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

Phase 2
18 Years
Open (Enrolling)
Brain and Nervous System

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Trial Information

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

The combination of sorafenib, valproic acid, and sildenafil may have therapeutic potential
for the treatment of GBM in the clinic. The combination of sorafenib and valproic acid is
predicated on the basis that sorafenib activity is enhanced by HDAC inhibition. The addition
of sildenafil is based on its ability to block ABCB1 and ABCG2 drug efflux pumps. As the
ABCG2 transporter is the primary transporter involved in the efflux of sorafenib at the BBB,
blocking its action is predicted to increase the concentration of sorafenib in the brain.

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

- 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

Type of Study:


Study Design:

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

Outcome Measure:

Determine the efficacy of the combination of sorafenib (sorafenib tosylate), valproic acid, and sildenafil (sildenafil citrate), in terms of 6-month progression-free survival (PFS) in glioblastoma (GBM).

Outcome Description:

The Kaplan-Meier method will be used to describe the time to progression and the median time to progression will be estimated, along with its 95% confidence intervals, for the entire population and for PDGFRa expression, respectively. Cox regression analysis will be used to evaluate baseline characteristics and any potential covariates.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Asadullah Khan, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Virginia Commonwealth University


United States: Institutional Review Board

Study ID:




Start Date:

April 2013

Completion Date:

December 2017

Related Keywords:

  • Brain and Nervous System
  • adult giant cell glioblastoma
  • adult glioblastoma
  • adult gliosarcoma
  • recurrent adult brain tumor
  • Glioblastoma



Virginia Commonwealth UniversityRichmond, Virginia