Glioblastoma, Malignant Glioma, Recurrent Adult Brain Neoplasm, WHO Grade III Glioma
Conditions
Keywords
central nervous system, Brain and Nervous System
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
Interventions
DRUGsorafenib tosylate
Given by mouth
DRUGvalproic acid
Given by mouth
DRUGsildenafil citrate
Given by mouth
Sponsors
National Cancer Institute (NCI)
Virginia Commonwealth University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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 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 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) * 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)
sorafenib tosylate: Given by mouth
valproic acid: Given by mouth
sildenafil citrate: Given by mouth | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 41 Participants |
| Region of Enrollment United States | 47 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 47 |
| other Total, other adverse events | 47 / 47 |
| serious Total, serious adverse events | 17 / 47 |
Outcome results
Primary
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.
Time frame: Up to 6 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With 6-Month Progression Free Survival (PFS) | Met 6 month PFS | 8 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With 6-Month Progression Free Survival (PFS) | Did not meet 6 month PFS | 25 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With 6-Month Progression Free Survival (PFS) | Not Evaluable | 14 Participants |
Secondary
Evaluation of Safety and Toxicity of Sorafenib, Valproic Acid, and Sildenafil
Number of patients with adverse events
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Evaluation of Safety and Toxicity of Sorafenib, Valproic Acid, and Sildenafil | 47 Participants |
Secondary
Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS.
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.
Time frame: Up to 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS. | Expressed PDGFRa with12 month OS | 6 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS. | Expressed PDGFRa with less than 12 month survival | 6 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS. | Negative for PDGFRa with 12 month OS | 3 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS. | Negative for PDGFRa without 12 month OS | 6 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month OS. | Not Evaluable | 12 Participants |
Secondary
Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS.
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.
Time frame: Up to 6 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS. | Express PDGFRa that met 6 month PFS | 5 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS. | Express PDGFRa that did not meet 6 month PFS | 7 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS. | Did not express PDGFRa that met 6 month PFS | 2 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS. | Did not express PDGFRa that did not met 6 months | 7 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants Whose Tumors Express PDGFRa With and Without 6-Month PFS. | Not evaluable | 12 Participants |
Secondary
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.
Overall response rate (CR+PR), using RANO or Macdonald criteria, in patients who are evaluable for response and who have tumors that express PDGFRα.
Time frame: From initiation of study treatment to time of best response or off-study (up to 4 years)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | 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. | # Pts with best response of CR | 0 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | 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. | # Pts with best response of PR | 0 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | 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. | # Pts without best response of PR or CR | 12 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | 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. | # Pts not evaluable | 5 Participants |
Secondary
Number of Participants With 12-Month Overall Survival (OS)
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.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With 12-Month Overall Survival (OS) | 14 Participants |
Secondary
Number of Participants With Best Response of CR Plus Number of Participants With Best Response of PR.
Overall response rate (CR+PR), using RANO or Macdonald criteria, in patients evaluable for response regardless of tumor PDGFR status
Time frame: From the first day of study treatment until best response or off study, up to 4 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With Best Response of CR Plus Number of Participants With Best Response of PR. | # Pts with best response of CR | 0 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With Best Response of CR Plus Number of Participants With Best Response of PR. | # Pts with best response of PR | 1 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With Best Response of CR Plus Number of Participants With Best Response of PR. | # Pts without best response of PR or CR | 32 Participants |
| Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil) | Number of Participants With Best Response of CR Plus Number of Participants With Best Response of PR. | # Pts not evaluable | 14 Participants |