Back to resultsAutologous Transplant Followed by Allogeneic Transplant for High Risk Neuroblastoma
Primary Purpose
Neuroblastoma
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Related donor transplant
Cord blood transplant
Busulfan
Thymoglobulin
Fludarabine
Sponsored by
About this trial
This is an interventional treatment trial for Neuroblastoma focused on measuring Neuroblastoma, Autologous Transplant, Allogeneic Transplant, Immunotherapy
Eligibility Criteria
Inclusion Criteria:
- 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 58. (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 4.
- 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/1.73m2.
- 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).
Exclusion Criteria:
- Patients who are pregnant. Patients of childbearing potential must practice an effective method of birth control while participating on this study.
Sites / Locations
- Columbia Presbyterian Medical Center, Morgan Stanley Children's Hospital New York Presbyterian
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arm A - Related Donor
Arm B - Cord Blood Donor
Arm Description
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).
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).
Outcomes
Primary Outcome Measures
Rate of engraftment following NAT/AlloSCT from either a related donor or umbilical cord donor.
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.
Progression Free Survival (PFS) in patients with high-risk neuroblastoma receiving sequential MAT/AutoSCT and NAT/AlloSCT.
Progression Free (PFS) will be estimated using the product limit method of Kaplan and Meier.
Overall Survival (OS) in patient with high-risk neuroblastoma receiving sequential MAT/AutoSCT and NAT/AlloSCT.
Overall Survival (OS) will be estimated using the product limit method of Kaplan and Meier.
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00670410
Brief Title
Autologous Transplant Followed by Allogeneic Transplant for High Risk Neuroblastoma
Official Title
A Pilot Study of Sequential Autologous Stem Cell Transplantation and Immunotherapy With Reduced Intensity Allogeneic Stem Cell Transplant for High Risk Neuroblastoma
Study Type
Interventional
2. Study Status
Record Verification Date
June 2016
Overall Recruitment Status
Terminated
Why Stopped
Poor accrual
Study Start Date
November 2003 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
December 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Columbia University
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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).
Detailed Description
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.
Radiation Therapy Due to the potential risk of increased GVHD following radiation therapy, local radiation therapy to the primary tumor site (21 Gy) and metastatic sites, will be given after NAT/AlloSCT for patients on Arm A2 and Arm B, and prior to cis-RA therapy. Radiation therapy will be given following DLI in Arm A1, and prior to cis-RA therapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroblastoma
Keywords
Neuroblastoma, Autologous Transplant, Allogeneic Transplant, Immunotherapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm A - Related Donor
Arm Type
Experimental
Arm Description
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).
Arm Title
Arm B - Cord Blood Donor
Arm Type
Experimental
Arm Description
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).
Intervention Type
Procedure
Intervention Name(s)
Related donor transplant
Intervention Description
Patients with a related donor will get reduced intensity transplant conditioning with busulfan and fludarabine.
Intervention Type
Procedure
Intervention Name(s)
Cord blood transplant
Intervention Description
Patients with a matched cord blood donor will get reduced intensity conditioning with busulfan, fludarabine, and ATG.
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
Busulfex®
Intervention Description
Busulfan (Busulfex) [4mg/kg/dose for patients < 4 years; 3.2 mg/kg/dose for patients > 4 years] will be given IV in 0.9% sodium chloride or D5W to a final concentration > 0.5 mg/mL solution for infusion equal to 10 times the volume of diluent to Busulfex, through a central venous access device over 3 hours once daily.
Intervention Type
Drug
Intervention Name(s)
Thymoglobulin
Other Intervention Name(s)
ATG-rabbit
Intervention Description
Patients with an umbilical cord blood donor will also receive Thymoglobulin (ATG-rabbit) during the preparative regimen.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara®
Intervention Description
Fludarabine 30 mg/m2 x 5 days, total dose = 150 mg/m2. Patients < 12 kg will receive Fludarabine 1 mg/kg x 5 days, total dose = 5 mg/kg. Fludarabine will be given IV in 100 ml (or to a concentration of 1 mg/mL) of D5W or 0.9% sodium chloride, and infused over 30 min on Days -6 to 2.
Primary Outcome Measure Information:
Title
Rate of engraftment following NAT/AlloSCT from either a related donor or umbilical cord donor.
Description
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.
Time Frame
1 year
Title
Progression Free Survival (PFS) in patients with high-risk neuroblastoma receiving sequential MAT/AutoSCT and NAT/AlloSCT.
Description
Progression Free (PFS) will be estimated using the product limit method of Kaplan and Meier.
Time Frame
5 years
Title
Overall Survival (OS) in patient with high-risk neuroblastoma receiving sequential MAT/AutoSCT and NAT/AlloSCT.
Description
Overall Survival (OS) will be estimated using the product limit method of Kaplan and Meier.
Time Frame
5 years
10. Eligibility
Sex
All
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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 58. (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 4.
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/1.73m2.
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).
Exclusion Criteria:
Patients who are pregnant. Patients of childbearing potential must practice an effective method of birth control while participating on this study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Darrell Yamashiro, MD
Organizational Affiliation
Columbia University
Official's Role
Study Chair
Facility Information:
Facility Name
Columbia Presbyterian Medical Center, Morgan Stanley Children's Hospital New York Presbyterian
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
Unknown.
Learn more about this trial
Autologous Transplant Followed by Allogeneic Transplant for High Risk Neuroblastoma
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