N2004-04: Fenretinide LXS in Treating Patients With Recurrent, Refractory, or Persistent Neuroblastoma

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