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| ID | Type | Description | Link |
|---|---|---|---|
| 1UG3HL157564-01A1 | U.S. NIH Grant/Contract | View source | |
| 1U24HL157560-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Center for International Blood and Marrow Transplant Research | NETWORK |
| National Institutes of Health (NIH) | NIH |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Immunosuppressive Therapy | Active Comparator | Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine. |
|
| Matched Unrelated Stem Cell Transplant | Active Comparator | Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| cyclosporine | Drug | cyclosporine |
|
| Measure | Description | Time Frame |
|---|---|---|
| The primary endpoint of this trial is time from randomization to treatment failure or death from any cause. | The median time to failure or death will be compared on the two arms using the log-rank test. Failure of IST is defined as the date that a second definitive therapy was recommended (BMT, second course of ATG) and failure of BMT defined as the date that a second definitive therapy was recommended (second BMT, course of ATG). | Randomization to 2 years post-randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Comparison of subjects with failure of IST or BMT before or at 2 years | The proportion of subjects with failure of IST or BMT before or at 2 years. Failure of IST is defined as initiation of a second definitive therapy (BMT, second course of ATG) and failure of BMT defined as initiation of a second definitive therapy (second BMT, course of ATG). | Randomization to 2 years post-randomization |
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Inclusion Criteria:
To be eligible to participate in the randomized trial, an individual must meet all the following criteria:
Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian.
Age ≤25 years old at time of randomized trial consent.
Confirmed diagnosis of idiopathic SAA, defined as:
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).
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).
In the treating physician's opinion, no obvious contraindications precluding them from BMT or IST.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David Williams, MD | Boston Children's Hospital | Principal Investigator |
| Michael Pulsipher, MD | University of Utah | Principal Investigator |
| Bronwen Shaw, MD | CIBMTR/Medical College of Wisconsin (MCW) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35249 | United States | ||
| Phoenix Children's Hospital |
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| North American Pediatric Aplastic Anemia Consortium |
| UNKNOWN |
| Pediatric Transplantation and Cellular Therapy Consortium | OTHER |
| Blood and Marrow Transplant Clinical Trials Network | NETWORK |
Unblinded, stratified, multi-center, phase 3, randomized controlled trial
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| Matched Unrelated Donor Hematopoetic Stem Cell Transplant | Procedure | Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT) |
|
| horse anti-thymocyte globulin (ATG) | Drug | horse anti-thymocyte globulin (ATG) |
|
|
| rabbit anti-thymocyte globulin (ATG) | Drug | rabbit anti-thymocyte globulin (ATG) |
|
|
| Methotrexate | Drug | methotrexate |
|
| Fludarabine | Drug | fludarabine |
|
| Cyclophosphamide | Drug | cyclophosphamide |
|
| low-dose total body irradiation (TBI) | Radiation | low-dose total body irradiation (TBI) |
|
| Immunosuppressive Therapy (IST) | Procedure | Immunosuppressive Therapy (IST) |
|
| Comparison of subjects with inadequate counts at 2 years among those who have not died or failed treatment. | The proportion of subjects with inadequate counts at 2 years among those who have not failed therapy or died. Adequate counts are defined as: Absolute Neutrophil Count (ANC) >1 x 10^9/L, Hemoglobin >10g/dL, and Platelets >50 x10^9/L. | Randomization to 2 years post-randomization |
| Comparison of subjects on immune suppression therapy at 2 years among those who have not died or failed treatment. | The proportion of subjects on immune suppression therapy at 2 years among those who have not failed therapy or died. Immune suppression is defined as systemic therapies necessary to treat SAA or GVHD (cyclosporine, tacrolimus, etc.). Isolated treatment with topical agents will not be considered as immune suppression therapy. | Randomization to 2 years post-randomization |
| Estimate the time from randomization to initiation of IST or BMT. | The median time in days from randomization to initiation of IST or BMT will be estimated. Initiation of therapy is first day of ATG for IST subjects, or day 0 (infusion day) for bone marrow transplant subjects. | Randomization through Day 100 |
| Comparison of the frequency of failure to receive primary assigned therapy (IST or BMT) and reasons for the failure. | The proportion of subjects who fail to receive randomized therapy and the frequency of reasons for failure. | Randomization through Day 100 |
| Comparison of the incidence of bacteremia, viremia, and invasive fungal infection in the first two years after randomization in the IST and BMT arms. | Proportion of subjects from the time of randomization in the first 2 years with each of the following:
| Randomization through two years post randomization |
| Estimate the median time to T- and B-cell immune reconstitution the first year for the URD BMT Arm | Absolute CD3, CD4, CD8, CD19, and CD56 (NK cell) numbers will be tracked at 100 days, 180 days, 1 year and 2 years post initiation of therapy in URT BMT arm. IgG levels free of IVIG replacement will be collected at the same timepoints. The median time to T- and B-cell reconstitution will be estimated. | Initiation of therapy (Day 0) to 100 days, 180 days, 1 year and 2 years |
| Comparison of overall survival at 1 and 2 years from randomization in both arms. | Proportion of subjects who have died at 1 year and 2 years after randomization for any reason. | Randomization to one year, randomization to two years |
| Comparison of treatment-related mortality (TRM) at 1 and 2 years from randomization in both arms. | Proportion of subjects who have died at 1 year and 2 years after randomization due to treatment-related reasons. TRM is defined as death in recipients without relapse or progression of their disease. Non-medical, accidental causes of death, e.g., natural disasters, are not considered TRM. | Randomization to 1 year, randomization to 2 years |
| Comparison of the median time from randomization to and rates of neutrophil recovery on both arms | The time from randomization to neutrophil recovery. Neutrophil recovery is defined as ANC 0.5 x109/L for 3 consecutive measures for neutrophils (recovery date is the first date). | Randomization to 100 days, 180 days, 1 year and 2 years |
| Comparison of the median time from randomization to and rate of platelet recovery on both arms | The time from randomization to platelet recovery. Platelet recovery is defined as platelet levels >= 20 x10^9/L for 3 consecutive measures (recovery is the first date) with no platelet transfusions for 1 full week. | Randomization to 100 days, 180 days, 1 year and 2 years |
| Comparison of the median time from randomization to and rates of red blood cell recovery on both arms | The time from randomization to red blood cell recovery. Red blood cell recovery is defined as RBC hemoglobin level >= 8g/dL and 10g/dL with no RBC transfusions for 4 weeks. | Randomization to 100 days, 180 days, 1 year and 2 years |
| Comparison of the median time from initiation of therapy to and rates of neutrophil recovery on both arms | The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to neutrophil recovery. Neutrophil recovery is defined as ANC 0.5 x109/L for 3 consecutive measures for neutrophils (recovery date is the first date). | Initiation of therapy to 100 days, 180 days, 1 year and 2 years |
| Comparison of the median time from initiation of therapy to and rate of platelet recovery on both arms | The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to platelet recovery. Platelet recovery is defined as platelet levels >= 20 x10^9/L for 3 consecutive measures (recovery is the first date) with no platelet transfusions for 1 full week. | Initiation of therapy to 100 days, 180 days, 1 year and 2 years |
| Comparison of the median time from initiation of therapy to and rates of red blood cell recovery on both arms. | The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to red blood cell recovery. Red blood cell recovery is defined as RBC hemoglobin level >= 8g/dL and 10g/dL with no RBC transfusions for 4 weeks. | Randomization to 100 days, 180 days, 1 year and 2 years |
| Estimate the rates of engraftment in patients who are randomized to URD BMT. | Proportion of subjects with engraftment in patients who receive URD BMT. | Randomization to 3-5 years |
| Estimate the rates of primary graft failure in patients who are randomized to URD BMT . | Proportion of subjects with primary graft failure in patients who receive URD BMT. Primary graft failure is defined as failure to achieve neutrophil recovery by Day +28 following a conditioning regimen induced neutrophil nadir < 0.5 x10^9/L. | Randomization to 3-5 years |
| Estimate the rates of secondary graft failure in patients who are randomized to URD BMT . | Proportion of subjects with secondary graft failure in patients who receive URD BMT. Secondary graft failure will be defined as a fall in the neutrophil count after documented primary engraftment to < 0.5 x10^9/L sustained for more than three days that cannot be attributed to other causes such as drugs, infection, GVHD, etc., and is not responsive to G-CSF or GM-CSF. | Randomization to 3-5 years |
| Estimate the rates of grade II-IV acute GVHD in patients who are randomized to URD BMT . | Proportion of subjects with grade II-IV in patients who receive URD BMT. | Randomization to 3-5 years |
| Estimate the rates of grade III-IV acute GVHD in patients who are randomized to URD BMT. | Proportion of subjects with grade III-IV acute GVHD in patients who receive URD BMT. | Randomization to 3-5 years |
| Estimate the rates of severe chronic GVHD in patients who are randomized to URD BMT. | Proportion of subjects with severe chronic GVHD in patients who receive URD BMT. | Randomization to 3-5 years |
| Estimate the rates of response of patients randomized to IST | Proportion of subjects with IST response. IST response criteria is: Complete Response: Hemoglobin ≥10 g/dL and ANC ≥1x10^9/L and Platelets ≥100x10^9/L Very Good Partial Response: Hemoglobin ≥8 g/dL and ANC ≥0.5x10^9/L and Platelets ≥50x10^9/L Partial Response: Hemoglobin ≥8 g/dL and ANC ≥0.5x10^9/L and Platelets ≥20x10^9/L and transfusion independent No Response (failure): Hemoglobin <8 g/dL or ANC <0.5x10^9/L or Platelets <20x10^9/L Lost Response: A lost response is captured by not meeting hematologic response criteria at a particular time point after having an initial response (complete, very good partial, or partial), or the need for additional treatment. | Randomization to 100 days, 180 days, 1 year and 2 years |
| Estimate the rates of failure of patients randomized to IST | Proportion of subjects with IST failure at 6 months (defined as Hemoglobin <8 g/dL or ANC <0.5x10^9/L or Platelets <20x10^9/L). | Randomization to 100 days, 180 days, 1 year and 2 years |
| Describe the secondary therapies given and outcomes achieved for patients failing initial therapy | Collect secondary therapies given for failure of primary randomized therapy (BMT after IST, second course of IST, second BMT). For the outcome after subsequent therapy, the median survival time will be estimated. | Randomization to 3-5 years |
| 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. | Proportion of subjects in each treatment arm with i) subsequent neoplasms, ii) presence of a PNH clone at time of randomization who go on to develop symptomatic PNH through the duration of the protocol. | Randomization to 3-5 years |
| Comparison of HR-QoL score between patients randomized to both arms | Change in score between baseline and two years and the trajectory of change over all timepoints. | Randomization to 2 years post-randomization, randomization to up to 5 years post-randomization |
| Comparison of gonadal function values between patients randomized to both arms | Proportion of subjects with gonadal function values outside the expected percentile for that age. | Randomization to 1 year post-randomization, randomization to 2 years post-randomization, and randomization to up to 5 years post-randomization |
| Phoenix |
| Arizona |
| 85016 |
| United States |
| Arkansas | Little Rock | Arkansas | 72202 | United States |
| Loma Linda | Loma Linda | California | 92354 | United States |
| Children's Hospital Los Angeles | Los Angeles | California | 90027 | United States |
| UCLA | Los Angeles | California | 90095 | United States |
| Children's Hospital & Research Center Oakland | Oakland | California | 94609 | United States |
| Children's Hospital of Orange County | Orange | California | 92868 | United States |
| Stanford | Palo Alto | California | 94304 | United States |
| Rady Children's Hospital San Diego | San Diego | California | 92123 | United States |
| University of California San Francisco | San Francisco | California | 94158 | United States |
| Children's Hospital Colorado | Aurora | Colorado | 80045 | United States |
| Yale University | New Haven | Connecticut | 06520 | United States |
| Nemours Children's Hospital, Delaware | Wilmington | Delaware | 19803 | United States |
| Children's National Hospital | Washington D.C. | District of Columbia | 20010 | United States |
| University of Florida | Gainesville | Florida | 32610 | United States |
| University of Miami | Miami | Florida | 33136 | United States |
| Nicklaus Children's Hospital | Miami | Florida | 33155 | United States |
| Johns Hopkins All Children's Hospital | St. Petersburg | Florida | 33701 | United States |
| Children's Hospital of Atlanta/Emory | Atlanta | Georgia | 30322 | United States |
| Ann & Robert H. Lurie Children's Hospital of Chicago | Chicago | Illinois | 60611 | United States |
| University of Chicago | Chicago | Illinois | 60637 | United States |
| Indiana University Hospital/Riley Hospital for Children | Indianapolis | Indiana | 46202 | United States |
| Children's Hospital NOLA | New Orleans | Louisiana | 70118 | United States |
| Maine Health | Scarborough | Maine | 04074 | United States |
| Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
| University of Michigan | Ann Arbor | Michigan | 48109 | United States |
| Helen DeVos Children's Hospital | Grand Rapids | Michigan | 49503 | United States |
| Mayo Clinic Rochestser | Rochester | Minnesota | 55902 | United States |
| University of Mississippi Medical Center | Jackson | Mississippi | 39216 | United States |
| Washington University in St. Louis | St Louis | Missouri | 63110 | United States |
| Hackensack University Medical Center | Hackensack | New Jersey | 07601 | United States |
| Roswell Park Comprehensive Cancer Center | Buffalo | New York | 14263 | United States |
| Cohen Children's Medical Center of New York | New Hyde Park | New York | 11040 | United States |
| Columbia University Medical Center | New York | New York | 10032 | United States |
| University of North Carolina | Chapel Hill | North Carolina | 27599 | United States |
| Levine Children's Hospital | Charlotte | North Carolina | 28203 | United States |
| Duke University | Durham | North Carolina | 27705 | United States |
| Nationwide Children's Hospital | Columbus | Ohio | 43205 | United States |
| Oregon Health & Science University | Portland | Oregon | 97239 | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| St. Jude Children's Research Hospital | Memphis | Tennessee | 38105 | United States |
| Vanderbilt University Medical Center | Nashville | Tennessee | 37203 | United States |
| Children's Medical Center Dallas | Dallas | Texas | 75235 | United States |
| Texas Children's Hospital | Houston | Texas | 77030 | United States |
| Methodist Healthcare | San Antonio | Texas | 78229 | United States |
| University of Utah/Primary Children's Hospital | Salt Lake City | Utah | 84112 | United States |
| Children's Hospital of the King's Daughter | Norfolk | Virginia | 23507 | United States |
| Fred Hutchinson Cancer Center | Seattle | Washington | 98109 | United States |
| University of Wisconsin | Madison | Wisconsin | 53792 | United States |
| British Columbia Children's | Vancouver | British Columbia | V6H 3V4 | Canada |
| Winnipeg CancerCare Manitoba | Winnipeg | Manitoba | R3E 0V9 | Canada |
| ID | Term |
|---|---|
| D000741 | Anemia, Aplastic |
| ID | Term |
|---|---|
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D000080983 | Bone Marrow Failure Disorders |
| D001855 | Bone Marrow Diseases |
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| ID | Term |
|---|---|
| D016572 | Cyclosporine |
| D000961 | Antilymphocyte Serum |
| C512542 | thymoglobulin |
| D008727 | Methotrexate |
| C024352 | fludarabine |
| D003520 | Cyclophosphamide |
| D014916 | Whole-Body Irradiation |
| D007165 | Immunosuppression Therapy |
| ID | Term |
|---|---|
| D003524 | Cyclosporins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D007106 | Immune Sera |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D011878 | Radiotherapy |
| D013812 | Therapeutics |
| D008919 | Investigative Techniques |
| D007167 | Immunotherapy |
| D056747 | Immunomodulation |
| D001691 | Biological Therapy |
| D007158 | Immunologic Techniques |
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