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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01817751
Recruitment Status : Recruiting
First Posted : March 25, 2013
Last Update Posted : December 21, 2018
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Glioblastoma Recurrent Adult Brain Neoplasm Malignant Glioma WHO Grade III Glioma Drug: sorafenib tosylate Drug: valproic acid Drug: sildenafil citrate Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma
Actual Study Start Date : April 11, 2013
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2020

Arm Intervention/treatment
Experimental: Treatment (sorafenib tosylate, valproic acid, sildenafil)

Patients receive sorafenib tosylate PO, valproic acid* PO, and sildenafil citrate PO BID for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

* NOTE: Patients not receiving antiepileptic therapy begin valproic acid 1 week prior to the first day of sorafenib tosylate and sildenafil citrate.

Drug: sorafenib tosylate
Given PO
Other Name: pyridinecarboxamide, chloro-trifluoromethylphenyl pyridine-carboxyllic acid methyamide-methylbenzenesulfonate tosylate, Nexavar

Drug: valproic acid
Given PO
Other Name: 2-Propylpentanoic or Propylvaleric Acid, Alti-Valproic, Depakene, Di-n-propylacetic Acid, Ergenyl, Novo-Valproic, VA, Valproate, Valproate Sodium

Drug: sildenafil citrate
Given PO
Other Name: Viagra

Primary Outcome Measures :
  1. PFS [ Time Frame: 6 months ]
    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.

Secondary Outcome Measures :
  1. Overall best response rate (complete response + partial response) using RANO or Macdonald criteria. [ Time Frame: Up to 4 years ]
    Will be estimated for the entire study population and for the PDGFRa expressing high-grade glioma cohort, along with the 95% confidence intervals.

  2. Overall survival [ Time Frame: From the first day of study treatment until death by any cause, assessed up to 12 months ]
    The Kaplan-Meier method will be used to describe the time to overall survival and the median time to overall survival will be estimated, and 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.

  3. Incidence of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [ Time Frame: Up to 30 days following the end of study treatment ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 1 week prior to cycle 1 day 1.
  • 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^3
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelets >= 100,000/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 calculated by standard Cockcroft-Gault equation
  • 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 study
  • 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
    • Documented bowel perforation within 6 months of the start of study treatment.
  • 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 (BP) > 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 polymerase γ.
  • 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.

  • Women who are pregnant or nursing
  • Persistent heart rate (HR) <50 or >120 beats per minute (bpm)
  • Corrected QT (QTc) > 480 ms (grade 2 or greater) on screening electrocardiogram (ECG)

    * If baseline QTc on screening ECG meets exclusion criteria on screening assessment:

    • 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 heart rate (HR) 60-100 bpm, no manual read of QT is required
    • For patients with baseline HR < 60 or > 100 bpm, manual read of QT by cardiologist is required using Fridericia correction
  • Other condition(s) that in the opinion of the investigator might compromise the objectives of the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01817751

Contact: Alison A Ryan, NP 804-628-1936
Contact: Solid Tumor Investigator-Initiated Trials (SIIT) Team 804-628-9238

United States, Virginia
Virginia Commonwealth University/Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Alison A Ryan, NP    804-628-1936   
Principal Investigator: Mark G Malkin, MD         
Sponsors and Collaborators
Virginia Commonwealth University
National Cancer Institute (NCI)
Principal Investigator: Mark G Malkin, MD Massey Cancer Center

Responsible Party: Virginia Commonwealth University Identifier: NCT01817751     History of Changes
Other Study ID Numbers: MCC-14816
HM14816 ( Other Identifier: VCU IRB )
NCI-2013-00705 ( Other Identifier: NCI )
P30CA016059 ( U.S. NIH Grant/Contract )
First Posted: March 25, 2013    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Virginia Commonwealth University:
central nervous system
Brain and Nervous System

Additional relevant MeSH terms:
Brain Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sildenafil Citrate
Valproic Acid
Citric Acid
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Growth Substances