Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma
This pilot clinical trial studies busulfan, melphalan, and stem cell transplant after chemotherapy in treating patients with newly diagnosed neuroblastoma. Giving chemotherapy to the entire body before a stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy or radiation therapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Localized Resectable Neuroblastoma
Localized Unresectable Neuroblastoma
Stage 4S Neuroblastoma
Drug: topotecan hydrochloride
Drug: vincristine sulfate
Drug: doxorubicin hydrochloride
Radiation: external beam radiation therapy
Procedure: autologous hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pilot Study Using Myeloablative Busulfan/Melphalan (BuMel) Consolidation Following Induction Chemotherapy for Patients With Newly Diagnosed High-Risk Neuroblastoma|
- Number of patients who experience one or more unacceptable toxicities (severe sinusoidal obstruction syndrome [SOS] or grade 4-5 pulmonary toxicity per Common Toxicity Criteria [CTC] version [v] 4.0) during the consolidation phase of therapy [ Time Frame: Up to 28 days post-consolidation therapy ] [ Designated as safety issue: Yes ]A one-sided O'Brien-Fleming group-sequential boundary (truncated at 2.38 standard deviations, so that the study is more conservative within the first 38 patients than in the later part of accrual) with a sample size of 96 will be used to monitor the number of patients who experience at least one unacceptable toxicity within 28 days of completing post-transplant radiotherapy.
- Incidence of non-hematologic organ toxicity (grade 3 and higher) and all cause mortality graded according to CTC v4.0 [ Time Frame: Up to 180 days ] [ Designated as safety issue: Yes ]Assessed by a descriptive analysis of the incidence of grade 3-5 non-hematologic toxicities (CTC v4.0) and all-cause mortality during consolidation therapy. In addition, a descriptive analysis of "late" onset grade 4-5 pulmonary and hepatic complications that occur within 180 days of the start of consolidation therapy will be examined, regardless if the patient has proceeded to other therapy (including chimeric antibody) during that 180 day period.
- Response rate determined using the International Response Criteria [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
- EFS [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
- Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
- First dose area under the curve (AUC) and average daily AUC for busulfan [ Time Frame: Within 28 days following consolidation ] [ Designated as safety issue: No ]Relationship with occurrence of non-hematologic toxicities assessed by a descriptive analysis. Association between busulfan exposure levels as measured by the area under the curve (AUC) and event-free survival and overall survival will be examined using Cox proportional hazards models.
- Percentage of centrally reviewed post-course 4 MIBG scans reporting a Curie score considered to have been determined in "real time" [ Time Frame: Up to week 12 (course 4 of induction therapy) ] [ Designated as safety issue: No ]
- Percentage of MIBG scans receiving institutionally and centrally reviewed and automated Advanced Assisted Scoring Platform Curie scores within 1 unit of each other [ Time Frame: Up to week 12 (course 4 of induction therapy) ] [ Designated as safety issue: No ]Cohen's kappa will be calculated to evaluate the concordance in Curie scores between each of the scoring methods at each time point. Up to 160 MIBG scans are expected at diagnosis and up to 144 MIBG scans from the 90% of patients estimated to be MIBG avid are projected post-course 4 of induction therapy, for a total of up to 304 MIBG scans.
- Proportion of high-risk neuroblastoma patients for whom ALK status can be obtained [ Time Frame: Within 6 weeks of diagnosis ] [ Designated as safety issue: No ]
- Proportion of high-risk neuroblastoma patients with MYCN non-amplified tumors for whom molecular profiling results can be obtained [ Time Frame: Within 8 weeks of diagnosis ] [ Designated as safety issue: No ]
- Melphalan pharmacokinetics and the combination of busulfan and melphalan AUC (Optional) [ Time Frame: Within 28 days post-consolidation ] [ Designated as safety issue: No ]A descriptive analysis of the relationship between melphalan pharmacokinetics and the combination of busulfan and melphalan AUC with the occurrence of non-hematologic toxicities within 28 days following completion of consolidation will be assessed. In addition, the association between melphalan exposure levels as measured by the AUC and event-free survival and overall survival will be examined using Cox proportional hazards models.
|Study Start Date:||April 2013|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (induction therapy, consolidation therapy, ASCT)
COURSES 1-2: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5. Treatment repeats every 3 weeks for 2 courses.
COURSES 3 AND 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide IV over 1-2 hours on days 1-3. Treatment repeats every 3 weeks for 2 courses.
COURSE 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2, vincristine sulfate IV over 1 minute on days 1-3, and doxorubicin hydrochloride IV over 24 hours on days 1-3. Treatment repeats every 3 weeks for 1 course.
Treatment continues in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION THERAPY: Beginning 4-8 weeks following the 5th course of induction therapy, patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan IV on day -1. Patients undergo ASCT on day 0.
Some patients also undergo EBRT after induction and consolidation.
Other Names:Drug: topotecan hydrochloride
Other Names:Drug: cisplatin
Other Names:Drug: etoposide
Other Names:Drug: vincristine sulfate
Other Names:Drug: doxorubicin hydrochloride
Other Names:Radiation: external beam radiation therapy
Other Name: EBRTDrug: busulfan
Other Names:Drug: melphalan
Other Names:Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous peripheral blood stem cell transplantProcedure: peripheral blood stem cell transplantation
Undergo autologous peripheral blood stem cell transplant
Other Names:Other: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
Optional correlative studiesBiological: filgrastim
Given SC or IV
Other Names:Drug: mesna
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01798004
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|Principal Investigator:||Mary Meaghan Granger, MD||Children's Oncology Group|