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