Valproic Acid With Temozolomide and Radiation Therapy to Treat Brain Tumors

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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High Grade Gliomas, Brain Tumors

Intervention / Treatment
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* Procedure: adjuvant therapy
* Drug: Temozolomide
* Drug: Valproic Acid
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valproic Acid<br>Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide. | Procedure: adjuvant therapy<br> <br> Drug: Temozolomide<br>* Orally 75mg/m^2 first day of radiation until completion. Restart 4 weeks post radiation.<br>* Other names: Temodar;Drug: Valproic Acid<br>* Orally 25mg/kg/day twice a day concurrently with radiation therapy and temozolomide.<br>* Other names: Depakote;Radiation: Radiation therapy<br>* External beam radiation Monday-Friday in 2 Gy fractions to 60 Gy total.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival. | Progression free survival is the interval from initiation of treatment on protocol to symptomatic or radiographic progression. Progressive disease is a >25% increase in contrast enhancing tumor volume documented at the initiation of treatment on protocol. | up to 51 months | 
| Percentage of Participants With Progression Free Survival at 6, 12, and 24 Months | Percentage of participants who were progression free by 6, 12, or 24 months. Progressive disease is a >25% increase in contrast enhancing tumor volume documented at the initiation of treatment on protocol. | 6, 12, and 24 months | 
| Number of Participants With Best Response | Best response recorded from the start of treatment until disease progression/recurrence. Complete response is complete resolution of all contrast enhancing tumor documented at initiation of treatment on protocol, with no appearance of new lesions. Partial response is a >50% reduction in the contrast enhancing tumor volume documented at the initiation of treatment on protocol. Minor response is a >25%, but <50% reduction in the contrast enhancing tumor volume documented at the initiation of treatment on protocol. Stable disease is a change in tumor size less than MR but not demonstrating progressive disease. Progressive disease is a >25% increase in contrast enhancing tumor volume documented at the initiation of treatment on protocol. Not evaluable means the participant cannot be evaluated (e.g., quality of scan). | up to 63.8 months | 
| Median Overall Survival | Survival is the interval from the initiation of treatment on protocol to date of death. | up to 63.8 months | 
| Percentage of Participants With Overall Survival at 6, 12, and 24 Months | Percentage of participants who were alive at 6, 12, and 24 months. | 6, 12, and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 6 years, 7 months and 27 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemotherapy, Radiation, Brain Tumor, GBM, Radiosensitizer, Glioblastoma, Glioblastoma Multiforme