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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Virginia Commonwealth University
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University
ClinicalTrials.gov Identifier:
NCT01817751
First received: March 20, 2013
Last updated: March 23, 2017
Last verified: March 2017
  Purpose
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 Intervention Phase
Glioblastoma
Glioma
Recurrent Adult Brain Neoplasm
Drug: sorafenib tosylate
Drug: valproic acid
Drug: sildenafil citrate
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase II Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma

Resource links provided by NLM:


Further study details as provided by Virginia Commonwealth University:

Primary Outcome Measures:
  • 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:
  • 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.

  • 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.


Estimated Enrollment: 66
Study Start Date: April 11, 2013
Estimated Study Completion Date: December 31, 2018
Estimated Primary Completion Date: December 31, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.
  Eligibility

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

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
  • 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 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. Examples of clinical inhibitors and clinical inducers for P450-mediated metabolisms and classification of strong, moderate and weak interactions are available through the FDA website, Table 3-2 and 3-3.

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01817751

Contacts
Contact: Mary Beth Tombes, NP 804-628-1357 mtombes@vcu.edu
Contact: Solid Tumor Investigator-Initiated Trials (SIIT) Team 804-628-9238 masseysiit@vcu.edu

Locations
United States, Virginia
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23298
Contact: Mary Beth Tombes, NP    804-628-1357    mtombes@vcu.edu   
Principal Investigator: Mark Malkin, MD         
Sponsors and Collaborators
Virginia Commonwealth University
National Cancer Institute (NCI)
Investigators
Principal Investigator: Mark Malkin, MD Virginia Commonwealth University
  More Information

Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT01817751     History of Changes
Other Study ID Numbers: MCC-14816
HM14816 ( Other Identifier: VCU IRB )
NCI-2013-00705 ( Other Identifier: NCI )
Study First Received: March 20, 2013
Last Updated: March 23, 2017

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:
Glioblastoma
Glioma
Brain Neoplasms
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
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
Sorafenib
Sildenafil Citrate
Valproic Acid
Niacinamide
Citric Acid
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances

ClinicalTrials.gov processed this record on April 26, 2017