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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00107458
• Other study ID #: ADVL0419
• Secondary ID: COG-ADVL0419NCI-
• Status: Completed
• Phase: Phase 1
• First received: April 5, 2005
• Last updated: August 6, 2014
• Start date: May 2005
• Est. completion date: March 2012

Study information

• Verified date: August 2014
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: March 2012
• Est. primary completion date: October 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 21 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• valproic acid

Locations

Country	Name	City	State
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Baylor University Medical Center - Houston	Houston	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Minnesota Children's Hospital - Fairview	Minneapolis	Minnesota
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health & Science University Cancer Institute	Portland	Oregon
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Stanford Comprehensive Cancer Center - Stanford	Stanford	California
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

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. do — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy of oral etoposide at 50 mg/m2/day given concurrently with radiotherapy			Yes