Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma

PRIMARY OBJECTIVES:

I. To eliminate therapy as the initial approach for infants < 12 months of age with small
International Neuroblastoma Risk Group (INRG) stage L1 neuroblastoma while maintaining an
overall survival (OS) of 99%.

II. To eliminate therapy as the initial approach for non-high-risk patients < 18 months of
age with localized neuroblastoma and favorable biology (histologic and genomic features)
while maintaining an OS of 99%.

III. To achieve a 3-year OS of > 81% for infants < 18 months of age with INRG stage Ms
neuroblastoma using objective criteria for early initiation of a response-based treatment
algorithm.

SECONDARY OBJECTIVES:

I. To describe the time to intervention or tumor progression, type of intervention and site
of progression for patients with localized neuroblastoma who experience progression after an
initial period of observation.

II. To characterize the pharmacokinetic profile of the chemotherapeutic agents carboplatin
and etoposide in patients with stage Ms disease.

III. To define the genomic profile of tumors from patients with non-high-risk neuroblastoma
both at initial biopsy and at the time of subsequent biopsy or surgical resection.

IV. To describe the histology of tumor specimens obtained at the time of subsequent biopsy or
surgical resection.

V. To determine the salvage rate (OS) of patients with tumor relapse or disease progression.

VI. To determine the procedural complication rate (initial biopsy, resection [intraoperative
and postoperative], subsequent biopsy) and correlate with the degree of surgical resection.

VII. To determine the rate of reduction in image defined risk factors (IDRF) in L2 tumors
following observation or chemotherapy.

OUTLINE: Patients are assigned to 1 of 3 treatment groups.

GROUP A: Patients undergo clinical observation for 96 weeks in the absence disease
progression.

GROUP B: Patients undergo clinical observation for 3 years in the absence of disease
progression. Upon disease progression, patients undergo surgery or receive first-line
chemotherapy comprising carboplatin intravenously (IV) over 1 hour on day 1 (courses 1, 2, 4,
6, and 7), etoposide IV over 1 hour on days 1-3 (courses 1, 3, 4, 5, and 7), cyclophosphamide
IV over 1 hour on day 1 (courses 2, 3, 5, 6, and 8), and doxorubicin hydrochloride IV over 15
minutes on day 1 (courses 2, 4, 6 and 8). Treatment with chemotherapy repeats every 21 days
for 2-8 courses in the absence of disease progression or unacceptable toxicity. Once a
partial response (PR) or better is achieved, patients undergo clinical observation for 3
years.

GROUP C: Patients at high risk for deterioration and a poor outcome immediately receive
first-line chemotherapy as in Group B. All other patients undergo clinical observation for 3
years in the absence of disease progression. Upon disease progression, patients receive
first-line chemotherapy as in Group B. Once a PR or better is achieved, patients undergo
clinical observation for 3 years.

After completion of study treatment, patients are followed up annually for 3 years.

Inclusion Criteria:

- Patients must be:

- < 12 months (< 365 days) of age at diagnosis with INRG stage L1; or

- < 18 months (< 547 days) of age at diagnosis with INRG stage L2 or stage Ms
neuroblastoma/ganglioneuroblastoma

- Enrollment on ANBL00B1 or APEC14B1 is required for all newly diagnosed patients

- Patients must have newly diagnosed v-myc avian myelocytomatosis viral oncogene
neuroblastoma derived homolog (MYCN) non-amplified neuroblastoma (International
Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or MYCN
non-amplified ganglioneuroblastoma verified by histology

- Patients must meet the specified criteria for one of the treatment groups defined
below; genomic features include MYCN gene amplification, segmental chromosome
aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number
gain at 1q, 2p, or 17q) and deoxyribonucleic acid (DNA) index

- ?Favorable? genomic features are defined by one or more whole-chromosome gains or
hyperdiploid tumor (DNA index > 1) in the absence of segmental chromosome
aberrations as defined above

- ?Unfavorable? genomic features are defined by the presence of any segmental
chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic
copy number gain at 1q, 2p, or 17q) or diploid tumor (DNA index = 1); this
includes copy neutral loss of heterozygosity (LOH)

- Only patients with MYCN non-amplified tumors are eligible for this study

- Group A: patients < 12 months (< 365 days) of age with newly diagnosed INRG stage L1
neuroblastoma/ganglioneuroblastoma who meet the following criteria:

- Greatest tumor diameter < 5 cm of adrenal or non-adrenal origin

- Patients with non-adrenal primaries are eligible, but must have positive uptake
on metaiodobenzylguanidine (MIBG) scan or elevated catecholamine metabolites
(urine or serum) to support the diagnosis of neuroblastoma

- No prior tumor resection or biopsy

- Group A will be further split into two subsets, which are mutually exclusive, for
statistical purposes

- Group A1:

- > 6 months and < 12 months of age with an adrenal primary tumor < 5 cm in
greatest diameter OR

- Patients less than 6 months of age with an adrenal primary tumor > 3.1 and <
5 cm in greatest diameter OR

- < 12 months of age with a non-adrenal primary site < 5 cm in greatest
diameter

- Group A2: =< 6 months of age with an adrenal primary site and tumor =< 3.1 cm in
greatest diameter.

- Group B: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage L2
neuroblastoma/ganglioneuroblastoma who meet the following criteria:

- No life threatening symptoms or no impending neurologic or other organ function
compromise (e.g. epidural or intraspinal tumors with existing or impending
neurologic impairment, periorbital or calvarial-based lesions with existing or
impending cranial nerve impairment, anatomic or mechanical compromise of critical
organ function by tumor [abdominal compartment syndrome, urinary obstruction,
etc.]); horner syndrome is not considered neurologic compromise

- No prior tumor resection, tumor biopsy ONLY

- Only patients with both favorable histology and favorable genomic features will
remain on study as part of Group B; the institution will be notified of
histologic and genomic results within 3 weeks of specimen submission on ANBL00B1
or APEC14B1

- Group C: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage Ms
neuroblastoma/ganglioneuroblastoma

- No prior radiotherapy or chemotherapy, with the exception of dexamethasone, which is
allowed

- 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 with MYCN amplified tumors are not eligible

- Group B and C patients who do not enroll on ANBL1232 within 4 weeks of definitive
diagnostic procedure

- Group A and C patients, not required to undergo tumor biopsy, who do not enroll on
ANBL1232 within 4 weeks of confirmatory imaging study