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

NCT ID: NCT00107458

Last Updated: 2014-08-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-05-31
• Study Completion Date: 2012-03-31

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Treatment 1

VPA Target Trough Concentration 75-100 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid

Group Type: EXPERIMENTAL

valproic acid

Intervention Type: DRUG

Treatment 10

VPA Target Trough Concentration 100-150 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid

Group Type: EXPERIMENTAL

valproic acid

Intervention Type: DRUG

Treatment 20

VPA Target Trough Concentration 150-200 mcg/mL

Group Type: EXPERIMENTAL

valproic acid

Intervention Type: DRUG

Interventions

valproic acid

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Children's Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jack M. Su, MD

Role: STUDY_CHAIR

Texas Children's Cancer Center

Heidi V. Russell, MD

Role: STUDY_CHAIR

Texas Children's Cancer Center

Locations

Children's Hospital of Orange County

Orange, California, United States

Stanford Comprehensive Cancer Center - Stanford

Stanford, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Children's Memorial Hospital - Chicago

Chicago, Illinois, United States

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Boston, Massachusetts, United States

University of Minnesota Children's Hospital - Fairview

Minneapolis, Minnesota, United States

Mayo Clinic Cancer Center

Rochester, Minnesota, United States

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

New York, New York, United States

SUNY Upstate Medical University Hospital

Syracuse, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Oregon Health & Science University Cancer Institute

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Baylor University Medical Center - Houston

Houston, Texas, United States

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Hopital Sainte Justine

Montreal, Quebec, Canada

Countries

United States; Canada

References

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.

Reference Type: RESULT

PMID: 21115653 (View on PubMed)

Other Identifiers

COG-ADVL0419

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-05-C-0235

Identifier Type: -

Identifier Source: secondary_id

NCI-P6631

Identifier Type: -

Identifier Source: secondary_id

CDR0000417845

Identifier Type: OTHER

Identifier Source: secondary_id

ADVL0419

Identifier Type: -

Identifier Source: org_study_id