Dinutuximab, Sargramostim, and Combination Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To assess the feasibility and tolerability of administering ch14.18 (dinutuximab) and
sargramostim (GM-CSF) in combination with a multi-agent chemotherapy regimen during cycles
3-5 of the Induction phase for patients with newly-diagnosed high-risk neuroblastoma.

SECONDARY OBJECTIVES:

I. To describe the response rates, event-free survival (EFS) and overall survival (OS) for
patients receiving the combination of standard Induction chemotherapy and ch14.18
(dinutuximab) followed by tandem transplant, radiation therapy, and post-consolidation
immunotherapy.

EXPLORATORY OBJECTIVES:

I. To describe the clinical relevance of naturally occurring anti-glycan antibodies in
patients receiving ch14.18 (dinutuximab).

II. To describe the clinical relevance of natural killer (NK) receptor NKp30 isoforms in
patients receiving ch14.18 (dinutuximab).

III. To describe the association between host factors, including human anti-chimeric
antibodies (HACA), and response to protocol therapy.

IV. To describe the immune environment (gene expression; immune effector cells, activities
and signaling molecules; immune target expression) during and following treatment.

V. To describe the association between levels of circulating GD2, and tumor cell GD2
expression with response to therapy.

OUTLINE:

INDUCTION CYCLES 1-2 (21 days): Patients receive cyclophosphamide intravenously (IV) over
15-30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days
for 2 cycles in the absence of disease progression or unacceptable toxicity.

INDUCTION CYCLE 3: Patients receive cisplatin IV over 1 hour on days 1-3, etoposide IV over 2
hours on days 1-3, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim
subcutaneously (SC) on day 6 or 7 of a 21-day cycle.

INDUCTION CYCLE 4: Patients receive vincristine IV over 1 minute on day 1, doxorubicin IV
over 1-15 minutes on days 1-2, cyclophosphamide IV over 1 hour on days 1-2, dinutuximab IV
over 10-20 hours on days 2-5, and sargramostim SC on day 6 or 7 of a 21-day cycle.

INDUCTION CYCLE 5: Patients receive cisplatin IV over 1 hour on days 1-3, etoposide IV over 2
hours on days 1-3, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC on day 6
or 7 of a 21-day cycle.

Patients may undergo surgery after the fifth cycle of Induction at the discretion of treating
doctor. Patients with stable disease or better tumor response at the end of Induction proceed
to Consolidation. Consolidation treatments begin between 4 and 6 weeks from the start date of
Induction chemotherapy cycle 5. For patients who have surgical resection delayed until after
Induction chemotherapy cycle 5, Consolidation starts within 4 weeks from the date of surgery.

CONSOLIDATION #1: Patients receive thiotepa IV over 2 hours on days -7 to -5 and
cyclophosphamide IV over 1 hour on days -5 to -2. Patients then undergo autologous stem cell
transplant (ASCT) on day 0.

CONSOLIDATION #2: Patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide
IV over 24 hours on days -7 to -4, and carboplatin IV over 24 hours on days -7 to -4.
Patients then undergo ASCT on day 0.

RADIATION THERAPY: Beginning 42-80 days following Consolidation #2, patients receive external
beam radiation therapy (EBRT) daily for up to 20 days.

Patients then receive post-Consolidation therapy starting 1 week following radiation therapy.

POST-CONSOLIDATION CYCLES 1, 3, AND 5: Patients receive sargramostim SC on days 1-14,
dinutuximab IV over 10-20 hours on days 4-7, and isotretinoin orally (PO) twice daily (BID)
on days 11-24. Treatment repeats every 24 days in the absence of disease progression or
unacceptable toxicity.

POST-CONSOLIDATION CYCLES 2 AND 4: Patients receive aldesleukin IV continuously over 96 hours
on days 1-4 and 8-11, dinutuximab IV over 10-20 hours on days 8-11, and isotretinoin PO BID
on days 15-28. Treatment repeats every 32 days in the absence of disease progression or
unacceptable toxicity.

POST-CONSOLIDATION CYCLE 6: Patients receive isotretinoin PO BID on days 15-28 of a 28-day
cycle

After completion of study treatment, patients are followed up at months 3, 6, 9, 12, 15, 18,
24, 30, 36, 42, 48, 54, and 60.

Inclusion Criteria:

- Patients must be enrolled on ANBL00B1 or APEC14B1 prior to enrollment on ANBL17P1.

- Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular)
verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone
marrow with elevated urinary catecholamine metabolites. The following disease groups
are eligible:

- Patients with International Neuroblastoma Risk Group (INRG) stage M disease are
eligible if found to have either of the following features:

- MYCN amplification (> 4-fold increase in MYCN signals as compared to
reference signals), regardless of age or additional biologic features; OR

- Age > 547 days regardless of biologic features;

- Patients with INRG stage MS disease with MYCN amplification

- Patients with INRG stage L2 disease with MYCN amplification

- Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS
disease who progress to stage M without prior chemotherapy may enroll within 4
weeks of progression to stage M.

- Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1
disease who progress to stage M without systemic therapy may enroll within 4
weeks of progression to stage M.

- Patients initially recognized to have high-risk disease must have had no prior
systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis
and within allowed timing as described).

- Patients observed or treated with a single cycle of chemotherapy per a low or
intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar)
for what initially appeared to be non-high risk disease but subsequently found to meet
the criteria will also be eligible.

- Patients who receive localized emergency radiation to sites of life-threatening or
function-threatening disease prior to or immediately after establishment of the
definitive diagnosis will be eligible.

- Creatinine clearance (CrCl) or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows:

- Age 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)

- Age 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)

- Age 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)

- Age 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)

- Age 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)

- Age 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)

- 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)

- >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to
enrollment).

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment).

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
ULN. For the purposes of this study, ULN for ALT is 45 IU/L (within 7 days prior to
enrollment).

- Shortening fraction of >= 27% by echocardiogram (within 7 days prior to enrollment).

- Ejection fraction of >= 50% by echocardiogram or radionuclide angiogram (within 7 days
prior to enrollment).

- No known contraindication to peripheral blood stem cell (PBSC) collection. Examples of
contraindications might be a weight or size less than the collecting institution finds
feasible, 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 >18 months of age with INRG stage L2, MYCN non-amplified, regardless of
additional biologic features.

- Patients with bone marrow failure syndromes.

- Patients that are >= 12 and =< 18 months of age with INRG stage M and all 3 favorable
biologic features (i.e., non-amplified MYCN, favorable pathology, and deoxyribonucleic
acid [DNA] index > 1) are not eligible.

- Patients on immunosuppressive medications (e.g. tacrolimus, cyclosporine,
corticosteroids for reasons other than prevention/treatment of allergic reactions,
adrenal replacement therapy, etc.) are not eligible.

- Female patients who are pregnant are ineligible since fetal toxicities and teratogenic
effects have been noted for several of the study drugs. A pregnancy test is required
for female patients of childbearing potential.

- Lactating females who plan to breastfeed their infants.

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method during study therapy and for two months after the last
dose of ch14.18 (dinutuximab) are not eligible.