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

• ClinicalTrials.gov Identifier: NCT01817751
• Recruitment Status: Active, not recruiting
• First Posted: March 25, 2013
• Last Update Posted: May 1, 2020
• Sponsor: Virginia Commonwealth University
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Virginia Commonwealth University

Study Description

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 47 participants
• Allocation: N/A
• 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: June 30, 2020
• Estimated Study Completion Date: June 30, 2021

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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
  • 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

Contacts and Locations

Locations

United States, Virginia

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, United States, 23298

Sponsors and Collaborators

Virginia Commonwealth University

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mark G Malkin, MD; Massey Cancer Center

More Information

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT01817751
• 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
• Last Update Posted: May 1, 2020
• Last Verified: April 2020

• 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; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Urological Agents; Anticonvulsants; GABA Agents