Iobenguane I-131 or Crizotinib and Standard Therapy in Treating Younger Patients With Newly-Diagnosed High-Risk Neuroblastoma or Ganglioneuroblastoma

PRIMARY OBJECTIVES:

I. To determine in the context of a randomized trial whether the event-free survival (EFS) of
patients with newly diagnosed high-risk neuroblastoma (NBL) is improved with the addition of
iobenguane I-131 (131I-MIBG) during induction, prior to tandem autologous stem cell
transplantation (ASCT).

II. To determine whether the addition of crizotinib to intensive multimodality therapy for
patients with high-risk NBL whose tumors harbor activating point mutations in or
amplification of the ALK gene results in superior EFS compared to a contemporaneously treated
cohort of patients whose tumors lack these ALK aberrations.

SECONDARY OBJECTIVES:

I. To describe the toxicities associated with treatment for high-risk NBL with and without
the addition of 131I-MIBG or crizotinib.

II. To compare EFS and toxicity in patients with newly diagnosed high?risk NBL randomized to
treatment with an 131I-MIBG-containing induction prior to either tandem or busulfan/melphalan
(BuMel) ASCT.

III. To describe the overall survival (OS) and response rates (evaluated per International
Neuroblastoma Response Criteria [INRC] criteria prior to ASCT and prior to post-consolidation
therapy) for patients with high-risk neuroblastoma treated with or without 131I-MIBG or
crizotinib.

IV. To prospectively evaluate the relationship of response rate per revised International
Neuroblastoma Response Criteria (INRC) to EFS and OS in patients with high-risk NBL treated
with and without the addition of 131I-MIBG or crizotinib.

TERTIARY OBJECTIVES:

I. To evaluate whole body radiation dose, tumor factors, and host factors as potential
predictors of efficacy and/or toxicity associated with 131I-MIBG therapy and transplant
conditioning.

II. To determine whether the efficacy (end-induction response, EFS, and OS) of crizotinib is
associated with specific ALK mutations or ALK amplification.

III. To characterize changes in tumor markers (circulating tumor deoxyribonucleic acid [DNA],
including ALK and other tumor specific genetic aberrations, and circulating GD2) over time in
response to protocol therapy.

IV. To correlate results of tumor and host profiling with end-induction response and EFS.

V. To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to
patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG.

VI. To correlate Curie scores calculated from 131I-MIBG post-treatment scans with
end-induction response, EFS and OS.

VII. To describe changes in image defined risk factors (IDRFs) over the course of induction
therapy, with correlation to surgical outcomes and local failure rates following primary
tumor resection.

VIII. To define patterns of failure at time of first relapse or progression in patients with
high-risk NBL.

IX. To determine the feasibility of prospectively monitoring adverse events using electronic
health records.

X. To compare local, central, and computer assisted Curie score assignment at baseline and
during therapy in patients with MIBG-avid high-risk NBL.

XI. To compare late toxicities (including impaired organ function and secondary tumor
occurrence) in patients treated with 131I-MIBG or crizotinib to late toxicities in patients
who have not received these therapies.

OUTLINE: Patients are randomized or assigned to 1 of 4 arms.

All patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan
hydrochloride IV over 30 minutes on days 1-5 during course 1 of induction therapy in the
absence of disease progression or unacceptable toxicity. Patients not assigned to an Arm may
receive an addition course of cyclophosphamide and topotecan.

ARM A:

INDUCTION THERAPY: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan
hydrochloride IV over 30 minutes on days 1-5 of course 2 and cisplatin IV over 4 hours and
etoposide phosphate IV over 2 hours on days 1-3 of courses 3 and 5. Patients also receive
vincristine sulfate IV over 1 minute on day 1 and dexrazoxane hydrochloride IV over 5-15
minutes, doxorubicin hydrochloride IV over 1-15 minutes, and cyclophosphamide IV over 1-6
hours on days 1-2 of course 4 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV
over 1 hour on days -5 to -2 in the absence of disease progression or unacceptable toxicity.

HSCT#2: Patients receive melphalan IV over 15-30 minutes on days -7 to -5, and etoposide
phosphate IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4 in the absence
of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim subcutaneously (SC) on days 1-14,
dinutuximab IV over 10 hours on days 4-7 of courses 1, 3, and 5 and days 8-11 of courses 2
and 4, aldesleukin IV over 96 hours on days 1-4 and 8-11 of courses 2 and 4, and isotretinoin
orally (PO) twice daily (BID) on days 11-24 of courses 1, 3, and 5, and days 15-28 during
courses 2, 4, and 6 in the absence of disease progression or unacceptable toxicity.

ARM B:

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, and
etoposide phosphate as in Arm A, iobenguane I-131 IV over 1.5-2 hours on day 1 beginning 3
weeks after the start of course 3, and vincristine sulfate, dexrazoxane hydrochloride,
doxorubicin hydrochloride, and cyclophosphamide as in Arm A beginning no sooner than 35 days
after the infusion of iobenguane I-131.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A.

HSCT#2: Patients receive melphalan, etoposide phosphate, and carboplatin as in Arm A.

POST-CONSLIDATION THERAPY: Patients receive sargramostim, dinutuximab, aldesleukin, and
isotretinoin as in Arm A-D.

ARM C:

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin,
etoposide phosphate, iobenguane I-131, vincristine sulfate, dexrazoxane hydrochloride,
doxorubicin hydrochloride, and cyclophosphamide as in Arm B.

CONSOLIDATION THERAPY: Patients receive busulfan IV over 3 hours on days -6 to -3 and
melphalan IV over 15-30 minutes on day -1 in the absence of disease progression or
unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, aldesleukin, and
isotretinoin as in Arm A.

ARM D: Patients receive treatment identical to Arm A.

ARM E:

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin,
etoposide phosphate, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin
hydrochloride, and cyclophosphamide as in Arm A. Patients also receive crizotinib PO BID on
days 1-21 of courses 2-5 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. Patients also receive
crizotinib PO BID until day -7 of HSCT#2 in the absence of disease progression or
unacceptable toxicity.

HSCT#2: Patients receive melphalan, etoposide phosphate, carboplatin, and crizotinib PO BID
on days 1-42 in the absence of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and aldesleukin as in
Arm A-D. Patients also receive isotretinoin PO BID on days 11-24 of courses 1, 3, and 5, and
days 15-28 of courses 2 and 4, and crizotinib PO BID on days 1-24 of courses 1, 3 and 5, and
days 1-28 of courses 2, 4, and 6 in the absence of disease progression or unacceptable
toxicity.

CONTINUATION THERAPY: Patients receive crizotinib PO BID on days 1-28. Courses repeat every
28 days for 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients in Arms A and D are followed up every 3 months
for 18 months, and then every 6 months for 42 months; patients in Arm E are followed up every
3 months for 6 months, and then every 6 months for 42 months.

Inclusion Criteria:

- Patients must be enrolled on ANBL00B1 or APEC14B1 prior to enrollment on ANBL1531

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

- 1 to < 2 years: male = 0.6; female = 0.6

- 2 to < 6 years: male = 0.8; female = 0.8

- 6 to < 10 years: male = 1; female = 1

- 10 to < 13 years: male = 1.2; female = 1.2

- 13 to < 16 years: male = 1.5; female = 1.4

- >= 16 years: male = 1.7; female = 1.4

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
ULN; for the purposes of this study, ULN for SGPT (ALT) is 45

- Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by
echocardiogram or radionuclide angiogram

- 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

Exclusion Criteria:

- Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor
histology (may meet criteria for may meet criteria for high risk classification but
are not eligible for this trial)

- Patients with bone marrow failure syndromes

- Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to
underlying medical disorders

- Female patients who are pregnant; 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 for the duration of their study participation