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

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of fenretinide (4-HPR) Lym-X-Sorb™ (LXS) oral
powder (4-HPR/LXS oral powder) in patients with recurrent, refractory, or persistent
neuroblastoma.

- Define the toxicities of 4-HPR/LXS oral powder in these patients.

- Determine the plasma pharmacokinetics of 4-HPR/LXS oral powder and its metabolites in
these patients.

- Determine the tolerability of the combination of ketoconazole and 4-HPR/LXS oral powder
in these patients.

Secondary

- Determine the response rate in patients treated with 4-HPR/LXS oral powder.

- Determine the level of 4-HPR/LXS oral powder in normal peripheral blood mononuclear
cells (PBMC) as a tumor cell surrogate tissue.

- Determine plasma levels of 4-HPR/LXS oral powder when given in combination with
ketoconazole.

- Determine whether ketoconazole increases 4-HPR/LXS oral powder plasma levels.

OUTLINE: This is a dose-escalation study of fenretinide (4-HPR) Lym-X-Sorb™ (LXS) oral
powder, followed by an open-label study. Patients are sequentially assigned to 1 of 2
intervention groups.

- Group I: Patients receive 4-HPR/LXS oral powder 3 times daily on days 0-6.

- Group II: Patients receive 4-HPR/LXS oral powder as in group I and oral ketoconazole
once daily on days 0-6.

In both groups, treatment repeats every 21 days for at least 6 courses in the absence of
disease progression or unacceptable toxicity. Patients in complete remission at study
enrollment may receive up to 12 courses (9 months) of therapy.

Blood samples are collected at baseline and during courses 1, 2, and 6 for pharmacokinetic
and correlative studies.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 32 patients will be accrued for the dose-escalation portion
and 36 will be accrued for the open-label portion of this study.

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