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Phase II Trial of Phenylbutyrate Given as a Continuous Infusion in Pediatric Patients With Progressive or Recurrent CNS Malignancy

Phase 2
Not Enrolling
Brain Tumor

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Trial Information

Phase II Trial of Phenylbutyrate Given as a Continuous Infusion in Pediatric Patients With Progressive or Recurrent CNS Malignancy

Phenylbutyrate is an aromatic fatty acid that is converted to phenylacetate in vivo by
mitochondrial Beta-oxidation to phenylacetate. Preclinical studies have shown that
continuous exposure to phenylacetate or phenylbutyrate can induce tumor cytostasis and
differentiation in a wide variety of cell lines including malignant gliomas and
neuroblastomas. However, phenylbutyrate has been shown to be a more potent differentiating
agent than phenylacetate in a variety of tumor cell lines. In addition, phenylbutyrate
appears to have molecular activities that are distinct from phenylacetate and may induce
apoptosis. Phase I trials in adults and children have established the feasibility of
administering phenylbutyrate on a prolonged schedule. A phase II trial of phenylbutyrate
administered as a continuous intravenous infusion will be performed in children with
recurrent or progressive brain tumors.

Inclusion Criteria


Age: Patients must be between 2 and 21 years old.

Histologic diagnosis: Previously treated brain tumor patients with any histologic
diagnosis who have recurrent or progressive disease after radiation or chemotherapy,
including bone marrow transplant. For patients with brainstem tumors the requirement for
histologic verification may be waived. However, for patients with brainstem tumors
treated with hyperfractionated radiotherapy a biopsy, a PET scan or NMR spectroscopy is
strongly recommended prior to study entry to rule out radionecrosis as a possible cause of
MRI changes. A biopsy, PET scan, or NMR spectroscopy is required for patients treated
with radiosurgery prior to study entry.

Phenylbutyrate will be studied within each of the following disease strata as defined by
the initial tumor histology:

1. High grade glioma (anaplastic astrocytoma or glioblastoma multiforme)

2. Brainstem glioma

3. Medulloblastoma or primitive neuroectodermal tumors (PNET) present in the
supratentorial or posterior fossa locations.

4. Other

Radiologic evaluation: (must be obtained within two weeks prior to starting therapy)
Patients must have a CT or MRI imaging studies documenting the measurable lesion(s) that
clearly demonstrates the recurrent or progressive nature of the lesion(s).

Recovery from prior therapy:

1. Patients must have recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study and must be without
significant systemic illness (e.g. Infection).

2. Patients must not have received myelosuppressive chemotherapy within 3 weeks (six
weeks if prior nitrosourea) of entry onto this protocol.

3. Evaluable lesions must not have had any radiotherapy within 8 weeks, or radiosurgery
within 4 months of the start of this protocol.

4. Patients receiving dexamethasone must be on a stable or decreasing dose during the 2
weeks prior to study entry.

Life Expectancy: Patients must have a life expectancy of at least 8 weeks.

Performance status: For patients older than or equal to 10 years the Karnofsky
performance score must be 50 percent or greater. For children younger than 10 years, the
Lansky score must be 50 percent or greater. Patients who are unable to walk because of
paralysis, but who are up in a wheel chair will be considered ambulatory for the purpose
of calculating the performance score.

Informed consent: All patients or their legal guardians (if the patient is younger than
18 years of age) must sign a document of informed consent indicating their awareness of
the investigational nature and the risks of this study. When appropriate the patient will
be included in all discussions in order to obtain verbal assent.

Hematological parameters: (must be obtained within 1 week prior to starting therapy).
Patients must have adequate bone marrow function (ANC greater than 1,000/mm(3); platelet
count greater than 50,000/mm(3); hgb greater than 8.0 mg/dL).

Patients with histologic evidence of bone marrow involvement by tumor, or a history of
either bone marrow transplantation or extensive radiotherapy (craniospinal XRT or field
encompassing a region greater than the hemipelvis) will be eligible and for the study but
will be evaluated separately for hematologic toxicity. Transfusion support may be used to
obtain hematologic parameters in such patients.

Biochemical parameters:

1. Hepatic Function: Patients must have a bilirubin less than 1.5 mg/dl and SGPT less
than 2x normal.

2. Renal Function: Patients must have an age-adjusted normal serum creatinine (see
below) or a creatinine clearance of 70 mL/min/1.73m(2) or greater.


Age (Years) Maximum Serum Creatinine (mg/dl)


5 or greater 0.8

Between 5 and 10 1.0

Between 10 and 15 1.2

Greater than 15 1.5


Electrolytes: Patients must have normal serum electrolytes (Na+, K+, Cl-, CO2).
Note: They may be receiving electrolyte supplements to maintain their electrolytes
in the normal range.

Central venous access: Patients must be willing to have a central venous access
device (e.g. Broviac or Hickman or Port-a-Cath). An external central venous access
device is preferable.

Durable Power of Attorney (DPA): A DPA must be offered to all patients 18 - 21 years
of age.


Women of childbearing potential who are pregnant or lactating.

Patients with significant systemic illness.

Patients with amino acidurias or organic acidemias.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment


United States: Federal Government

Study ID:




Start Date:

November 2000

Completion Date:

July 2002

Related Keywords:

  • Brain Tumor
  • Children
  • Brain
  • Maturation
  • Phenylacetate
  • Differentiation
  • Brain Neoplasms



National Cancer Institute (NCI) Bethesda, Maryland  20892