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)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 53
- 试验地点
- 52
- 主要终点
- The primary endpoint of this trial is time from randomization to treatment failure or death from any cause.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •Bone marrow cellularity <25%, or <30% hematopoietic cells.
- •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.
- •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.
排除标准
- •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.
- •Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination.
- •Known severe allergy to ATG.
- •Prior allogeneic or autologous stem cell transplant.
- •Prior solid organ transplant.
- •Infection with human immunodeficiency virus (HIV).
- •Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs).
- •Female patients who are pregnant or breast-feeding.
- •Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ.
- •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
研究组 & 干预措施
Immunosuppressive Therapy
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
干预措施: Immunosuppressive Therapy (IST) (Procedure)
Immunosuppressive Therapy
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
干预措施: horse anti-thymocyte globulin (ATG) (Drug)
Immunosuppressive Therapy
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
干预措施: cyclosporine (Drug)
Matched Unrelated Stem Cell Transplant
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.
干预措施: low-dose total body irradiation (TBI) (Radiation)
Matched Unrelated Stem Cell Transplant
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.
干预措施: rabbit anti-thymocyte globulin (ATG) (Drug)
Matched Unrelated Stem Cell Transplant
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.
干预措施: Methotrexate (Drug)
Matched Unrelated Stem Cell Transplant
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.
干预措施: Matched Unrelated Donor Hematopoetic Stem Cell Transplant (Procedure)
Matched Unrelated Stem Cell Transplant
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.
干预措施: cyclosporine (Drug)
Matched Unrelated Stem Cell Transplant
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.
干预措施: Fludarabine (Drug)
Matched Unrelated Stem Cell Transplant
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.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
The primary endpoint of this trial is time from randomization to treatment failure or death from any cause.
时间窗: Randomization to 2 years post-randomization
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).
次要结局
- Comparison of subjects on immune suppression therapy at 2 years among those who have not died or failed treatment.(Randomization to 2 years post-randomization)
- Estimate the time from randomization to initiation of IST or BMT.(Randomization through Day 100)
- Comparison of the frequency of failure to receive primary assigned therapy (IST or BMT) and reasons for the failure.(Randomization through Day 100)
- Comparison of subjects with failure of IST or BMT before or at 2 years(Randomization to 2 years post-randomization)
- Comparison of the median time from initiation of therapy to and rates of red blood cell recovery on both arms.(Randomization to 100 days, 180 days, 1 year and 2 years)
- Estimate the rates of primary graft failure in patients who are randomized to URD BMT .(Randomization to 3-5 years)
- Comparison of subjects with inadequate counts at 2 years among those who have not died or failed treatment.(Randomization to 2 years post-randomization)
- Comparison of the incidence of bacteremia, viremia, and invasive fungal infection in the first two years after randomization in the IST and BMT arms.(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(Initiation of therapy (Day 0) to 100 days, 180 days, 1 year and 2 years)
- Comparison of treatment-related mortality (TRM) at 1 and 2 years from randomization in both arms.(Randomization to 1 year, randomization to 2 years)
- Comparison of the median time from randomization to and rates of neutrophil recovery on both arms(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(Randomization to 100 days, 180 days, 1 year and 2 years)
- Estimate the rates of engraftment in patients who are randomized to URD BMT.(Randomization to 3-5 years)
- Estimate the rates of response of patients randomized to IST(Randomization to 100 days, 180 days, 1 year and 2 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.(Randomization to 3-5 years)
- Comparison of HR-QoL score between patients randomized to both arms(Randomization to 2 years post-randomization, randomization to up to 5 years post-randomization)
- Comparison of overall survival at 1 and 2 years from randomization in both arms.(Randomization to one year, randomization to two years)
- Comparison of the median time from randomization to and rate of platelet recovery on both arms(Randomization 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(Initiation of therapy to 100 days, 180 days, 1 year and 2 years)
- Estimate the rates of grade II-IV acute GVHD in patients who are randomized to URD BMT .(Randomization to 3-5 years)
- Estimate the rates of failure of patients randomized to IST(Randomization to 100 days, 180 days, 1 year and 2 years)
- Describe the secondary therapies given and outcomes achieved for patients failing initial therapy(Randomization to 3-5 years)
- Comparison of the median time from initiation of therapy to and rates of neutrophil recovery on both arms(Initiation of therapy to 100 days, 180 days, 1 year and 2 years)
- Estimate the rates of secondary graft failure in patients who are randomized to URD BMT .(Randomization to 3-5 years)
- Estimate the rates of grade III-IV acute GVHD in patients who are randomized to URD BMT.(Randomization to 3-5 years)
- Estimate the rates of severe chronic GVHD in patients who are randomized to URD BMT.(Randomization to 3-5 years)
- Comparison of gonadal function values between patients randomized to both arms(Randomization to 1 year post-randomization, randomization to 2 years post-randomization, and randomization to up to 5 years post-randomization)
研究者
David Williams
Chief - Division of Hematology/Oncology
Boston Children's Hospital