Phase II Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent Glioblastoma

Inclusion Criteria:

- Pathologically confirmed GBM, with documented computed tomography (CT) or magnetic
resonance imaging (MRI) progression after first line therapy; biopsy is also an
acceptable method of confirming progression

- Measurable or evaluable disease by RANO criteria

- Fixed or decreasing dose of corticosteroids (or no corticosteroids) for at least
1week prior to registration

- At least 12 weeks since the completion of radiation therapy

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

- White blood cell (WBC) >= 3.0

- Absolute neutrophil count (ANC) >= 1.5

- Platelets >= 80,000

- Hemoglobin (Hgb) >= 8.5

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 5 x upper
institutional limit

- Total bilirubin =< 2.5 mg/dl

- Creatinine clearance (CrCL) >= 30 as measured by the standard Cockroft-Gault equation

- Life expectancy > 3 months

- Willingness to use contraception as required

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Investigational agent within 4 weeks or 5 half-lives, whichever is longer, of first
dose of study treatment

- Prior systemic therapy for relapsed GBM

- History of coagulopathy

- History of allergic reactions or intolerance to any of the required agents on the
study

- Seizure disorder necessitating the use of enzyme-inducing antiepileptic drugs
(EIAEDs); efforts may be made by the treating physician to change the antiepileptic
drug from another agent to valproic acid or non-EIAED prior to excluding the patient
from study

- Contraindication to antiangiogenic agents, including:

- Pulmonary hemorrhage/bleeding event >= grade 2 (Common Terminology Criteria for
Adverse Events [CTCAE] version 4) within 4 weeks of first dose of study drug

- Any other hemorrhage/bleeding event >= grade 3 within 4 weeks of first dose of
study treatment

- MRI evidence of any intracranial hemorrhage within the past 4 weeks, or prior
history of significant intratumoral, intracerebral, or subarachnoid hemorrhage

- Serious non-healing wound, ulcer, or bone fracture

- Major surgery within 2 weeks of the start of study treatment, or ongoing
complications from surgeries performed previously

- Clinically significant cardiac disease, including major cardiac dysfunction, such as
uncontrolled angina, clinical congestive heart failure with New York Heart
Association (NYHA) class III or higher, ventricular arrhythmias requiring
antiarrhythmic therapy

- Systolic blood pressure > 160 mm Hg or diastolic pressure > 100 mm Hg despite optimal
medical management

- History of priapism

- Known history of retinitis pigmentosa

- Arterial thromboembolic events less than 6 months prior to first study treatment

- Serious uncontrolled infection > grade 2

- Patient with known human immunodeficiency virus (HIV) positivity

- Unable to swallow medication or suspected malabsorption

- Patients on chronic nitrate therapy or alpha-blockers

- Women who are pregnant or nursing

- Baseline corrected QT (QTc) > 500 msec, on screening electrocardiogram (EKG)

- Other condition(s) that in the opinion of the investigator might compromise the
objectives of the study