A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab with or without Eflornithine (DFMO) (IND# 141913) in Children with Relapsed, Refractory or Progressive Neuroblastoma

This phase II trial studies how well irinotecan hydrochloride, temozolomide, and
dinutuximab work with or without eflornithine in treating patients with neuroblastoma
that has come back (relapsed) or that isn't responding to treatment (refractory). Drugs
used in chemotherapy, such as irinotecan hydrochloride and temozolomide, work in
different ways to stop the growth of tumor cells, either by killing the cells, by
stopping them from dividing, or by stopping them from spreading. Immunotherapy with
monoclonal antibodies, such as dinutuximab, may induce changes in the body's immune
system and may interfere with the ability of tumor cells to grow and spread. Eflornithine
blocks the production of chemicals called polyamines that are important in the growth of
cancer cells. Giving eflornithine with irinotecan hydrochloride, temozolomide, and
dinutuximab, may work better in treating patients with relapsed or refractory
neuroblastoma.

Inclusion Criteria:

- Patients must have had histologic verification of neuroblastoma or
ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with
elevated urinary catecholamines (i.e. > 2 x upper limit of normal [ULN]), at the
time of initial diagnosis.

- For the purposes of this study, aggressive multidrug chemotherapy is defined as
chemotherapy including 2 or more agents that must include an alkylating agent and a
platinum-containing compound as intended to treat high-risk disease. The doses of
chemotherapy must be comparable to those used in frontline high-risk neuroblastoma
therapies (examples include A3973, ANBL0532, ANBL09P1, ANBL12P1, and ANBL1531).
Patients must have ONE of the following:

- First episode of recurrent high-risk disease following completion of aggressive
multi-drug frontline high-risk therapy.

- First episode of progressive high-risk disease during aggressive multi-drug
frontline therapy.

- Primary resistant/refractory disease (less than partial response by
International Neuroblastoma Response Criteria [INRC]) detected at the
conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy
on or according to a high-risk neuroblastoma protocol (examples include A3973,
ANBL0532, ANBL09P1, ANBL12P1, ANBL1531, etc.).

- Patients must have at least ONE of the following at the time of enrollment:

- Measurable tumor on magnetic resonance imaging (MRI) or computed tomography
(CT) scan. Measurable is defined as >= 10 mm in at least one dimension on
spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates
increased fludeoxyglucose F-18 (FDG) uptake on positron emission tomography
(PET) scan.

- MIBG-avid lesion detected on MIBG scan with positive uptake at a minimum of one
site. This site must represent disease recurrence after completion of therapy,
progressive disease on therapy, or refractory disease during induction.

- Patients with resistant/refractory soft tissue disease that is not MIBG avid or
does not demonstrate increased FDG uptake on PET scan must undergo biopsy to
document the presence of viable neuroblastoma. Biopsy is not required for
patients who have a new site of soft tissue disease (radiographic evidence of
disease progression) regardless of whether progression occurs while receiving
therapy or after completion of therapy.

- Patients with bone marrow disease only will be eligible if they have more than
5% disease involvement (documented neuroblastoma cells) in at least one sample
from bilateral bone marrow biopsies.

- Note: Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT
eligible for this study.

- Patients must have a performance status corresponding to Eastern Cooperative
Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of
age and Lansky for patients =< 16 years of age.

- Primary refractory/resistant patients must have received at least 4 cycles of
frontline high-risk chemotherapy. Frontline therapy may also have included surgery,
chemotherapy, autologous stem cell transplantation (SCT) +/- MIBG, immunotherapy,
radiotherapy, and retinoids but must NOT have received second line therapy for
resistant/refractory, relapsed, or progressive disease. Patients who received
intensified therapy for poor induction response or refractory disease (e.g. MIBG)
will be considered to have received second line therapy and will not be eligible.

- At least 14 days must have elapsed since completion of myelosuppressive therapy.

- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
last dose of agent.

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and
toxicity related to prior antibody therapy must be recovered to grade =< 1.

- No interim time prior to study entry is required following prior radiation therapy
(RT) for non-target lesions. However, patients must not have received radiation for
a minimum of 4 weeks prior to study entry at the site of any lesion that will be
identified as a target lesion to measure tumor response. Lesions that have been
previously radiated cannot be used as target lesions unless there is radiographic
evidence of progression at the site following radiation or a biopsy done following
radiation shows viable neuroblastoma. Palliative radiation while on study is not
permitted.

- Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell
infusions (including stem cell infusions given as supportive care following 131
I-MIBG therapy) as long as hematologic and other eligibility criteria have been met.

- Patients are eligible >= 6 weeks after therapeutic 131 I-MIBG provided that all
other eligibility criteria are met.

- Subjects who have previously received anti-GD2 monoclonal antibodies with or without
retinoids for biologic therapy are eligible unless they have had progressive disease
while receiving prior anti-GD2 therapy or progressed/relapsed within 3 months of
receiving anti-GD2 therapy. However, eligible patients may NOT have received
anti-GD2 monoclonal antibodies in combination with chemotherapy.

- Subjects who have received autologous marrow infusions or autologous stem cell
infusions that were purged using monoclonal antibody linked to beads are eligible.

- Subjects who have previously received DFMO are eligible for this study provided they
have not had progressive disease while receiving DFMO or progressed/relapsed within
3 months of completing DFMO.

- Patients must not have received long-acting myeloid growth factors (e.g.
pegfilgrastim) within 14 days of entry on this study. Seven days must have elapsed
since administration of a short-acting myeloid growth factor.

- For patients with solid tumors (without marrow involvement) including status post
SCT: peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to
enrollment).

- For patients with solid tumors (without marrow involvement) including status post
SCT: platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to
enrollment).

- Patients known to have bone marrow involvement with neuroblastoma are eligible
provided that minimum ANC and transfusion independent platelet count criteria are
met (as above). However, these patients are not evaluable for hematological
toxicity.

- Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 or a serum creatinine
based on age/gender as follows:

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

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

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

- 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 ULN for age (within 7 days prior to enrollment).

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0
x ULN for age (=< 225 U/L). For the purpose of this study, the ULN for SGPT is 45
U/L (within 7 days prior to enrollment).

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

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

- No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen
requirement, and room air pulse oximetry > 94% if there is a clinical indication for
pulse oximetry. Normal pulmonary function tests in patients who are capable of
cooperating with testing (including diffusion capacity of the lung for carbon
monoxide [DLCO)] are required if there is a clinical indication for determination.
For patients who do not have respiratory symptoms, full pulmonary function tests
(PFTs) are NOT required.

- Patients with a history of central nervous system (CNS) disease must have no
clinical or radiological evidence of active CNS disease at the time of study
enrollment.

- Patients with seizure disorders may be enrolled if seizures are well controlled on
anti-convulsants.

- CNS toxicity =< grade 2.

Exclusion Criteria:

- Men and women of childbearing potential and their partners must agree to use
adequate contraception while enrolled on this study. Based on the established
teratogenic potential of alkylating agents, pregnant women will be excluded from
this study. Because of potential risks to breastfed infants due to drug metabolites
that could be excreted in breast milk, female patients who are lactating must agree
to stop breastfeeding or will otherwise be excluded from this study. Females of
childbearing potential must have a negative pregnancy test to be eligible for this
study.

- Patients with only elevated catecholamines (i.e. > 2 x ULN) are NOT eligible for
this study.

- Patients must have been off pharmacologic doses of systemic steroids for at least 7
days prior to enrollment. Patients who require or are likely to require
pharmacologic doses of systemic corticosteroids while receiving treatment on this
study are ineligible. The only exception is for patients known to require 2 mg/kg or
less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as
premedication for blood product administration in order to avoid allergic
transfusion reactions. The use of conventional doses of inhaled steroids for the
treatment of asthma is permitted, as is the use of physiologic doses of steroids for
patients with known adrenal insufficiency.

Patients on any other immunosuppressive medications (e.g. cyclosporine, tacrolimus) are
not eligible.

- Patients must not have received prior treatment with irinotecan and temozolomide.

- Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
phenobarbital, or carbamazepine for at least 7 days prior to study enrollment.
Patients receiving non-enzyme inducing anticonvulsants such as gabapentin, valproic
acid, or levetiracetam will be eligible.

- Patients who have received drugs that are strong inducers or inhibitors of CYP3A4
within 7 days prior to study enrollment are not eligible.

- Patients must not have been diagnosed with myelodysplastic syndrome or with any
malignancy other than neuroblastoma.

- Patients with symptoms of congestive heart failure are not eligible.

- Patients must not have >= grade 2 diarrhea.

- Patients who are unable to tolerate oral/nasogastric/gastrostomy medications will
not be eligible for this trial. Additionally, patients with significant
malabsorption will not be eligible for this trial.

- Patients must not have uncontrolled infection.

- Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
reactions that required permanent discontinuation of the anti-GD2 therapy are not
eligible.

- Patients with a significant intercurrent illness (any ongoing serious medical
problem unrelated to cancer or its treatment) that is not covered by the detailed
exclusion criteria and that is expected to interfere with the action of study agents
or to significantly increase the severity of the toxicities experienced from study
treatment are not eligible.