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

Status: Active

Description

This phase II trial studies how well sorafenib tosylate, valproic acid, and sildenafil citrate work in treating patients with high-grade glioma that has returned (recurrent) or is growing, spreading, or getting worse (progressive). Sorafenib tosylate and valproic acid may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sildenafil citrate may help with getting sorafenib tosylate into the brain tumor. Giving sorafenib tosylate, valproic acid, and sildenafil citrate may work better in treating patients with high-grade glioma.

Eligibility Criteria

Inclusion Criteria

  • Pathologically confirmed high-grade glioma (World Health Organization [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; 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 PDGFR alpha-positive tumors), patients will be pre-registered for PDGFR alpha analysis and registered to the combination treatment schema only if PDGFR alpha-positive and all other enrollment criteria are met
  • Measurable or evaluable disease by RANO criteria (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 >= 50 Gy
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • White blood cells (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 the 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 >= lower limit of normal [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 (National Cancer Institute [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 (CTCAE version [v]4.0) within 4 weeks or less prior to first dose of study treatment * Radiological evidence of any intracranial hemorrhage within the 4 weeks or less 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 deoxyribonucleic acid (DNA) polymerase gamma
  • Arterial thromboembolic or embolic events such as myocardial infarction, cerebrovascular accident, including transient ischemic attacks within 6 months prior to first study treatment
  • Serious uncontrolled infection > grade 2 (CTCAE v4.0)
  • 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 cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and/or STRONG CYP3A4 inducers and/or STRONG cytochrome P450, family 2, subfamily C, polypeptide 9 (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

Locations & Contacts

Virginia

Richmond
Virginia Commonwealth University / Massey Cancer Center
Status: Active
Contact: Mark G. Malkin
Phone: 804-828-8340
Email: mark.malkin@vcuhealth.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. Determine the efficacy of the combination of sorafenib, valproic acid, and sildenafil, in terms of 6-month PFS in high-grade glioma patients who are evaluable for response and who have tumors that express platelet-derived growth factor receptor (PDGFR) alpha.

II. Evaluate the overall response rate, based on Response Assessment in Neuro-Oncology (RANO) criteria or Macdonald criteria, to the drug combination in patients who are evaluable for response (those who express PDGFR alpha and those who do not).

III. Evaluate the overall response rate, based on RANO or Macdonald criteria, to the drug combination in PDGFR alpha expressing tumors in patients who are evaluable for response.

IV. Determine the efficacy of the drug combination, in terms of 12-month survival and median overall survival in patients who are evaluable for response (those who express PDGFR alpha and those who do not).

V. Determine the efficacy of the drug combination, in terms of 12-month survival and median overall survival in high-grade glioma patients who are evaluable for response and who have tumors that express PDGFR alpha.

VI. Evaluate the safety and toxicity of the drug combination.

OUTLINE:

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

After completion of study treatment, patients are followed up for 30 days and then every 2 months thereafter.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Virginia Commonwealth University / Massey Cancer Center

Principal Investigator
Mark G. Malkin

Trial IDs

Primary ID MCC-14816
Secondary IDs NCI-2013-00705, CTC-11-011, MCC-14816 (CTC-11-011)
Clinicaltrials.gov ID NCT01817751