Phase I Study of Fenretinide (4-HPR, NSC 374551) Lym-X-Sorb™ (LXS) Oral Powder in Patients With Recurrent or Resistant Neuroblastoma

Inclusion Criteria

DISEASE CHARACTERISTICS:

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

- High-risk disease, as evidenced by ≥ 1 of the following:

- Recurrent/progressive disease at any time

- Refractory disease (i.e., less than a partial response to frontline therapy)

- No biopsy required

- Persistent disease after at least a partial response to frontline therapy (i.e.,
patient has had at least a partial response to frontline therapy but still has
residual disease by MIBG scan, CT scan/MRI, or bone marrow)

- Biopsy of at least one residual site demonstrating viable neuroblastoma
required

- Patients must have ≥ 1 of the following sites of disease:

- Measurable tumor, defined as ≥ 2 cm in at least 1 dimension by MRI, CT scan, or
x-ray OR ≥ 1 cm in at least 1 dimension by spiral CT scan

- For persistent disease, a biopsy of bone and/or soft tissue site seen on
CT/MRI must have been done to demonstrate viable neuroblastoma

- If lesion was irradiated, biopsy must be done ≥ 2 weeks after
radiation completed

- MIBG scan with positive uptake at ≥ 1 site

- For persistent disease, a biopsy of an MIBG-positive site must have been
done to demonstrate viable neuroblastoma

- If lesion was irradiated, biopsy must be done at least 2 weeks after
radiation completed

- Tumor cells on routine morphology (not by neuron-specific enolase staining only)
of bilateral bone marrow aspirate and/or biopsy on one bone marrow sample

- Patients enrolled in group I may have had a prior relapse or progression, even if
they have no measurable or evaluable tumor sites at time of study entry, including
any of the following:

- No tumor sites on all evaluations

- Non-measurable tumor on MRI /CT scan and/or measurable tumor on CT/MRI that was
previously irradiated

- MIBG-avid site that was previously irradiated

- No CNS parenchymal or meningeal-based lesions

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

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy ≥ 2 months

- Hemoglobin ≥ 8.0 g/dL (transfusion allowed)

- ANC ≥ 500/mm^3

- Platelet count ≥ 50,000/mm^3 (transfusion independent [ i.e., ≥ 1 week since last
platelet transfusion])

- Creatinine ≤ 1.5 times normal for age as follows:

- No greater than 0.8 mg/dL (for patients 5 years of age and under)

- No greater than 1.0 mg/dL (for patients 6-10 years of age)

- No greater than 1.2 mg/dL (for patients 11-15 years of age)

- No greater than 1.5 mg/dL (for patients over 15 years of age)

- Ejection fraction ≥ 55% by echocardiogram or MUGA OR fractional shortening ≥ 27% by
echocardiogram

- Bilirubin ≤ 1.5 times normal

- ALT and AST ≤ 3 times normal (for ALT, upper limit of normal is 45 U/L)

- Triglycerides < 300 mg/dL (fasting or random plasma test)

- Calcium < 11.6 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

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

- Normal lung function (i.e., no dyspnea at rest or oxygen requirement)

- Seizure disorder allowed provided seizures are controlled on anticonvulsants that are
not contraindicated

- No EKG abnormality severe enough to justify cardiac medications

- No skin toxicity > grade 1

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

- No known allergy to soy products

- No known severe allergy or sensitivity to wheat gluten

- No known history of intolerance to ketoconazole (group II)

PRIOR CONCURRENT THERAPY:

- Fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy

- Prior CNS irradiation allowed

- Prior complete surgical resection of CNS lesions allowed provided there is no
evidence of CNS lesions by MRI or CT scan at study entry

- At least 4 weeks since prior corticosteroid therapy for CNS lesions

- More than 3 weeks since prior myelosuppressive chemotherapy and/or biologics (4 weeks
for nitrosoureas)

- More than 2 weeks since prior radiotherapy to the site of biopsied lesion or the only
site of measurable disease

- At least 6 weeks since prior large-field radiotherapy (e.g., total body irradiation,
craniospinal therapy, or radiotherapy to the whole abdomen, total lung, or more than
50% marrow space)

- At least 3 months since prior autologous stem cell transplantation

- At least 6 weeks since prior therapeutic MIBG

- More than 7 days since prior hematopoietic growth factors

- No prior allogeneic stem cell transplantation

- No prior organ transplantation

- No prior IV fenretinide (4-HPR) emulsion (other retinoids allowed)

- Prior therapy with 3% 4-HPR Lym-X-Sorb™ (LXS) oral powder allowed provided
patient is still on drug and it is not available for continued use

- Prior NCI 4-HPR corn oil capsule allowed provided patient did not go off drug
for toxicity

- No concurrent antiarrhythmia medications

- No other concurrent anticancer agents, including chemotherapy

- No concurrent immunomodulatory agents, including systemic corticosteroids

- No concurrent supplemental vitamin A, E, or ascorbic acid (vitamin C) except as
contained in routine total parenteral nutrition vitamin supplements or in a single
daily standard-dose oral multivitamin supplement

- No concurrent drugs suspected of causing pseudotumor cerebri, including tetracycline,
nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, amiodarone, or
vitamin A (except as routine multivitamin supplement)

- No concurrent herbal supplements or other alternative therapy medications

- No concurrent medications that may potentially act as modulators of intracellular
ceramide levels or ceramide cytotoxicity, sphingolipid transport, or p-glycoprotein
(MDR1) or MRP1 drug/lipid transporters, including cyclosporine or analogue,
verapamil, tamoxifen or analogue, ketoconazole (except if enrolled in group II),
chlorpromazine, mifepristone, indomethacin, or sulfinpyrazone

- No concurrent medications that decrease gastric acid output (e.g., ranitidine) or
increase gastric pH (e.g., Tums) (group II)

- No concurrent corticosteroids for emesis control

- Systemic corticosteroids for asthma control allowed if minimized

- Inhaled corticosteroids for asthma control and steroids for routine metabolic
deficiency states allowed

- Concurrent palliative radiotherapy allowed only to sites not used to measure response