A Phase I Study of Intravenous (Emulsion) Fenretinide in Children With Recurrent or Resistant Neuroblastoma

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Diagnosis of neuroblastoma either by histological confirmation and/or demonstration
of tumor cells in the bone marrow with increased urinary catecholamines

- Differentiating ganglioneuroblastoma allowed

- No histological evidence only of ganglioneuroma by tumor biopsy or bone
marrow biopsy

- High-risk disease meeting at least one of the following criteria:

- Recurrent/progressive disease at any time

- Refractory disease (i.e., less than a partial response to front-line therapy
that included ≥ 4 courses of chemotherapy)

- Persistent disease after at least a partial response to front-line therapy
(i.e., still has residual disease by MIBG, CT/MRI, or bone marrow biopsy)

- Biopsy of at least one residual site demonstrating viable neuroblastoma
required (tumor by bone marrow morphology is considered adequate
documentation of disease)

- Measurable disease meeting at least one of the following criteria:

- Measurable tumor on MRI or CT scan, defined as at least one unidimensionally
measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT
scan

- For patients with persistent disease, a biopsy* of bone marrow or bone or
soft tissue site must have demonstrated viable neuroblastoma

- MIBG scan with positive uptake at a minimum of one site

- For patients with persistent disease, a biopsy* of a MIBG positive site
must have demonstrated viable neuroblastoma

- Bone marrow with tumor cells seen on routine morphology (not by NSE staining
only) of bilateral aspirate and/or biopsy of one bone marrow sample NOTE: *If
the lesion was irradiated, the biopsy must have been done at least 4 weeks after
completion of radiotherapy

- No CNS parenchymal or meningeal-based lesions

- Skull-based tumor lesions with or without intracranial extension are allowed
provided there are no neurologic signs or symptoms or hydrocephalus related to
the lesion

- Patients with a history of complete surgical resection of CNS lesions are
eligible provided there is no evidence of CNS lesions by MRI or CT scan at study
entry

- Patients with a history of CNS lesions must be off corticosteroid therapy for
CNS lesions for ≥ 4 weeks

PATIENT CHARACTERISTICS:

- Performance status 0-2

- Life expectancy ≥ 2 months

- ANC ≥ 500/mm³

- Platelet count ≥ 50,000/mm³ (transfusion independent)

- Hemoglobin ≥ 8.0 g/dL (transfusion independent)

- Serum creatinine ≤ 1.5 times normal for age

- Total bilirubin ≤ 1.5 times normal for age

- ALT and AST ≤ 3 times normal for age

- Serum triglycerides < 300 mg/dL

- Serum calcium < 11.6 mg/dL

- Lipase normal for age

- PT/PTT ≤ 1.5 times upper limit of normal for age (without fresh frozen plasma
support; vitamin K allowed)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception prior to, during, and for 2 months
after completion of study treatment

- LVEF ≥ 55% by ECHO or MUGA scan OR fractional shortening ≥ 27% by ECHO

- No EKG abnormality

- No dyspnea at rest or requirement for oxygen

- No hematuria and/or proteinuria > 1+ on urinalysis

- No known history of allergy to egg products

- No known history of allergy to soy bean oil

- No skin toxicity > grade 1 per CTCAE v3

- Seizure disorder allowed if seizures are controlled on anticonvulsants and the
anticonvulsant(s) is not contraindicated

- Known genetic, metabolic, or psychiatric conditions, or other ongoing serious medical
issues must be approved by the study chair prior to study registration

PRIOR CONCURRENT THERAPY:

- Recovered from all prior chemotherapy, immunotherapy, or radiotherapy

- More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for
nitrosoureas) and/or biologic therapy without stem cell support

- More than 7 days since prior hematopoietic growth factors

- No prior radiotherapy to the only site of measurable disease unless there has been
subsequent disease progression at that site or a biopsy of that site showed viable
neuroblastoma ≥ 4 weeks after completion of radiotherapy

- Prior CNS irradiation allowed

- At least 2 weeks since prior small field (focal) radiotherapy

- At least 6 weeks since prior large field radiotherapy (i.e., total-body irradiation,
craniospinal radiotherapy, whole abdominal or total lung radiotherapy, or
radiotherapy to > 50% of marrow space)

- At least 56 days since prior myeloablative autologous stem cell transplantation

- At least 4 weeks since prior myelosuppressive therapy with stem cell support

- At least 6 weeks since prior MIBG therapy

- Prior oral fenretinide therapy allowed

- At least 3 weeks since prior retinoid therapies

- No prior organ transplantation

- No prior myeloablative allogeneic stem cell transplantation unless stem cells were
from an identical twin sibling

- No concurrent systemic corticosteroids, including corticosteroids for emesis control

- Concurrent inhaled corticosteroids for asthma control or steroids for metabolic
deficiency states allowed

- Concurrent palliative radiotherapy allowed provided the irradiated sites will not be
used to measure response

- No concurrent parenteral intralipids

- No other concurrent chemotherapy or immunomodulating agents

- No concurrent drugs suspected of causing pseudotumor cerebri, including tetracycline,
nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, or amiodarone

- No concurrent vitamin A, C, or E supplements (except as part of routine total
parenteral nutrition [TPN] supplements or as part of a single daily standard dose of
oral multivitamin supplement)

- No concurrent medications that may potentially act as modulators of intracellular
ceramide levels or ceramide cytotoxicity, sphingolipid transport, or p-glycoprotein
(MDR1) or MDR1 drug/lipid transporters, including cyclosporine or analogue,
verapamil, tamoxifen or analogue, ketoconazole, chlorpromazine, mifepristone (RU486),
indomethacin, or sulfinpyrazone

- No other concurrent anticancer agents

- No concurrent herbal supplements or other alternative therapy medications

- No concurrent anti-arrhythmia or inotropic cardiac medications