Clinical Trials /

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

NCT01817751

Description:

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.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sorafenib Tosylate, Valproic Acid, and Sildenafil Citrate in Treating Patients With Recurrent High-Grade Glioma
  • Official Title: Phase II Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma

Clinical Trial IDs

  • ORG STUDY ID: MCC-14816
  • SECONDARY ID: HM14816
  • SECONDARY ID: NCI-2013-00705
  • NCT ID: NCT01817751

Conditions

  • Glioblastoma
  • Glioma
  • Recurrent Adult Brain Neoplasm

Interventions

DrugSynonymsArms
sorafenib tosylatepyridinecarboxamide, chloro-trifluoromethylphenyl pyridine-carboxyllic acid methyamide-methylbenzenesulfonate tosylate, NexavarTreatment (sorafenib tosylate, valproic acid, sildenafil)
valproic acid2-Propylpentanoic or Propylvaleric Acid, Alti-Valproic, Depakene, Di-n-propylacetic Acid, Ergenyl, Novo-Valproic, VA, Valproate, Valproate SodiumTreatment (sorafenib tosylate, valproic acid, sildenafil)
sildenafil citrateViagraTreatment (sorafenib tosylate, valproic acid, sildenafil)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sorafenib tosylate, valproic acid, sildenafil)ExperimentalPatients 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.
  • sorafenib tosylate
  • valproic acid
  • sildenafil citrate

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:PFS
Time Frame:6 months
Safety Issue:
Description: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

Measure:Overall best response rate (complete response + partial response) using RANO or Macdonald criteria.
Time Frame:Up to 4 years
Safety Issue:
Description:Will be estimated for the entire study population and for the PDGFRa expressing high-grade glioma cohort, along with the 95% confidence intervals.
Measure:Overall survival
Time Frame:From the first day of study treatment until death by any cause, assessed up to 12 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Virginia Commonwealth University

Trial Keywords

  • central nervous system
  • Brain and Nervous System

Last Updated

March 23, 2017