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Sorafenib Tosylate, Valproic Acid, and Sildenafil Citrate in Treating Patients With Recurrent High-Grade Glioma

Information source: Virginia Commonwealth University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Brain and Nervous System; Glioblastoma; Glioma

Intervention: sorafenib tosylate (Drug); valproic acid (Drug); sildenafil citrate (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Virginia Commonwealth University

Official(s) and/or principal investigator(s):
Mark Malkin, MD, Principal Investigator, Affiliation: Virginia Commonwealth University

Overall contact:
Mary Beth Tombes, NP, Phone: 804-628-1357, Email: mtombes@vcu.edu


This phase II trial studies how well sorafenib tosylate, valproic acid, and sildenafil citrate works in treating patients with recurrent high-grade glioma. Sorafenib tosylate, valproic acid, and sildenafil citrate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Clinical Details

Official title: Phase II Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma

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

Primary outcome: PFS

Detailed description: The combination of sorafenib, valproic acid, and sildenafil may have therapeutic potential for the treatment of recurrent high-grade glioma 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.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


Inclusion Criteria:

- Pathologically confirmed high-grade glioma (WHO grade 3 or 4), with documented

computed tomography (CT) or magnetic resonance imaging (MRI) progression or recurrence. Biopsy is also an acceptable method of confirming progression or recurrence. If initial tumor was grade 2 glioma, histological confirmation of high-grade recurrence is required

- After first interim analysis, if the study proceeds to enrollment of selected

patients (only those who have PDGFRa-positive tumors), patients will be pre-registered for PDGFRa analysis and registered to the combination treatment schema only if PDGFRa-positive an all other enrollment criteria are met.

- Measurable or evaluable disease by RANO (MRI) or MacDonald (CT) 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 to a total of >=50Gy.

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

- White blood cell (WBC) >= 3. 000/mm^300/mm^3

- Absolute neutrophil count (ANC) >= 1. 500/mm^3

- Platelets >= 80,000/mm^3

- Hemoglobin (Hgb) >= 8. 5 g/dL

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit

of normal (ULN) for the laboratory

- Total bilirubin =< 1. 5 x ULN for the laboratory (total bilirubin criteria may be

waived if a patient has documented Gilbert's disease)

- Creatinine clearance (CrCL) >= 30 mL/min as measured by the standard Cockcroft-Gault


- Women of childbearing potential must have a negative serum pregnancy test performed

within 7 days prior to the start of treatment. Women of childbearing potential and men must agree to use a medically accepted form of birth control for the duration of study participation and

- for 2 months following completion of study treatment.

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

Exclusion Criteria:

- Investigational agent within 4 weeks of first dose of study treatment

- Prior bevacizumab or tyrosine-kinase inhibitor

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


- Any condition that would prohibit patient from initiating valproic acid. Current or

prior valproic acid treatment is allowed (do not need to be ≥ LLN for laboratory for enrollment).

- 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:

- Bronchopulmonary hemorrhage/bleeding event >= grade 2 (NCI Common Terminology

Criteria for Adverse Events [CTCAE] version 4. 0) within 4 weeks or less prior to first dose of study drug

- Any other hemorrhage/bleeding event >= grade 3 (NCI CTCAE v4. 0) within 4 weeks

or less prior to first dose of study treatment

- Radiological evidence of any intracranial hemorrhage within the 4 weeks or less

less prior to first dose of study treatment

- 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, recent (within 6 months) myocardial infarction or unstable coronary artery disease.

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

medical management

- History of priapism

- Known history of retinitis pigmentosa

- Known mitochondrial disorder caused by mutations in mitochondrial DNA polymeraseγ.

- Arterial thromboembolic or embolic events such as myocardial infarction,

cerebrovascular accident, including transient ischemic attacks 6 months prior to first study treatment

- Serious uncontrolled infection > grade 2 (CTCAE v 4)

- Known human immunodeficiency virus (HIV) positivity

- Unable to swallow medication or suspected malabsorption

- Patients on chronic nitrate therapy or alpha-blockers

* Exclude persons who require ongoing administration of STRONG CYP3A4 inhibitors and/or STRONG CYP3A4 inducers and/or STRONG CYP2C9 inhibitors. The reference list of CYP isozymes and classification of strong, moderate and weak interactions is available through the FDA website.

- Women who are pregnant or nursing

- Persistent heart rate (HR) <50 or >120 beats per minute (bpm); ie. 3 separate

measurements obtained on different days

- QTc >480ms (grade 2 or greater) on screening EKG.

- If baseline QTC on screening EKG meets exclusion criteria on screening


- check potassium and magnesium levels;

- correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to

confirm exclusion of patient due to QTc

- For patients with a HR 60-100 bpm, no manual read of QTc is required

- For patients with baseline HR <60or >100 bpm, manual read of QTc by cardiologist

is required using Frederica correction

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

objectives of the study

Locations and Contacts

Mary Beth Tombes, NP, Phone: 804-628-1357, Email: mtombes@vcu.edu

Virginia Commonwealth University, Richmond, Virginia 23298, United States; Recruiting
Mary Beth Tombes, NP, Phone: 804-628-1357, Email: mtombes@vcu.edu
Mark Malkin, MD, Principal Investigator
Additional Information

Starting date: April 2013
Last updated: July 16, 2015

Page last updated: August 23, 2015

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