Valproic Acid With Temozolomide and Radiation Therapy to Treat Brain Tumors

NCT ID: NCT00302159

Last Updated: 2016-08-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 43 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-03-31
• Study Completion Date: 2014-11-30

Brief Summary

Background:

• Radiation therapy with temozolomide (an anti-cancer drug) is standard therapy for treating brain tumors called glioblastomas.
• The drug valproic acid, currently approved for treating seizures, has been shown in laboratory tests to increase the radiosensitivity of glioma cells.

Objectives:

-To determine the effectiveness of adding valproic acid to standard treatment with radiation therapy and temozolomide for treating glioblastoma.

Eligibility:

-Patients 18 years of age and older with glioblastoma multiforme who have not been previously treated with chemotherapy of radiation.

Design:

• This Phase II trial will enroll 41 patients.
• Patients will receive radiation therapy to the brain once a day, Monday through Friday, for 6 1/2 weeks.
• Patients will take temozolomide once a day by mouth, Monday through Friday, during the period of radiation treatment. Starting 4 weeks after radiation therapy, patients will take temozolomide once a day for 5 days every 28 days for a total of six cycles.
• Patients will receive valproic acid by mouth twice a day beginning 1 week prior to the first day of radiation therapy and continuing until the completion of chemotherapy and radiation therapy.
• Patients will have follow-up visits 1 month after completing therapy, then every 3 months for 2 years, and then every 6 months for 3 years. Follow-up includes a physical examination, blood tests and magnetic resonance imaging of the brain.

Detailed Description

BACKGROUND:

• Histone deacetylase inhibitors (HDACi) have recently been shown to enhance the radiosensitivity of glioma cells both in vitro and in vivo.
• Valproic acid has also recently been demonstrated to be a potent HDAC.
• Valproic acid has a long clinical history in patients with and without brain tumors and is known to cross the blood-brain barrier. However, the use of valproic acid in combination with temozolomide and radiotherapy for patients with high-grade gliomas has never been tested.

OBJECTIVES:

-The primary measure of efficacy will be progression free survival and overall survival.

ELIGIBILITY:

• Patients greater than 18 years old
• Diagnosis glioblastoma multiforme
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Patients who have not been previously treated with chemotherapy or radiation

DESIGN:

• This is a Phase II trial to determine the efficacy of valproic acid in combination with external beam radiation therapy and temozolomide in patients with high-grade gliomas.
• Patients will be treated with external beam radiation therapy in a standard manner with temozolomide given daily during the radiation. The valproic acid will be administered daily beginning one week prior to the first day of irradiation and continuing until the completion of chemoradiation.
• We anticipate that accrual to this trial of 41 patients will take approximately 1 year.

Conditions

High Grade Gliomas; Brain Tumors

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Valproic Acid

Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Group Type: EXPERIMENTAL

adjuvant therapy

Intervention Type: PROCEDURE

Temozolomide

Intervention Type: DRUG

Orally 75mg/m\^2 first day of radiation until completion. Restart 4 weeks post radiation.

Valproic Acid

Intervention Type: DRUG

Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Radiation therapy

Intervention Type: RADIATION

External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Interventions

adjuvant therapy

Intervention Type: PROCEDURE

Temozolomide

Orally 75mg/m\^2 first day of radiation until completion. Restart 4 weeks post radiation.

Intervention Type: DRUG

Valproic Acid

Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.

Intervention Type: DRUG

Radiation therapy

External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.

Intervention Type: RADIATION

Other Intervention Names

Temodar; Depakote

Eligibility Criteria

Inclusion Criteria

Histological diagnosis:

Pathologically confirmed glioblastoma multiforme.

Histologic diagnosis of glioblastoma multiforme (GBM) will have been established by biopsy or resection no more than 6 weeks prior to enrollment.

The patient is a candidate for definitive external beam radiotherapy.

Patients must be older than 18 years with a life expectancy greater than 8 weeks.

Patients should have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

Patients must have a primary medical oncologist in the community who is willing to collaborate with the Radiation Oncology Branch (ROB) staff in the clinical management of the patient, specifically in the prescription of Temozolomide and toxicity monitoring in the adjuvant phase.

Laboratory functions:

Adequate bone marrow function defined as a peripheral absolute granulocyte count of greater than 1500/mm^3, hemoglobin greater than 10gm/dL, and platelet count greater than 100,000/mm^3.

Adequate liver function, defined as bilirubin and serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) less than 2 x the upper limit of normal.

Serum creatinine less than 1.5 mg/dl.

Serum albumin greater than 0.75 x normal.

All patients or their legal guardian must sign a document of informed consent indicating their understanding of the investigational nature and the risks of this study BEFORE any of the protocol related studies are performed (this does not include routine laboratory tests or imaging studies required to establish eligibility).

Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study.

Exclusion Criteria

Prior therapy:

Patients who have previously received valproic acid.

Patients who have previously received radiation therapy to the brain.

Patients who have received chemotherapy for the treatment of their high grade glioma or who are currently receiving other investigational chemotherapeutic agents.

Patients with a known history of disorders of urea metabolism.

Concurrent therapy:

The concurrent use of sulfamethoxazole, salicylates or naproxen is not allowed.

Patients with a history of or concurrent second malignancy other than non-melanoma skin cancer or cervical cancer less than 3 years since GBM diagnosis.

Pregnant or breast-feeding females are excluded because of the potential mutagenic effects on a developing fetus or newborn.

Clinically significant unrelated systemic illness which in the judgement of the Principal or Associate Investigator would compromise the patient's ability to tolerate this therapy or are likely to interfere with the study procedures or results, including but not limited to Insulin dependent diabetes.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Kevin Camphausen, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kevin A Camphausen, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Countries

United States

References

Davis FG, McCarthy BJ, Freels S, Kupelian V, Bondy ML. The conditional probability of survival of patients with primary malignant brain tumors: surveillance, epidemiology, and end results (SEER) data. Cancer. 1999 Jan 15;85(2):485-91.

Reference Type: BACKGROUND

PMID: 10023719 (View on PubMed)

Loeffler JS, Alexander E 3rd, Shea WM, Wen PY, Fine HA, Kooy HM, Black PM. Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol. 1992 Sep;10(9):1379-85. doi: 10.1200/JCO.1992.10.9.1379.

Reference Type: BACKGROUND

PMID: 1325539 (View on PubMed)

Related Links

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2006-C-0112.html

NIH Clinical Center Detailed Web Page

Other Identifiers

06-C-0112

Identifier Type: -

Identifier Source: secondary_id

060112

Identifier Type: -

Identifier Source: org_study_id

NCT00313664

Identifier Type: -

Identifier Source: nct_alias