Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Donor Engraftment
研究概览
简要总结
Phase II prospective trial to assess the rates of donor engraftment using reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) and post-transplant cyclophosphamide (PTCy) for patients with primary immune deficiencies (PID), immune dysregulatory syndromes (IDS), inherited bone marrow failure syndromes (IBMFS), short telomere syndromes, Fanconi anemia, and non-Fanconi DNA double-strand break (DNA-dsb) repair disorder.
详细描述
Allogeneic blood and marrow transplantation (alloBMT) is the only curative therapy for many primary immune deficiencies (PID), immune dysregulatory syndromes (IDS), and inherited bone marrow failure syndromes (IBMFS). The best reported outcomes are with human leukocyte antigen (HLA)- matched sibling donors, however, only 30% of children in need of a BMT have an HLA-matched sibling. Use of alternative donors has been limited by unacceptably high rates of transplant-related mortality (TRM), graft rejection, infection, and graft-versus-host disease (GVHD). Reduced intensity conditioning (RIC) regimens have been used for this patient population with improved survival and decreased TRM, but graft failure and sustained donor chimerism have emerged as significant obstacles. Thus, there is an urgent need to develop a RIC platform that improves survival and decreases TRM while maximizing donor engraftment, which is essential for cure.
A large and growing body of literature demonstrates that post-transplant cyclophosphamide (PTCy) allows for the safe and effective use of HLA-matched and mismatched related and unrelated donors and haploidentical related donors after RIC alloBMT. PTCy offers a unique opportunity to 1) broaden donor availability, 2) promote durable engraftment of donor cells, 3) achieve low rates of GVHD and TRM, 4) foster robust immune reconstitution and immunity, and 5) shorten the duration of additional post-transplant immune suppression (IS) required to prevent GVHD. The investigators proposed platform is uniquely suited for success in this context, to broaden the scope of RIC alloBMT with PTCy as a curative therapy for patients with PID/IDS and IBMFS.
This is a Phase II single arm trial to prospectively study a RIC BMT with PTCy to enhance durable engraftment of donor cells and improve outcomes for patients with PID/IDS and IBMFS.
Treatment Plan:
Indwelling central venous catheter Placement of a double lumen central venous catheter will be required for administration of IV medications and transfusion of blood products.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 4 Months 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
PID/IDS/IBMFS
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1.
Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Alemtuzumab (Drug)
PID/IDS/IBMFS
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1.
Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Fludarabine (Drug)
PID/IDS/IBMFS
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1.
Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Melphalan (Drug)
PID/IDS/IBMFS
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1.
Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Low Dose Total Body Irradiation (Radiation)
PID/IDS/IBMFS
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1.
Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Cyclophosphamide (Drug)
PID/IDS/IBMFS
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1.
Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Tacrolimus (Drug)
PID/IDS/IBMFS
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1.
Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Mycophenolate Mofetil (Drug)
Short Telomere Syndrome
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Alemtuzumab (Drug)
Short Telomere Syndrome
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Fludarabine (Drug)
Short Telomere Syndrome
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Low Dose Total Body Irradiation (Radiation)
Short Telomere Syndrome
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Cyclophosphamide (Drug)
Short Telomere Syndrome
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Tacrolimus (Drug)
Short Telomere Syndrome
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Mycophenolate Mofetil (Drug)
Fanconi Anemia or DNA-dsb repair
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Alemtuzumab (Drug)
Fanconi Anemia or DNA-dsb repair
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Fludarabine (Drug)
Fanconi Anemia or DNA-dsb repair
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Low Dose Total Body Irradiation (Radiation)
Fanconi Anemia or DNA-dsb repair
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Cyclophosphamide (Drug)
Fanconi Anemia or DNA-dsb repair
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Tacrolimus (Drug)
Fanconi Anemia or DNA-dsb repair
Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if <10 kg). Day -12 20 mg (or 10 mg if <10 kg).
Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant.
Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours.
Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Mycophenolate Mofetil (Drug)
结局指标
主要结局
Donor Engraftment
时间窗: 60 Days
Rate of donor engraftment ≥95% at day 60 as measured by donor chimerism in whole blood.
次要结局
- Number of patients that have survived at 1 year(1 year)
- Disease Free Survival at 1 year(1 year)