Clinical trial NCT00107458: Valproic Acid in Treating Young Patients With Recurrent or Refractory Solid Tumors or CNS Tumors
Official title: A Phase I Study of Valproic Acid in Children With Recurrent/Progressive Solid Tumors Including CNS Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-04-06
Enrollment: 26
Sex: ALL
Minimum age (years): 2
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility 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

Primary outcomes:
measure: Efficacy of oral etoposide at 50 mg/m2/day given concurrently with radiotherapy
Secondary outcomes:
Other outcomes:
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Stanford
country: United States
facility: Stanford Comprehensive Cancer Center - Stanford
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Children's Hospital - Fairview
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University Cancer Institute
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Baylor University Medical Center - Houston
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
Study officials:
affiliation: Texas Children's Cancer Center
name: Jack M. Su, MD
role: STUDY_CHAIR
affiliation: Texas Children's Cancer Center
name: Heidi V. Russell, MD
role: STUDY_CHAIR
References:
citation: Su JM, Li XN, Thompson P, Ou CN, Ingle AM, Russell H, Lau CC, Adamson PC, Blaney SM. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report. Clin Cancer Res. 2011 Feb 1;17(3):589-97. doi: 10.1158/1078-0432.CCR-10-0738. Epub 2010 Nov 29.