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

NCT01817751 | Completed Phase 2 Results DMC FDA Drug

• 4 other identifiers: MCC-14816HM14816NCI-2013-00705P30CA016059
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to test the safety, tolerability, and effectiveness of the combination of three drugs, sorafenib (Nexavar®), valproic acid (Depakote®), and sildenafil (Viagra®), when used to treat high-grade glioma, a type of brain tumor.

Conditions

Glioblastoma; Recurrent Adult Brain Neoplasm; Malignant Glioma; WHO Grade III Glioma

Keywords

central nervous system; Brain and Nervous System

Outcome Measures

Primary Outcomes (1)

• Number of Participants With 6-Month Progression Free Survival (PFS)

  Number of patients evaluable for response, regardless of tumor platelet derived growth factor receptor (PDGFR) status, with 6- month PFS defined as the time from the first day a patient receives study treatment until time of progression per response assessment in neuro-oncology (RANO) or Macdonald criteria or death, whichever occurs first.

  Up to 6 months

Secondary Outcomes (6)

• Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS.

  Up to 6 months

• Number of Participants With Best Response of CR Plus Number of Participants With Best Response of PR.

  From the first day of study treatment until best response or off study, up to 4 years

• Number of Participants Whose Tumors Express PDGFRa With Best Response of CR Plus Number of Participants Whose Tumor Expresses PDGFRa With Best Response of PR.

  From initiation of study treatment to time of best response or off-study (up to 4 years)

• Number of Participants With 12-Month Overall Survival (OS)

  12 months

• Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS.

  Up to 12 months

Study Arms (1)

Treatment (sorafenib tosylate, valproic acid, sildenafil)

EXPERIMENTAL

* Sorafenib 400 mg orally twice a day; * Valproic acid (to levels ≥ Lower Level of Normal (LLN) orally twice a day; * Sildenafil 50 mg orally twice a day A cycle consists of 4 weeks. \*The first 6 patients evaluable for qualifying toxicity assessment will be treated as a safety lead-in; enrollment will be gated (the first 3 evaluable patients must complete 4 weeks of the combination therapy before the next 3 patients start combination treatment on protocol)

Drug: sorafenib tosylate; Drug: valproic acid; Drug: sildenafil citrate

Interventions

sorafenib tosylate DRUG

Given by mouth

Also known as: pyridinecarboxamide, chloro-trifluoromethylphenyl pyridine-carboxylic acid methylamide-methylbenzenesulfonate tosylate, Nexavar

Treatment (sorafenib tosylate, valproic acid, sildenafil)

valproic acid DRUG

Given by mouth

Also known as: 2-Propylpentanoic or Propylvaleric Acid, Alti-Valproic, Depakene, Di-n-propylacetic Acid, Ergenyl, Novo-Valproic, VA, Valproate, Valproate Sodium

Treatment (sorafenib tosylate, valproic acid, sildenafil)

sildenafil citrate DRUG

Given by mouth

Also known as: Viagra

Treatment (sorafenib tosylate, valproic acid, sildenafil)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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 platelet-derived growth factor receptor (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 response assessment in neuro-oncology (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 \>=50 Gray (Gy).
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Virginia Commonwealth University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, 23298, United States

Location

Related Publications (1)

• Lang F, Liu Y, Chou FJ, Yang C. Genotoxic therapy and resistance mechanism in gliomas. Pharmacol Ther. 2021 Dec;228:107922. doi: 10.1016/j.pharmthera.2021.107922. Epub 2021 Jun 23.

  PMID: 34171339 DERIVED

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms; Glioma; Neurologic Manifestations

Interventions

Sorafenib; Valproic Acid; Sildenafil Citrate

Condition Hierarchy (Ancestors)

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; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Fatty Acids, Volatile; Fatty Acids; Lipids; Sulfonamides; Sulfones; Sulfur Compounds; Piperazines; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Massey Cancer Center CTO Operations Managers
• Organization: Virginia Commonwealth University Massey Cancer Center

ctoclinops@vcu.edu

877-4627739

Study Officials

• Andrew Poklepovic, MD

  Massey Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2013
• First Posted: March 25, 2013
• Study Start: April 11, 2013
• Primary Completion: August 27, 2020
• Study Completion: May 12, 2023
• Last Updated: July 17, 2024
• Results First Posted: October 28, 2021

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)