A Pilot Study of Sequential Autologous Stem Cell Transplantation and Immunotherapy With Reduced Intensity Allogeneic Stem Cell Transplant for High Risk Neuroblastoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Rate of engraftment following NAT/AlloSCT from either a related donor or umbilical cord donor.
研究概览
简要总结
Neuroblastoma is a malignant tumor of the sympathetic nervous system. It is the second most common malignant tumor of childhood. Although modest advances have been made over the past 20 years children with high-risk neuroblastoma continue to have an unsatisfactory long-term survival. This study will administer induction chemotherapy followed by high-dose (myeloablative) chemotherapy with autologous stem cell transplantation, followed by radiation therapy, then immunotherapy with a non myeloablative allogeneic stem cell transplant for treatment of neuroblastoma. The purpose of this clinical research trial is to study the feasibility of giving immunotherapy with a non-myeloablative allogeneic transplant (NAT/AlloSCT), following myeloablative therapy and autologous stem cell transplant (MAT/AutoSCT). This study will also determine the side effects as well as the response rate for each group of patients (treatment arm).
详细描述
Despite the modest advances made over the past two decades with the addition of more intensive chemotherapy and high dose myeloablative therapy with allogeneic or autologous bone marrow transplantation, children with high-risk neuroblastoma continue to have an unsatisfactory long-term survival. The current survival for a child > 1 year of age at diagnosis with stage 4 neuroblastoma is only 20-35% 1,7. The overall treatment plan for high-risk patients with neuroblastoma will be:
Induction Therapy Intensive induction chemotherapy with the cardioprotectant dexrazoxane (Zinecard), vincristine, doxorubicin (Adriamycin), and cyclophosphamide (ZVAC), alternating with cisplatin and etoposide (CiE). Patients who receive induction chemotherapy on an alternate protocol and achieve a CR, VGPR, or PR will also be eligible for entry to receive consolidation therapy and AlloSCT immunotherapy after discussion and approval of the Principal Investigators ).
Consolidation Therapy with AutoSCT Consolidation therapy with a myeloablative preparative regimen of carboplatin, thiotepa, and topotecan (CaTT) followed by AutoSCT with PBSCs (CD34+ selection optional).
Immunotherapy with Non-myeloablative AlloSCT Immunotherapy with a non-myeloablative preparative regimen of busulfan and fludarabine followed by AlloSCT with either: (Arm A) a related donor (5/6 or 6/6 HLA matched); or (Arm B) an umbilical cord blood donor (unrelated 4/6, 5/6, or 6/6 HLA matched, or related 3/6, 4/6, 5/6, or 6/6 HLA matched). Patients with an umbilical cord blood donor will also receive Thymoglobulin (ATG-rabbit) during the preparative regimen. GVHD prophylaxis will consist of Tacrolimus and mycophenolate mofetil (MMF).
Maintenance Therapy Patients with a related donor who have persistent disease detected prior to NAT/AlloSCT will be assigned to Arm A1 and will receive two courses of DLI, followed by cis-RA for 6 cycles. Patients with a related donor with no persistent disease detected prior to NAT/AlloSCT will be assigned to Arm A2 and receive cis-RA for 6 cycles. Patients with an umbilical cord blood donor will receive cis-RA for 6 cycles.
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
- — 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age be < 30 years of age at the time of initial diagnosis.
- •Patients must have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) verified by histology and/or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. Patients with the following disease stages at diagnosis are eligible, if they meet the other specified criteria. The revised International Neuroblastoma Staging System (INSS) will be used to stage all patients
- •(See 14.3 for risk assignment).
- •Patients with newly diagnosed neuroblastoma and age > 547 days with the following:
- •INSS Stage 4 neuroblastoma regardless of biologic factors
- •INSS Stage 2A/2B with MYCN amplification (> 10)
- •INSS Stage 3 with MYCN amplification (> 10) OR Unfavorable histology
- •Patients with newly diagnosed neuroblastoma and age < 365 days with the following:
- •* INSS Stage 3, 4, OR 4S neuroblastoma AND MYCN amplification (> 10).
- •Patients with newly diagnosed Neuroblastoma and age 365 - <547 days with the following:
- •INSS Stage 3 with MYCN amplification (> 10)
- •INSS Stage 4 with MYCN amplification (> 10) OR with deoxyribonucleic acid (DNA) Index (ploidy) = 1 OR with Unfavorable histology
- •Patients > 365 days with INSS Stage 1, 2, and 4S who have progressed to Stage
- •Newly Diagnosed patients should be entered on this study within 4 weeks of diagnosis, or after receiving only one cycle of intermediate dose chemotherapy for patients initially treated on/according to the low or intermediate risk Children's Oncology Group (COG) neuroblastoma studies, or within 4 weeks of progression to Stage 4 for INSS Stage 1, 2, 4S.
- •Patients treated with alternative induction regimens and/or consolidation regimens (AutoSCT) who were not enrolled at diagnosis but who achieve a complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) and meet all other criteria will be eligible for either the consolidation MAT/AutoSCT and NAT/AlloSCT immunotherapy or NAT/AlloSCT, which ever is clinically appropriate after discussion with the Principal Investigators.
- •Liver Function: alanine aminotransferase (ALT) and bilirubin < 3x normal
- •Cardiac Function: Shortening fraction > 27%, or ejection fraction > 47%, no clinical congestive heart failure.
- •Renal Function: Creatinine clearance and/or glomerular filtration rate (GFR) > 60 ml/min/1.73m
- •Hematologic Function: Patients must have adequate hematopoietic function (absolute neutrophil count (ANC) > 1000/mm3 and platelets > 100,000/mm3) unless inadequate hematopoiesis documented to be due to bone marrow involvement with tumor (> 10% tumor infiltration).
排除标准
- •Patients who are pregnant. Patients of childbearing potential must practice an effective method of birth control while participating on this study.
研究组 & 干预措施
Arm A - Related Donor
Related donor transplant: Patients with a related donor (5/6 or 6/6 HLA matched) will receive immunotherapy with a non-myeloablative preparative regimen of Busulfan and Fludarabine followed by allogeneic stem cell transplant (AlloSCT).
干预措施: Related donor transplant (Procedure)
Arm A - Related Donor
Related donor transplant: Patients with a related donor (5/6 or 6/6 HLA matched) will receive immunotherapy with a non-myeloablative preparative regimen of Busulfan and Fludarabine followed by allogeneic stem cell transplant (AlloSCT).
干预措施: Busulfan (Drug)
Arm A - Related Donor
Related donor transplant: Patients with a related donor (5/6 or 6/6 HLA matched) will receive immunotherapy with a non-myeloablative preparative regimen of Busulfan and Fludarabine followed by allogeneic stem cell transplant (AlloSCT).
干预措施: Fludarabine (Drug)
Arm B - Cord Blood Donor
Unrelated cord blood transplant: Patients without a related donor will receive immunotherapy with a non-myeloablative preparative regimen of busulfan and fludarabine followed by allogeneic stem cell transplant (AlloSCT) with either an unrelated umbilical cord blood donor (4/6, 5/6, or 6/6 HLA matched), or a related umbilical cord blood donor (3/6, 4/6, 5/6, or 6/6 HLA matched). Patients will receive Thymoglobulin ((rabbit) Anti-Thymocyte Globulin (ATG)) during the preparative regimen. GVHD prophylaxis will be Tacrolimus and mycophenolate mofetil (MMF).
干预措施: Cord blood transplant (Procedure)
Arm B - Cord Blood Donor
Unrelated cord blood transplant: Patients without a related donor will receive immunotherapy with a non-myeloablative preparative regimen of busulfan and fludarabine followed by allogeneic stem cell transplant (AlloSCT) with either an unrelated umbilical cord blood donor (4/6, 5/6, or 6/6 HLA matched), or a related umbilical cord blood donor (3/6, 4/6, 5/6, or 6/6 HLA matched). Patients will receive Thymoglobulin ((rabbit) Anti-Thymocyte Globulin (ATG)) during the preparative regimen. GVHD prophylaxis will be Tacrolimus and mycophenolate mofetil (MMF).
干预措施: Busulfan (Drug)
Arm B - Cord Blood Donor
Unrelated cord blood transplant: Patients without a related donor will receive immunotherapy with a non-myeloablative preparative regimen of busulfan and fludarabine followed by allogeneic stem cell transplant (AlloSCT) with either an unrelated umbilical cord blood donor (4/6, 5/6, or 6/6 HLA matched), or a related umbilical cord blood donor (3/6, 4/6, 5/6, or 6/6 HLA matched). Patients will receive Thymoglobulin ((rabbit) Anti-Thymocyte Globulin (ATG)) during the preparative regimen. GVHD prophylaxis will be Tacrolimus and mycophenolate mofetil (MMF).
干预措施: Thymoglobulin (Drug)
Arm B - Cord Blood Donor
Unrelated cord blood transplant: Patients without a related donor will receive immunotherapy with a non-myeloablative preparative regimen of busulfan and fludarabine followed by allogeneic stem cell transplant (AlloSCT) with either an unrelated umbilical cord blood donor (4/6, 5/6, or 6/6 HLA matched), or a related umbilical cord blood donor (3/6, 4/6, 5/6, or 6/6 HLA matched). Patients will receive Thymoglobulin ((rabbit) Anti-Thymocyte Globulin (ATG)) during the preparative regimen. GVHD prophylaxis will be Tacrolimus and mycophenolate mofetil (MMF).
干预措施: Fludarabine (Drug)
结局指标
主要结局
Rate of engraftment following NAT/AlloSCT from either a related donor or umbilical cord donor.
时间窗: 1 year
The distribution of the time to neutrophil and platelet engraftment following consolidation (myeloablative) and intensification (non-ablation) will be estimated using the product-limit method of the Kaplan and Meier.
Overall Survival (OS) in patient with high-risk neuroblastoma receiving sequential MAT/AutoSCT and NAT/AlloSCT.
时间窗: 5 years
Overall Survival (OS) will be estimated using the product limit method of Kaplan and Meier.
Progression Free Survival (PFS) in patients with high-risk neuroblastoma receiving sequential MAT/AutoSCT and NAT/AlloSCT.
时间窗: 5 years
Progression Free (PFS) will be estimated using the product limit method of Kaplan and Meier.
次要结局
未报告次要终点