This is a pharmacokinetic trial. Patients receive phenylbutyrate through a central venous
catheter for each 28 day cycle. The first several days of drug administration should be
inpatient. Cycles may be repeated if there is no tumor progression or dose limiting
toxicities (DLT). There are no breaks between cycles.
Once a minimum of 3 patients have completed at least 4 weeks of therapy without DLT, new
patients will be entered at the next dose level.
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. The objective of
this trial is to determine the maximum tolerated dose and the toxicities of phenylbutyrate
administered as a continuous intravenous infusion for 28 days. In addition, the
pharmacokinetics of phenylbutyrate and its metabolite, phenylacetate, will be studied using
both model-dependent and model-independent parameters.
Histologically proven cancer that is refractory to standard therapy.
Patients with neurofibromatosis having progressive inoperable plexiform neurofibromas with
potential to cause significant morbidity are eligible.
Patients with brainstem gliomas histology may have histology requirements waived.
Patients without prior therapy are eligible if they have diseases with no available
Patients with evidence of bone marrow involvement by tumor, or a history of either bone
marrow transplantation or extensive radiotherapy will be eligible, but inevaluable for
Patients with greater than grade 2 neurocortical toxicity will be excluded.
Biologic Therapy: No concurrent hematopoietic growth factor.
Chemotherapy: No chemotherapy within 3 weeks of study.
No nitrosoursea within 6 weeks of study.
No concurrent chemotherapy allowed.
Must be on stable or decreasing dose of dexamethasone within 2 weeks of study.
Endocrine Therapy: Not specified.
Radiotherapy: No radiotherapy within 6 weeks of study.
Surgery: Not specified.
Patient must be recovered from toxic effects of all prior therapy.
Concurrent antibiotic therapy when appropriate.
Age: 2 to 21.
Performance Status: ECOG 0-2.
Life Expectancy: At least 8 weeks.
Hematopoietic (hematologic requirements below do not apply to patients with histologically
confirmed bone marrow involvement or history of either bone marrow transplantation or
extensive radiotherapy; these patients are inevaluable for hematologic toxicity):
Absolute granulocyte count (AGC) at least 1500/mm3.
Platelet count at least 100,000/mm3.
Hemoglobin at least 8 g/dL.
Bilirubin no greater than 2 mg/Dl.
SGPT less than 2 times normal.
Creatinine no greater than 1.5 mg/Dl OR
Creatinine clearance at least 60 Ml/min/square meter.
No systemic illness.
Not pregnant or nursing.
No amino acidurias or organic acidemias.