Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Acute Myelogenous Leukemia/Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia (AML/MDS/JMML)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO)
研究概览
简要总结
Allogeneic stem cell transplantation (AlloSCT) followed by targeted immune therapy Gemtuzumab Ozogamicin patients with acute myeloid leukemia (AML)/juvenile myelomonocytic leukemia (JMML)/myelodysplastic syndromes (MDS) will be safe and well tolerated.
详细描述
Gemtuzumab Ozogamicin (CMA-676) is a chemotherapeutic agent consisting of a recombinant humanized anti-CD33 antibody conjugated with calicheamicin, a highly potent cytotoxic antitumor antibiotic. The antibody portion of Gemtuzumab binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein expressed on the surface of leukemic blasts, normal and leukemic myeloid colony-forming cells, including leukemic clonogenic precursors, but excluding pluripotent hematopoietic stem cells and nonhematopoietic cells. This results in formation of a complex that is internalized, upon which the calicheamicin derivative is released within the lysosomes of the myeloid cell. The free calicheamicin derivative then binds to deoxyribonucleic acid (DNA), resulting in DNA double strand breaks and consequential cell death. Over 80% of AML patients possess myeloid blast cells with CD33 surface antigen expression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Month 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Disease Status
- •AML 1st complete remission (CR) with a matched family donor (excluding Downs Syndrome, acute promyelocytic leukaemia (APL), poor cytogenetics (12p, 5q, -7 and FMS-like tyrosine kinase 3 (FLT3) mutations or duplication t(9;11) and others)) and patients consented to and registered on an upfront AML COG study with a matched family donor)
- •AML 1st CR (excluding Downs Syndrome, APL, and chromosome translocation (8;21) or inversion (16) or poor cytogenetics (12p, 5q, -7, FLT3 mutation or duplication t(9;11) and others)) with unrelated donor
- •AML 2nd CR
- •Myelodysplastic Syndrome (MDS) and ≤ 5% bone marrow myeloblasts at diagnosis (de novo patients only)
- •Juvenile Myelomonocytic Leukemia (JMML) and ≤ 5% bone marrow myeloblasts at diagnosis
- •In regards to disease immunophenotype, disease must express a minimum of ≥10% Cell Differential 33 (CD33) positivity for patients with AML
- •Organ Function:
- •Patients must have adequate organ function as defined below:
- •Adequate renal function defined as:
- •Serum creatinine < 1.5 x normal, or
- •Creatinine clearance or radioisotope glomerular filtration rate (GFR) 40 ml/min/m2 or > 60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range
- •Adequate liver function defined as total bilirubin 2.0 x upper limit of normal (ULN), or serum glutamic-oxaloacetic transaminase (SGOT)(aspartate aminotransferase (AST)) or serum glutamic-pyruvic transaminase (SGPT)(alanine aminotransferase (ALT)) < 5.0 x ULN
- •Adequate cardiac function defined as:
- •Shortening fraction of ≥ 25% by echocardiogram, or
- •Ejection fraction of ≥ 45% by radionuclide angiogram or echocardiogram
- •Adequate pulmonary function defined as:
- •Diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 40% by pulmonary function tests (PFT) (Uncorrected)
- •For children who are uncooperative, no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% on room air
排除标准
- •Patients with active central nervous system (CNS) AML/JMML disease at time of preparative regimen
- •Secondary MDS
- •Poor cytogenetics (12p, 5q, -7, FLT3 mutation or duplication)
- •Female patients who are pregnant (positive human chorionic gonadotropin(hCG))
- •Karnofsky <70% or Lansky <50% if 10 years or less
- •Age >30 years
- •Seropositive for Human Immunodeficiency Virus (HIV)
- •Patients consented to and registered on an upfront Children's Oncology Group (COG) AML study with a matched family donor
研究组 & 干预措施
Matched Family Donor
Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from a related family donor using bone marrow or cord blood stem cells. Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).
During and following transplantation patients will receive methylprednisolone for immune suppression. Graft-versus-host-disease (GVHD) prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.
干预措施: Fludarabine (Drug)
Matched Family Donor
Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from a related family donor using bone marrow or cord blood stem cells. Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).
During and following transplantation patients will receive methylprednisolone for immune suppression. Graft-versus-host-disease (GVHD) prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.
干预措施: Busulfan (Drug)
Matched Family Donor
Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from a related family donor using bone marrow or cord blood stem cells. Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).
During and following transplantation patients will receive methylprednisolone for immune suppression. Graft-versus-host-disease (GVHD) prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.
干预措施: GVHD Prophylaxis (Drug)
Matched Family Donor
Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from a related family donor using bone marrow or cord blood stem cells. Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).
During and following transplantation patients will receive methylprednisolone for immune suppression. Graft-versus-host-disease (GVHD) prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.
干预措施: Gemtuzumab Ozogamicin (Drug)
Unrelated Donor
Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from an unrelated donor using matched bone marrow or cord blood stem cells.Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).
During and following transplantation patients will receive methylprednisolone for immune suppression and unrelated donor transplant recipients will additionally receive Anti-Thymocyte Globulin. GVHD prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.
干预措施: Anti-Thymocyte Globulin (Drug)
Unrelated Donor
Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from an unrelated donor using matched bone marrow or cord blood stem cells.Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).
During and following transplantation patients will receive methylprednisolone for immune suppression and unrelated donor transplant recipients will additionally receive Anti-Thymocyte Globulin. GVHD prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.
干预措施: Isotretinoin (Drug)
结局指标
主要结局
Maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO)
时间窗: Up to 2 years
To determine the maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO) (anti CD33 immunotoxin) therapy following reduced intensity (RI) allogeneic stem cell transplantation (alloSCT) in patients with average risk AML/JMML/MDS.
次要结局
- Incidence of minor histocompatibility antigen (MHA) expression on acute myeloid leukemia (AML) tissue(Up to 2 years)
- Degree of mixed/complete donor chimerism(Up to 2 years)
- Event free survival (EFS) rate(Up to 2 years)
- Change of minimal residual disease(Day 60, Day 100, Day 180, 1 year, 2 years)
- Overall survival (OS) rate(Up to 2 years)
研究者
Monica Bhatia
Associate Professor of Pediatrics, Section Head of Pediatric Stem Cell Transplant at Columbia University
Columbia University