Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for the Treatment of Bone Marrow Failure Diseases
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 33
- 主要终点
- Graft-Versus Host-Disease (GVHD)-Free Event-Free Survival (EFS)
研究概览
简要总结
This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs, such as treosulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. rATG is used to decrease the body's immune response and may improve bone marrow function and increase blood cell counts. Adding treosulfan to a conditioning regimen with fludarabine and rATG may result in patients having less severe complications after a blood or bone marrow transplant.
详细描述
OUTLINE:
CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and lapine T-lymphocyte immune globulin (rATG) IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus orally (PO). Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) as well as possible chest radiography (x-ray) or computed tomography (CT) at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 49 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient must be >= 1.0 year of age and less than 50.0 years of age at the time of enrollment (i.e. patient must have celebrated their 1st birthday when enrolled and must NOT have celebrated their 50th birthday when enrolled; 49.99 years)
- •Underlying BMFD treatable by allogenic HCT
- •Shwachman-Diamond syndrome
- •Criteria for Diagnosis:
- •A pathogenic mutation(s) for Shwachman-Diamond syndrome
- •For those patients tested but lacking a genetic mutation they must meet both *** criteria below:
- •Exocrine pancreatic dysfunction as defined by at least one of the following:
- •Pancreatic isoamylase below normal (age >= 3 years old), OR
- •Fecal elastase < 200, AND
- •Bone marrow failure as evidence by at least one of the following:
- •Intermittent or persistent neutropenia (absolute neutrophil count < 1,500/uL), OR
- •Hypo-productive anemia with a hemoglobin concentration below the age-related adjusted norms, OR
- •Unexplained macrocytosis, OR
- •Platelet count < 150,000/uL without alternative etiology, OR
- •Hypocellular bone marrow
- •Indications for HCT:
- •Severe neutropenia (absolute neutrophil count [ANC] < 500/uL), OR
- •Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR
- •Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR
- •Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 eligibility review committee (ERC). In addition, patients with severe or recurrent infections will be reviewed by the ERC if they do not meet the indications for transplant listed above
- •Diamond Blackfan Anemia
- •Criteria for Diagnosis:
- •A pathogenic mutation for Diamond Blackfan anemia
- •For those patients tested but lacking a genetic mutation the patient must meet the first *** criteria and at least one of the subsequent *** criteria listed below:
- •History of deficiency of erythroid precursors in an otherwise cellular bone marrow AND,
- •Reticulocytopenia, OR
- •Elevated adenosine deaminase activity, OR
- •Elevated hemoglobin F, OR
- •Macrocytosis, OR
- •Congenital anomalies
- •Indications for HCT:
- •Red blood cell (RBC) transfusion dependent anemia despite an adequate trial of steroids; OR
- •Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
- •Congenital Sideroblastic anemia
- •Criteria for Diagnosis:
- •A pathogenic mutation(s) for sideroblastic anemia
- •For those patients tested but lacking a genetic mutation:
- •Presence of ringed sideroblasts in the bone marrow excluding acquired causes of ringed sideroblasts such as lead poisoning & zinc toxicity
- •Indications for HCT:
- •Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia OR
- •Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
- •GATA2 mutation with associated marrow failure
- •Criteria for Diagnosis:
- •** A pathogenic mutation(s) for GATA2
- •Indications for HCT:
- •Severe neutropenia (ANC < 500/uL), OR
- •Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR
- •Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR
- •Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC. In addition, patients with severe or recurrent infections will be reviewed by the ERC if they do not meet indications for transplant listed above
- •SAMD9 or SAMD9L disorders
- 另有 51 项未显示
排除标准
- •Patients with idiopathic aplastic anemia, Fanconi anemia, dyskeratosis congenita, and congenital neutropenia
- •Patients with MDS as defined by the World Health Organization (WHO) or leukemia
- •Prior allogeneic HCT
- •Patient's weight =< 10.0 kg (actual body weight and adjusted body weight) at time of study enrollment
- •Lansky (patients < 16 years of age) or Karnofsky (patients >= 16 years of age) performance < 70%
- •Left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition (MUGA) scan
- •* For patients unable to obtain a left ventricular ejection fraction, left ventricular shortening fraction of < 26%
- •Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) < 50%, forced expiratory volume (FEV)1 < 50% predicted, and forced vital capacity (FVC) < 50% predicted
- •For patients unable to perform pulmonary function tests (PFTs) due to age or developmental delay: oxygen (O2) saturation < 92% on room air
- •On supplemental oxygen
- •Estimated creatinine clearance < 60 mL/minute/1.73m^2 (estimated per institutional practice)
- •Dialysis dependent
- •Conjugated bilirubin > 2 x upper limit of normal for age (ULN, unless attributable to Gilbert's syndrome)
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 4 x ULN for age, or
- •Fulminant liver failure or cirrhosis
- •Iron overload - This exclusion criterion only applies to patients who are considered at risk for hepatic or cardiac iron overload. Therefore, not all patients enrolled on this protocol will undergo formal hepatic or cardiac iron assessment
- •* For patients with a history of significant transfusions defined as >= 8 packed red blood cell transfusions per year for >= 1 year or have received >= 20 packed red blood cell transfusions (lifetime cumulative) will require formal hepatic and cardiac iron measurement. In addition, patients with a prior history of hepatic or cardiac iron overload will also require formal assessment for iron overload. Patients are excluded if:
- •Hepatic iron content >= 8 mg Fe/g dry weight by liver magnetic resonance imaging (MRI) using a validated methodology (such as T2 * MRI or ferriscan) or liver biopsy per institutional practice
- •Cardiac iron content < 25 msec by cardiac T2 * MRI
- •Uncontrolled bacterial infection within 1 week of study enrollment. Uncontrolled is defined as currently taking medication with no clinical improvement or progression on adequate medical treatment
- •Uncontrolled viral or fungal infection within 30 days of study enrollment. Uncontrolled is defined as currently taking medication with no clinical improvement or progression on adequate medical treatment
- •Positive for human immunodeficiency virus (HIV)
- •Presence of clinically significant anti-donor human leukocyte antigen (HLA)-antibodies per institutional practice
- •Prior solid organ transplant
- •Patients with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ
- •Females who are pregnant or breast-feeding
- •Females and males of childbearing potential who are unwilling to practice an effective method of contraception or agree to abstinence from the time of signing informed consent through 12 months post-transplant or off tacrolimus whichever is later
- •Known hypersensitivity to treosulfan or fludarabine
- •Known life-threatening reaction (i.e. anaphylaxis) to Thymoglobulin that would prohibit use for the patient as this study requires use of the Thymoglobulin preparation of anti-thymocyte globulin (ATG)
研究组 & 干预措施
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Treosulfan (Drug)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Fludarabine Phosphate (Drug)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Tacrolimus (Drug)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Methotrexate (Drug)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Lapine T-Lymphocyte Immune Globulin (Biological)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Peripheral Blood Stem Cell Transplantation (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Allogeneic Bone Marrow Transplantation (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Quality-of-Life Assessment (Other)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Echocardiography (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Multigated Acquisition Scan (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: X-Ray Imaging (Procedure)
Treatment (conditioning regimen; transplant; GVHD prophylaxis)
CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.
干预措施: Computed Tomography (Procedure)
结局指标
主要结局
Graft-Versus Host-Disease (GVHD)-Free Event-Free Survival (EFS)
时间窗: 1 year post-HCT
The primary endpoint is the incidence of 1-year GVHD free, EFS (GEFS). An event is defined as death due to any cause, primary or secondary graft failure/rejection, or 2nd HCT whichever occurs first. Grade III-IV acute GVHD and chronic GVHD (using National Institutes of Health \[NIH\] consensus criteria) requiring systemic immune suppression will be considered in this estimate.
次要结局
- Overall Survival(1 year post-HCT)
- Event-Free Survival(1 year post-HCT)
- Hematologic Recovery: Neutrophil recovery(Assessed up to 1 year post-HCT)
- Hematologic Recovery: Platelet recovery(Day 100 post-HCT)
- Donor Chimerism (CD3 and Myeloid)(1 year post-HCT)
- Primary graft failure/rejection(Day 42 post-HCT)
- Secondary graft failure/rejection post-HCT(Assessed up to 1 year post-HCT)
- Grade II-IV and grade III-IV GVHD at day 100(Day 100 post-HCT)
- Grade II-IV and grade III-IV GVHD at day 180(Day 180 post-HCT)
- Chronic GVHD(1 year post-HCT)
- Incidence of grade 3-5 toxicities(Day 100 post-HCT)
- Incidence of grade 2-3 systemic infections(6 months post-HCT)
- Incidence of Epstein Barr virus (EBV) reactivation requiring therapy(Day 180 post-HCT)
- Incidence of EBV-associated lymphoproliferative disorder(Day 180 post-HCT)
- Incidence of cytomegalovirus (CMV) reactivation requiring therapy by day 180 post-HCT(Up to day 180 post-HCT)
- Overall Survival(Day 100 post-HCT)
- Overall Survival(6 months post-HCT)
- Donor Chimerism (CD3 and Myeloid)(Day 28 post-HCT)
- Donor Chimerism (CD3 and Myeloid)(Day 100 post-HCT)
- Incidence of grade 3-5 toxicities(Day 30 post-HCT)