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Hospital/Riley Hospital for Children
state: Indiana
city: New Orleans
country: United States
facility: Children's Hospital NOLA
state: Louisiana
city: Scarborough
country: United States
facility: Maine Health
state: Maine
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochestser
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Medical Center of New York
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Levine Children's Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
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: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah/Primary Children's Hospital
state: Utah
city: Norfolk
country: United States
facility: Children's Hospital of the King's Daughter
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Winnipeg
country: Canada
facility: Winnipeg CancerCare Manitoba
state: Manitoba
Study officials:
affiliation: Boston Children's Hospital
name: David Williams, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Michael Pulsipher, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CIBMTR/Medical College of Wisconsin (MCW)
name: Bronwen Shaw, MD
role: PRINCIPAL_INVESTIGATOR
References: