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

Phase 2

Completed

Conditions: Recurrent Adult Brain Neoplasm
Glioblastoma
Malignant Glioma
WHO Grade III Glioma

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

Registration Number: NCT01817751

Lead Sponsor: Virginia Commonwealth University

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.

Detailed Description: The study is a single-center, open-label phase 2 study, with an early stopping rule in place for safety. The trial will include patients with recurrent or progressive high-grade glioma.

The trial will be conducted in an adaptive design, with a Simon's mini-max 2-stage design incorporating an interim analysis for efficacy

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 47

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 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.
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (sorafenib tosylate, valproic acid, sildenafil)	sorafenib tosylate	* 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)
Treatment (sorafenib tosylate, valproic acid, sildenafil)	sildenafil citrate	* 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)
Treatment (sorafenib tosylate, valproic acid, sildenafil)	valproic acid	* 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)

Primary Outcome Measures

Name	Time	Method
Number of Participants With 6-Month Progression Free Survival (PFS)	Up to 6 months	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS.	Up to 6 months	Number of patients evaluable for response, with tumors that express PDGFRα, with 6-month PFS defined as the time from the first day a patient receives study treatment until time of progression per RANO or Macdonald criteria or death, whichever occurs first.
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	Overall response rate (CR+PR), using RANO or Macdonald criteria, in patients evaluable for response regardless of tumor PDGFR status
Number of Participants With 12-Month Overall Survival (OS)	12 months	Number of patients evaluable for response, regardless of tumor PDGFR status, who are alive at 12 months after the first day a patient receives study treatment. Overall Survival (OS) defined as the time from the first day a patient receives study treatment until death by any cause.
Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS.	Up to 12 months	Number of patients evaluable for response with tumors that express PDGFRα who are alive at 12 months after the first day a patient receives study treatment. On study is defined as the time from the first day a patient receives study treatment until death by any cause.
Evaluation of Safety and Toxicity of Sorafenib, Valproic Acid, and Sildenafil	From initiation of study therapy to completion of adverse event (AE) observation period, up to 30 days following the end of study treatment, up to 7 years.	Number of patients with adverse events
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)	Overall response rate (CR+PR), using RANO or Macdonald criteria, in patients who are evaluable for response and who have tumors that express PDGFRα.