Abatacept for Post-Transplant Immune Suppression in Children and Adolescents Receiving Allogeneic Hematopoietic Stem Cell Transplants for Non-Malignant Diseases
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Tolerability of Abatacept
研究概览
简要总结
This is a single arm, phase I study to assess the tolerability of abatacept when combined with cyclosporine and mycophenolate mofetil as graft versus host disease prophylaxis in children undergoing unrelated hematopoietic stem cell transplant for serious non-malignant diseases as well as to assess the immunological effects of abatacept. Participants will be followed for 2 years.
详细描述
Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only viable cure for children who suffer from a wide variety of rare, serious non-malignant diseases, such as Fanconi Anemia, Hurler syndrome, and hemophagocytic lymphohistiocytosis. A major obstacle to the success of HSCT is morbidity and mortality from graft versus host disease (GVHD), driven by donor T cells recognizing and reacting against disparate host antigens. This trial is being conducted as a step toward testing the long-term hypothesis that the costimulation blockade agent abatacept can be added to a standard post-transplant GVHD prophylaxis regimen, cyclosporine and mycophenolate mofetil, to improve disease-free survival after unrelated hematopoietic stem cell transplantation (HSCT) using reduced intensity conditioning for children with non-malignant diseases (NMD). This study will have the following Specific Aims:
Specific Aim #1: To conduct a multicenter pilot assessing the tolerability of abatacept (n=10). Patients will receive four doses (10 mg/kg IV on days -1, +5, +14 and +28), a schedule well tolerated by adolescents and adults with hematologic malignancies in a previous pilot. Abatacept will be combined with cyclosporine and mycophenolate mofetil.
Specific Aim #2: To examine the immunological effects of abatacept in this setting.
Three reduced intensity conditioning regimens that have been shown to be effective in achieving sustained engraftment in patients with non-malignant diseases are available for use, depending on the patient's disease:
- Patients with Fanconi anemia will receive fludarabine, low dose cyclophosphamide, and anti-thymocyte globulin.
- Patients with severe aplastic anemia will receive low dose total body irradiation, fludarabine, cyclophosphamide, and anti-thymocyte globulin.
- Patients with other NMD will receive either the low dose total body irradiation regimen or an alemtuzumab, fludarabine, thiotepa, and melphalan regimen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must be between the ages of 0-21 years at the time of admission for transplant.
- •Must have one of the following diseases:
- •Glanzmann thrombasthenia
- •Wiskott-Aldrich syndrome or other combined immune deficiency
- •Chronic-granulomatous disease
- •Severe congenital neutropenia (with resistance to granulocyte-colony stimulating factor (GCSF) or chronic requirement of GCSF doses ≥10 mcg/kg)
- •Leukocyte adhesion deficiency
- •Shwachman-Diamond syndrome
- •Diamond-Blackfan anemia ((transfusion dependent, including steroid failure or inability to wean steroids)
- •Thalassemia major
- •Fanconi anemia
- •Hemophagocytic lymphohistiocytosis (inherited or acquired refractory to therapy or with recurrent episodes of hyperinflammation)
- •Dyskeratosis-congenita
- •Hurler Syndrome
- •Chediak-Higashi syndrome
- •Acquired (immune; non-inherited, non-congenital) severe aplastic anemia
- •Sickle cell disease (SCD) (Hgb SS or S-Beta 0 thalassemia) will be eligible between ages 3 and 9.99 and with severe disease.
- •Other inherited or congenital marrow failure syndromes complicated by severe aplastic anemia
- •Other inherited or congenital red blood cell disorders requiring monthly chronic transfusion therapy.
- •Congenital platelet disorders requiring frequent platelet transfusions (patient must have received at least 10 transfusions in the last 3 years).
- •Other inherited or congenital granulocyte disorders resulting in at least three inpatient hospitalizations in the past three years for infection.
- •Must have an unrelated adult donor (marrow or PBSC) who is at least a 7/8 match (A, B, C, DRB1; the mismatch can be at an allele or antigen level) or an unrelated cord blood unit that is matched at least seven of eight loci (A, B and C antigen level-DRB1 allele level) and provides a minimum pre-cryopreservation total nucleated cell (TNC) dose of 7.5 x 107 TNC/kg recipient weight. Mismatches at the DRB1 locus may be at an antigen or allele level.
排除标准
- •Human leukocyte antigen (HLA) matched related donor.
- •Severe combined immune deficiency.
- •Bridging (portal to portal) fibrosis or cirrhosis of the liver.
- •Pulmonary: diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin), forced expiratory volume (FEV1) or forced vital capacity (FVC) < 40% of predicted. In child unable to perform pulmonary function testing, a chronic need for supplemental oxygen will serve as the exclusionary criterion.
- •Severe renal dysfunction defined as estimated glomerular filtration rate (GFR) of <60 ml/min/1.73m
- •Severe cardiac dysfunction defined as shortening fraction < 25%.
- •Neurologic impairment other than hemiplegia, defined as full-scale intelligence quotient (IQ) less than or equal to 70, quadriplegia or paraplegia, inability to ambulate, or any impairment resulting in decline of Lansky performance score to < 70%.
- •Clinical stroke within 6 months of anticipated transplant.
- •Karnofsky or Lansky functional performance score < 50%
- •HIV infection.
- •Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study enrollment.
- •Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate bone marrow transplantation.
- •Patient or patient's guardian(s) unable to understand the nature and risks inherent in the blood and marrow transplant process.
- •History of non-compliance severe enough in the estimation of the treating team to preclude the patient from undergoing unrelated donor transplantation.
- •Patient is pregnant or lactating
- •Patients HLA antibody testing demonstrates an antibody directed against a disparate HLA molecule.
研究组 & 干预措施
Abatacept
4 doses of abatacept 10 mg/kg/dose will be given on days -1, +5, +14, and +28.
干预措施: Abatacept (Drug)
结局指标
主要结局
Tolerability of Abatacept
时间窗: 1 year post-transplant
The primary endpoint for this trial will be tolerability, defined in terms of the success in administering all prescribed doses of abatacept. Abatacept will be deemed to be poorly tolerated if any of the following conditions are met: * More than one dose is withheld. * Death from an infection that occurs within 30 days of receiving the last prescribed dose of abatacept, but that is not preceded by systemic immunosuppressive therapy for GVHD * Post-transplant lymphoproliferative disorder (PTLD) that occurs within 100 days of receiving the last prescribed dose, but that is not preceded by systemic immunosuppressive therapy for GVHD. If less than 4 patients (of at least 18 evaluable patients) tolerate abatacept poorly, abatacept will be deemed tolerable. If there are fewer than 18 evaluable patients, if 3 of the first 10 patients treated tolerate abatacept poorly, abatacept will be deemed tolerable.
次要结局
- Days until Neutrophil Recovery(1 year post-transplant)
- Number of Participants with Graft Loss(1 year post-transplant)
- Number of Participants Experiencing Cytomegalovirus (CMV) Viremia(Up to Day 180)
- Number of Participants Experiencing Post-transplant Lymphoproliferative Disorder (PTLD)(1 year post-transplant)
- Proportion of Participants Experiencing Regimen-related Toxicity (RRT)(Day 42 post-transplant)
- Days until Platelet Recovery(1 year post-transplant)
- Number of Participants with Non-engraftment(1 year post-transplant)
- Number of Participants with Secondary Graft Failure(1 year post-transplant)
- Number of Participants Experiencing CMV Invasive Disease(1 year post-transplant)
- Number of Participants Experiencing Other Infections(1 year post-transplant)
- Number of Participants Experiencing Immune Reconstitution(1 year post-transplant)
- Number of Participants Experiencing Acute Graft Versus Host Disease (GVHD)(Up to 1 year post-transplant)
- Number of Participants Experiencing Chronic GVHD(2 years post-transplant)
- Immune Suppression-Free Survival Rate(1 year post-transplant)
- Immune Suppression-Free and Disease-Free Survival Rate(1 year post-transplant)
- Disease-free Survival Rate(1 year post-transplant)
- Overall Survival Rate(1 year post-transplant)
研究者
John Horan
Associate Professor
Emory University