Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information

Alternate Title

Phenylbutyrate in Treating Children With Refractory Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 2-21 NCI NCI-97-C-0051G BCM-H5292, NCI-T96-0044

Objectives

I.   Determine the maximum tolerated dose of phenylbutyrate.

II.  Determine the dose-limiting toxicity and severity of other toxic effects 
of phenylbutyrate.

III.  Study the pharmacokinetics of phenylbutyrate.

IV.  Determine the steady state plasma concentrations of phenylbutyrate and to 
attempt to correlate plasma concentrations with clinical toxic effects.

Entry Criteria

Disease Characteristics:

Histologically proven cancer that is refractory to standard therapy except
if disease is present for which no standard therapy exists and patient is not
a candidate for surgery

Histological verification not required for brainstem gliomas

Neurofibromatosis type I or type II accompanied by progressive inoperable
plexiform neurofibromas allowed

Neurocortical toxicity less than grade 2 

Prior/Concurrent Therapy:

Biologic therapy:
 No concurrent hematopoietic growth factor

Chemotherapy:
 At least 3 weeks since prior myelosuppressive chemotherapy (at least 6 weeks
  since nitrosourea) and recovered
 No concurrent chemotherapy allowed
 
Endocrine therapy:
 Dexamethasone allowed if on stable or decreasing dose for at least 2 weeks
  prior to study

Radiotherapy:
 At least 6 weeks since prior radiotherapy and recovered 

Surgery:
 Not specified

Other:
 Concurrent antibiotic therapy allowed

Patient Characteristics:

Age:
 2 to 21 

Performance Status:
 ECOG 0-2

Life Expectancy:
 At least 8 weeks

Hematopoietic:
 Absolute granulocyte count at least 1,500/mm3
 Platelet count at least 100,000/mm3
 Hemoglobin at least 8 g/dL
 (Above requirements do not apply to patients with histologically confirmed
  bone marrow involvement or history of either bone marrow transplantation or
  extensive radiotherapy; these patients are unevaluable for hematologic
  toxicity)

Hepatic:
 Bilirubin no greater than 2 mg/dL
 SGPT less than 2 times normal

Renal:
 Creatinine no greater than 1.5 mg/dL OR
 Creatinine clearance at least 60 mL/min

Other:
 No systemic illness
 Not pregnant or nursing
 No amino acidurias or organic acidemias

Expected Enrollment

A total of 30-35 patients will be accrued for this study.

Outline

This is a pharmacokinetic study.

Patients receive a continuous infusion of phenylbutyrate through a central 
venous catheter for each 28 day course.  Courses may be repeated in the 
absence of tumor progression or dose limiting toxicities (DLT).  There are no 
breaks between courses.

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.  If DLT is 
experienced in 1 of 3 patients, an additional 3 patients are evaluated at the 
same dose level.  If DLT is experienced in 1 or more of the additional 3 
patients, the maximum tolerated dose (MTD) has been exceeded and 3 more 
patients are treated at the next lower dose level.  

At least 3 patients without central nervous system tumor are treated at the 
dose defined as the MTD.  If none of these 3 patients experiences DLT, then 
further dose escalation in patients without CNS tumors is attempted.  The MTD 
is defined as the dose level immediately below the dose level at which 2 or 
more patients, of a cohort of 3 to 6, experiences a DLT. 

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Frank Balis, MD, Protocol chair		Ph: 301-496-0085 Email: balisf@nih.gov