Valproic Acid in Treating Young Patients With Recurrent or Refractory Solid Tumors or CNS Tumors
Valproic Acid in Treating Young Patients With Recurrent or Refractory Solid Tumors or CNS Tumors
RATIONALE: Drugs used in chemotherapy, such as valproic acid, work in different ways to stop
 the growth of tumor cells, either by killing the cells or by stopping them from dividing.
 Valproic acid may also stop the growth of solid tumors or CNS tumors by blocking blood flow
 to the tumor.

 PURPOSE: This phase I trial is studying the side effects and best dose of valproic acid in
 treating patients with recurrent or refractory solid tumors or CNS tumors.
OBJECTIVES:

 Primary

 -  Determine the toxic effects of valproic acid (VPA) administered at doses required to
 maintain serum trough VPA concentrations of 100-150 mcg/mL or 150-200 mcg/mL in young
 patients with recurrent or refractory solid tumors or CNS tumors.

 Secondary

 -  Determine the steady-state serum trough concentration of free and total VPA at the
 targeted total trough VPA concentration in these patients.

 -  Determine the steady state histone acetylation status of peripheral blood monocytes at
 the targeted trough VPA concentration in these patients.

 -  Determine the pharmacokinetic profile of this drug in these patients.

 -  Correlate histone acetylation with free or total trough VPA concentration in these
 patients.

 -  Determine, preliminarily, the antitumor activity of this drug in these patients.

 OUTLINE: This is a dose-escalation, multicenter study.

 For course 1, patients receive escalating doses of oral valproic acid (VPA) twice daily until
 a target serum trough VPA concentration range is maintained for 28 days. Patients who achieve
 the target serum trough VPA concentration range receive subsequent courses of oral VPA twice
 daily (at the dose found to maintain the target serum trough VPA concentration range) on days
 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease
 progression or unacceptable toxicity.

 The first cohort of 6 patients receives VPA to achieve an initial target trough serum VPA
 concentration. If fewer than 2 of 6 patients in the first cohort experience dose-limiting
 toxicity (DLT), then a second cohort of 6 patients receives VPA to achieve the next higher
 target trough serum VPA concentration. If fewer than 2 patients from the second cohort
 experience DTL, then 6 additional patients are enrolled in this cohort to better define
 pharmacokinetics and DLT at this VPA concentration range.

 After completion of study treatment, patients are followed annually.

 PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed* malignant solid tumor, including CNS tumors, at original
 diagnosis or relapse

 -  Recurrent or refractory disease NOTE: *Histologic confirmation not required for
 intrinsic brain stem or optic pathway tumors

 -  Measurable or evaluable disease, defined by 1 of the following criteria:

 -  Any unidimensionally measurable lesion ≥ 10 mm by standard MRI or CT scan for
 either solid or CNS tumors

 -  At least 1 nonmeasurable lesion that is evaluable by nuclear medicine,
 immunocytochemistry, tumor markers, cerebrospinal fluid cytology, or other
 reliable measures

 -  No known curative therapy exists

 -  No documented tumor involvement in the bone marrow

 PATIENT CHARACTERISTICS:

 Age

 -  2 to 21

 Performance status*

 -  Lansky 50-100% (for patients ≤ 10 years of age)

 -  Karnofsky 50-100% (for patients > 10 years of age)

 Life expectancy

 -  Not specified

 Hematopoietic

 -  Absolute neutrophil count ≥ 1,000/mm^3

 -  Platelet count ≥ 100,000/mm^3 (transfusion independent)

 -  Hemoglobin ≥ 8.0 g/dL (transfusions allowed)

 Hepatic

 -  Bilirubin ≤ 1.5 times upper limit of normal (ULN)

 -  ALT ≤ 110 (ULN for this study is 45 U/L)

 -  Albumin ≥ 2 g/dL

 Renal

 -  Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR

 -  Creatinine based on age as follows:

 -  No greater than 0.8 mg/dL (for patients ≤ 5 years of age)

 -  No greater than 1.0 mg/dL (for patients 6 to 10 years of age)

 -  No greater than 1.2 mg/dL (for patients 11 to 15 years of age)

 -  No greater than 1.5 mg/dL (for patients over 15 years of age)

 Other

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  Neurologic deficits in patients with CNS tumors must be stable for ≥ 1 week before
 study entry

 -  No uncontrolled infection

 -  No known urea cycle disorders or other metabolic disorders

 -  No other condition that would preclude study compliance

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Recovered from prior immunotherapy

 -  At least 7 days since prior hematopoietic growth factors that support platelet or WBC
 number or function

 -  At least 7 days since prior antineoplastic biologic agents

 -  At least 3 months since prior stem cell transplantation or rescue without total body
 irradiation

 -  No evidence of active graft vs host disease

 -  No other concurrent anticancer biologic therapy or immunotherapy

 Chemotherapy

 -  More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)
 and recovered

 -  No other concurrent anticancer chemotherapy

 Endocrine therapy

 -  Patients with CNS tumors must be on a stable or decreasing dose of dexamethasone for
 the past 7 days

 Radiotherapy

 -  See Biologic therapy

 -  Recovered from prior radiotherapy

 -  At least 6 months since prior total body irradiation, craniospinal radiotherapy, or
 radiotherapy to ≥ 50% of the pelvis

 -  At least 6 weeks since other prior substantial bone marrow radiotherapy

 -  At least 2 weeks since prior local palliative small port radiotherapy

 -  No concurrent anticancer radiotherapy

 Surgery

 -  Not specified

 Other

 -  No other concurrent investigational agents

 -  No other concurrent anticancer agents

 -  No other concurrent anticonvulsants

 -  Patients receiving valproic acid (VPA) before study entry must have a total
 trough VPA concentration < 100 mcg/mL within the past 7 days