Valproic Acid in Treating Young Patients With Recurrent or Refractory Solid Tumors or CNS Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Study of Valproic Acid in Children With Recurrent/Progressive Solid Tumors Including CNS Tumors

Conditions
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Brain and Central Nervous System Tumors, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: valproic acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment 1<br>VPA Target Trough Concentration 75-100 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid | Drug: valproic acid<br> <br> |
| Experimental: Treatment 10<br>VPA Target Trough Concentration 100-150 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid | Drug: valproic acid<br> <br> |
| Experimental: Treatment 20<br>VPA Target Trough Concentration 150-200 mcg/mL | Drug: valproic acid<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of oral etoposide at 50 mg/m2/day given concurrently with radiotherapy |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood brain stem glioma, recurrent childhood brain tumor, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood ependymoma, recurrent childhood medulloblastoma, recurrent childhood supratentorial primitive neuroectodermal tumor, unspecified childhood solid tumor, protocol specific, recurrent childhood visual pathway and hypothalamic glioma, childhood high-grade cerebral astrocytoma, childhood low-grade cerebral astrocytoma, childhood infratentorial ependymoma, childhood supratentorial ependymoma, childhood spinal cord neoplasm, childhood grade I meningioma, childhood grade II meningioma, childhood grade III meningioma, childhood craniopharyngioma, childhood central nervous system germ cell tumor