Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma

Phase 1

Completed

Conditions: Stage 2B Neuroblastoma
Stage 4S Neuroblastoma
Stage 1 Neuroblastoma
Stage 4 Neuroblastoma
Stage 2 Neuroblastoma
Ganglioneuroblastoma
Stage 2A Neuroblastoma
Stage 3 Neuroblastoma

Interventions: Procedure: Autologous Hematopoietic Stem Cell Transplantation
Drug: Busulfan
Drug: Cisplatin
Drug: Cyclophosphamide
Drug: Doxorubicin Hydrochloride
Drug: Etoposide
Radiation: External Beam Radiation Therapy
Biological: Filgrastim
Other: Laboratory Biomarker Analysis
Drug: Melphalan
Drug: Mesna
Procedure: Peripheral Blood Stem Cell Transplantation
Other: Pharmacological Study
Drug: Topotecan Hydrochloride
Drug: Vincristine Sulfate

Registration Number: NCT01798004

Lead Sponsor: Children's Oncology Group

Brief Summary: This pilot clinical trial studies busulfan, melphalan, and stem cell transplant after chemotherapy in treating patients with newly diagnosed neuroblastoma that is likely to come back or spread. 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.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine if the acute toxicity of an autologous stem cell transplant with a busulfan-melphalan (BuMel) based regimen is tolerable when given as consolidation therapy for high-risk neuroblastoma.

EXPLORATORY OBJECTIVES:

I. To determine the incidence of non-hematologic organ toxicity (grade 3 and higher) and all cause mortality in patients undergoing autologous stem cell transplant with a BuMel based regimen followed by local radiotherapy for the treatment of high-risk neuroblastoma.

II. To describe response rates, event-free survival (EFS), and overall survival (OS) for patients undergoing induction therapy followed by consolidation with myeloablative BuMel preparative regimen and local radiotherapy for the treatment of high-risk neuroblastoma.

III. To correlate busulfan pharmacokinetics with non-hematologic toxicity following a BuMel based autologous transplant regimen and event-free survival and overall survival.

IV. To determine the feasibility of performing Curie scores in "real time," as assessed by central scan committee review of a 123 I-meta-iodobenzylguanidine (MIBG) scan obtained after cycle 4 of induction therapy.

V. To examine the concordance between central reviewers and institutional reviewers in performing Curie scoring at diagnosis and after cycle 4 of induction therapy.

VI. To determine the feasibility of detecting aberrations in the anaplastic lymphoma kinase (ALK) gene in tumors obtained at the time of diagnosis in patients with high-risk neuroblastoma.

VII. To determine the feasibility of performing molecular profiling of neuroblastoma tumors obtained at the time of diagnosis in patients with high-risk neuroblastoma.

VIII. To correlate melphalan pharmacokinetics with non-hematologic toxicity following a BuMel based autologous transplant regimen and event-free survival and overall survival.

OUTLINE:

INDUCTION THERAPY:

COURSES 1-2: Patients receive cyclophosphamide intravenously (IV) over 15-30 minutes, topotecan hydrochloride IV over 30 minutes on days 1-5 and filgrastim subcutaneously (SC) or IV once daily (QD) beginning on day 6. 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, doxorubicin hydrochloride IV over 24 hours on days 1-3 and mesna IV over 15-30 minutes on days 1-2. 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 autologous stem cell transplant (ASCT) on day 0 and filgrastim SC or IV beginning on day 0.

Some patients also undergo external beam radiation therapy (EBRT) after induction and consolidation.

After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 6 months for 4 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 150

Inclusion Criteria

Patients must have a diagnosis of neuroblastoma (International Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or ganglioneuroblastoma (nodular or intermixed) verified by histology 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
Patients with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) stage 4 are eligible with the following:
- V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or
- Age > 18 months (> 547 days) regardless of biologic features or
- Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or deoxyribonucleic acid [DNA] index = 1) or any biologic feature that is indeterminate/unsatisfactory/unknown
Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with the following:
- MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or
- Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status
Patients with newly diagnosed neuroblastoma with INSS stage 2A/2B with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features
Patients with newly diagnosed neuroblastoma with INSS stage 4S with MYCN amplification (> 4-fold increase in MYCN expression signals as compared to reference signals), regardless of additional biologic features
Patients >= 365 days initially diagnosed with neuroblastoma INSS stage 1, 2, 4S who progressed to a stage 4 without interval chemotherapy; these patients must have been enrolled on ANBL00B1; study enrollment on ANBL12P1 must occur within 4 weeks of progression to stage 4 for INSS stage 1, 2, 4S
Patients must not have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- Age 1 month to < 6 months: 0.4 mg/dL
- Age 6 months to < 1 year: 0.5 mg/dL
- Age 1 to < 2 years: 0.6 mg/dL
- Age 2 to < 6 years: 0.8 mg/dL
- Age 6 to < 10 years: 1 mg/dL
- Age 10 to < 13 years: 1.2 mg/dL
- Age 13 to < 16 years: 1.5 mg/dL (males), 1.4 mg/dL (females)
- Age >= 16 years: 1.7 mg/dL (males), 1.4 mg/dL (females)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN for age
Shortening fraction of >= 27% by echocardiogram, or
Ejection fraction of >= 50% by radionuclide evaluation
No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure
All patients and/or their parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

Patients that are 12-18 months of age with INSS stage 4 and all 3 favorable biologic features (ie, nonamplified MYCN, favorable pathology, and DNA index > 1) are not eligible
Female patients who are pregnant are ineligible
Lactating females are not eligible unless they have agreed not to breastfeed their infants
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (induction therapy, consolidation therapy, ASCT)	Topotecan Hydrochloride	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Vincristine Sulfate	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Autologous Hematopoietic Stem Cell Transplantation	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Filgrastim	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Peripheral Blood Stem Cell Transplantation	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Pharmacological Study	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	External Beam Radiation Therapy	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Laboratory Biomarker Analysis	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Busulfan	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Cisplatin	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Cyclophosphamide	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Doxorubicin Hydrochloride	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Etoposide	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Melphalan	INDUCTION THERAPY: 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.
Treatment (induction therapy, consolidation therapy, ASCT)	Mesna	INDUCTION THERAPY: 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.

Primary Outcome Measures

Name	Time	Method
The Tolerability of BuMel Regimen	Up to 28 days post-consolidation therapy, up to 1 year	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 \[CTC\] v.4.0) during the Consolidation phase of therapy.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (123): Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸
Hollywood, Florida, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸
Lebanon, New Hampshire, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Saint Barnabas Medical Center
🇺🇸
Livingston, New Jersey, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
NYU Langone Hospital - Long Island
🇺🇸
Mineola, New York, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸
Toledo, Ohio, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Starship Children's Hospital
🇳🇿
Grafton, Auckland, New Zealand
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸
Indianapolis, Indiana, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Mayo Clinic in Rochester
🇺🇸
Rochester, Minnesota, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Miami Cancer Institute
🇺🇸
Miami, Florida, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Augusta University Medical Center
🇺🇸
Augusta, Georgia, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Tufts Children's Hospital
🇺🇸
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Columbia Regional
🇺🇸
Columbia, Missouri, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸
Las Vegas, Nevada, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸
New Hyde Park, New York, United States
Mission Hospital
🇺🇸
Asheville, North Carolina, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Mercy Children's Hospital
🇺🇸
Toledo, Ohio, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸
Bethlehem, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
Naval Medical Center - Portsmouth
🇺🇸
Portsmouth, Virginia, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Marshfield Medical Center-Marshfield
🇺🇸
Marshfield, Wisconsin, United States
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦
Quebec, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸
Orlando, Florida, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Maine Children's Cancer Program
🇺🇸
Scarborough, Maine, United States
Summerlin Hospital Medical Center
🇺🇸
Las Vegas, Nevada, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
T C Thompson Children's Hospital
🇺🇸
Chattanooga, Tennessee, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Nevada Cancer Research Foundation NCORP
🇺🇸
Las Vegas, Nevada, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
Prisma Health Richland Hospital
🇺🇸
Columbia, South Carolina, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
Children's Hospital New Orleans
🇺🇸
New Orleans, Louisiana, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
University of Florida Health Science Center - Gainesville
🇺🇸
Gainesville, Florida, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
University of Rochester
🇺🇸
Rochester, New York, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸
Oakland, California, United States