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

Protocol # :
High Risk Neuroblastoma
Recurrent Neuroblastoma
Refractory Neuroblastoma
Disease Sites
Brain and Nervous System
Principal Investigator
Shusterman, Suzanne

Trial Description

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.

Eligibility Requirements

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)

- 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

- 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

- 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

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

- 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

- 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

- 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

- 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

- 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

- 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

- 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

- 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.