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

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 or pegfilgrastim SQ once 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 and filgrastim subcutaneously (SC) or IV once daily (QD) beginning on
day 6 or pegfilgrastim SQ once on day 6. 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 and filgrastim subcutaneously (SC) or IV once
daily (QD) beginning on day 6 or pegfilgrastim SQ once on day 6. 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 until recovery.

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.

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