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Valproic Acid With Temozolomide and Radiation Therapy to Treat Brain Tumors

Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: High Grade Gliomas; Brain Tumors

Intervention: adjuvant therapy (Procedure); Temozolomide (Drug); Valproic Acid (Drug); Radiation therapy (Radiation)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Kevin A Camphausen, M.D., Principal Investigator, Affiliation: National Cancer Institute (NCI)

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.

Clinical Details

Official title: A Phase II Clinical Trial of the Histone Deacetylase Inhibitor Valproic Acid in Combination With Temodar and Radiation Therapy in Patients With High Grade Gliomas: Multi-Institutional Trial

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Median Progression Free Survival.

Percentage of Participants With Progression Free Survival at 6, 12, and 24 Months

Number of Participants With Best Response

Median Overall Survival

Percentage of Participants With Overall Survival at 6, 12, and 24 Months

Secondary outcome: Number of Participants With Adverse Events

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.

Eligibility

Minimum age: 18 Years. Maximum age: 90 Years. Gender(s): Both.

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.

Locations and Contacts

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States

University of Pennsylvania, Philadelphia, Pennsylvania 19104-6056, United States

Virginia Commonwealth University, Richmond, Virginia 23284, United States

Additional Information

NIH Clinical Center Detailed Web Page

Related publications:

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.

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.

Starting date: March 2006
Last updated: July 7, 2015

Page last updated: August 20, 2015

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