Valproic Acid With Temozolomide and Radiation Therapy to Treat Brain Tumors

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.

- 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.