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


Phase 1
2 Years
21 Years
Not Enrolling
Both
Brain and Central Nervous System Tumors, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

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

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Jack M. Su, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Texas Children's Cancer Center

Authority:

United States: Federal Government

Study ID:

CDR0000417845

NCT ID:

NCT00107458

Start Date:

May 2005

Completion Date:

Related Keywords:

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

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Mayo Clinic Cancer CenterRochester, Minnesota  55905
Children's Hospital of Orange CountyOrange, California  92668
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Baylor University Medical Center - HoustonHouston, Texas  77030-2399
Indiana University Melvin and Bren Simon Cancer CenterIndianapolis, Indiana  46202-5289
Herbert Irving Comprehensive Cancer Center at Columbia University Medical CenterNew York, New York  10032
Oregon Health & Science University Cancer InstitutePortland, Oregon  97239-3098
Stanford Comprehensive Cancer Center - StanfordStanford, California  94305
University of Minnesota Children's Hospital - FairviewMinneapolis, Minnesota  55455