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


Phase 1
N/A
30 Years
Open (Enrolling)
Both
Neuroblastoma

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Trial Information

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


OBJECTIVES:

Primary

- To determine the maximum tolerated dose of fenretinide when given as a continuous
intravenous infusion in young patients with recurrent and/or resistant neuroblastoma.

- To define the toxicities of this drug in these patients.

- To determine the plasma pharmacokinetics of this drug in these patients.

Secondary

- To determine the response rate in patients treated with this drug.

- To determine the bioavailability of fenretinide in normal peripheral blood mononuclear
cells as a surrogate marker for drug bioavailability to tumor tissue.

OUTLINE: This is a multicenter study.

Patients receive fenretinide IV continuously over 120 hours on days 0-4. Treatment repeats
every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for pharmacokinetic analysis by high performance
liquid chromatography.

After completion of study treatment, patients are followed periodically.

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

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To define the toxicities of intravenous emulsion 4-HPR given on this schedule.

Outcome Description:

Adverse events, clinically significant changes in lab results or vitals will be captured throughout the duration of the study.

Outcome Time Frame:

Adverse events, clinically significant changes in lab results or vitals will be captured throughout the duration of the study.

Safety Issue:

Yes

Principal Investigator

Barry J. Maurer, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Texas Tech University Health Sciences Center

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000584267

NCT ID:

NCT00646230

Start Date:

December 2006

Completion Date:

December 2013

Related Keywords:

  • Neuroblastoma
  • recurrent neuroblastoma
  • Neuroblastoma

Name

Location

Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Cook Children's Medical Center - Fort WorthFort Worth, Texas  76104
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Childrens Hospital Los AngelesLos Angeles, California  90027
Lucile Packard Children's Hospital at Stanford University Medical CenterPalo Alto, California  95798
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston CampusAtlanta, Georgia  30322
C.S. Mott Children's Hospital at University of Michigan Medical CenterAnn Arbor, Michigan  48109-0286
Texas Children's Cancer Center and Hematology Service at Texas Children's HospitalHouston, Texas  77030-2399
University of Chicago Comer Children's HospitalChicago, Illinois  60637
Children's Hospital BostonBoston, Massachusetts  02115
Morgan Stanley Children's Hospital of New York-PresbyterianNew York, New York  10032