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

• Sponsor: Virginia Commonwealth University (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01817751
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 47
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 174.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

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 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

Study Design

• Study Type: Interventional
• Actual 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: Apr 11, 2013
• Actual Primary Completion Date: Aug 27, 2020
• Anticipated Study Completion Date: Oct 30, 2027

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 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)

Drug: sorafenib tosylate; Given by mouth; Other Names: pyridinecarboxamide, chloro-trifluoromethylphenyl pyridine-carboxylic acid methylamide-methylbenzenesulfonate tosylate, Nexavar ; Drug: valproic acid; Given by mouth; Other Names: 2-Propylpentanoic or Propylvaleric Acid, Alti-Valproic, Depakene, Di-n-propylacetic Acid, Ergenyl, Novo-Valproic, VA, Valproate, Valproate Sodium ; Drug: sildenafil citrate; Given by mouth; Other Names: Viagra

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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

3. 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.

4. Number of Participants With 12-Month Progression Free Survival (PFS). [Up to 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.

5. Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month PFS. [Up to 12 months]

   Proportion 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.

6. 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.]

   Number of patients with adverse events, and types of events, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 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

	Site	City	State	Country	Postal Code
1	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• Virginia Commonwealth University
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Zhi-Jian Chen, MD, Massey Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 22, 2021
• Informed Consent Form - Jun 8, 2021

More Information

Publications

None provided.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT01817751
• Other Study ID Numbers: MCC-14816; HM14816; NCI-2013-00705; P30CA016059
• First Posted: Mar 25, 2013
• Last Update Posted: Mar 23, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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; Recurrence; Sorafenib; Sildenafil Citrate; Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Period Title: Overall Study
STARTED	47
COMPLETED	46
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Overall Participants	47
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	32 68.1%
>=65 years	15 31.9%
Sex: Female, Male (Count of Participants)
Female	12 25.5%
Male	35 74.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.1%
Not Hispanic or Latino	46 97.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.1%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 10.6%
White	41 87.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	47 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Measure Participants	47
Met 6 month PFS	8 17%
Did not meet 6 month PFS	25 53.2%
Not Evaluable	14 29.8%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Measure Participants	17
Met 6 month PFS	5 10.6%
Did not meet 6 month PFS	7 14.9%
Not evaluable	5 10.6%

3. Secondary Outcome

Title	Number of Participants With Best Response of CR Plus Number of Participants With Best Response of PR.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Measure Participants	47
# Pts with best response of CR	0 0%
# Pts with best response of PR	1 2.1%
# Pts without best response of PR or CR	32 68.1%
# Pts not evaluable	14 29.8%

4. Secondary Outcome

Title	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.
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Measure Participants	17
# Pts with best response of CR	0 0%
# Pts with best response of PR	0 0%
# Pts without best response of PR or CR	12 25.5%
# Pts not evaluable	5 10.6%

5. Secondary Outcome

Title	Number of Participants With 12-Month Progression Free Survival (PFS).
Description	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	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Measure Participants	47
# That met 12 month PFS	3 6.4%
# That did not meet 12 month PFS	30 63.8%
# Not evaluable	14 29.8%

6. Secondary Outcome

Title	Number of Participants Whose Tumors Express PDGFRa With and Without 12-Month PFS.
Description	Proportion 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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
Measure Participants	17
# That met 12 month PFS	1 2.1%
# That did not meet 12 month PFS	11 23.4%
# Not evaluable	5 10.6%

7. Secondary Outcome

Title	Evaluation of Safety and Toxicity of Sorafenib, Valproic Acid, and Sildenafil
Description	Number of patients with adverse events, and types of events, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).
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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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.
Adverse Event Reporting Description	Number of patients with adverse events, and types of events, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).
Arm/Group Title	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
Arm/Group Description	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
All Cause Mortality
	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
	Affected / at Risk (%)	# Events
Total	1/47 (2.1%)
Serious Adverse Events
	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
	Affected / at Risk (%)	# Events
Total	17/47 (36.2%)
Blood and lymphatic system disorders
Anemia	1/47 (2.1%)	1
Gastrointestinal disorders
Abdominal Distension	1/47 (2.1%)	1
abdominal Pain	1/47 (2.1%)	1
Colonic Perforation	1/47 (2.1%)	1
ileal fistula	1/47 (2.1%)	1
pancreatitis	1/47 (2.1%)	1
General disorders
Fatigue	2/47 (4.3%)	2
gait disturbance	3/47 (6.4%)	3
general disorders and administration site conditions	1/47 (2.1%)	1
multi-organ failure	1/47 (2.1%)	1
Hepatobiliary disorders
edema Limbs	1/47 (2.1%)	1
Infections and infestations
appendicitis	1/47 (2.1%)	47
Injury, poisoning and procedural complications
fall	2/47 (4.3%)	2
fracture	1/47 (2.1%)	47
Investigations
alanine aminotransferase increased	2/47 (4.3%)	2
aspartate aminotransferase increased	1/47 (2.1%)	1
investigations-other, specify	2/47 (4.3%)	2
lipase increased	1/47 (2.1%)	1
neutrophil count decreased	1/47 (2.1%)	1
Platelet count decreased	1/47 (2.1%)	1
White blood cell decreased	1/47 (2.1%)	1
Metabolism and nutrition disorders
Alkalosis	1/47 (2.1%)	1
dehydration	1/47 (2.1%)	1
hyperglycemia	1/47 (2.1%)	1
hypokalemia	1/47 (2.1%)	1
hyponatremia	1/47 (2.1%)	1
hypophosphatemia	1/47 (2.1%)	1
Musculoskeletal and connective tissue disorders
generalized muscle weakness	4/47 (8.5%)	4
muscle weakness, right-sided	1/47 (2.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/47 (2.1%)	1
Nervous system disorders
concentration impairment	1/47 (2.1%)	1
dysphasia	2/47 (4.3%)	2
hypersomnia	1/47 (2.1%)	1
lethargy	1/47 (2.1%)	1
seizure	5/47 (10.6%)	5
somnolence	1/47 (2.1%)	1
Psychiatric disorders
confusion	3/47 (6.4%)	3
Renal and urinary disorders
hematuria	1/47 (2.1%)	1
renal calculi	1/47 (2.1%)	1
urinary incontinence	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
hypoxia	1/47 (2.1%)	1
Social circumstances
social circumstances-other, specify	1/47 (2.1%)	1
Vascular disorders
hematoma	1/47 (2.1%)	1
hypotension	1/47 (2.1%)	1
thromboembolic event	1/47 (2.1%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Sorafenib Tosylate, Valproic Acid, Sildenafil)
	Affected / at Risk (%)	# Events
Total	47/47 (100%)
Blood and lymphatic system disorders
anemia	19/47 (40.4%)	22
Cardiac disorders
atrial fibrillation	1/47 (2.1%)	1
cardiac disorders-other, specify	1/47 (2.1%)	1
sinus bradycardia	7/47 (14.9%)	8
sinus tachycardia	5/47 (10.6%)	5
Ear and labyrinth disorders
ear and labyrinth disorders-other, specify	2/47 (4.3%)	2
hearing impaired	3/47 (6.4%)	3
tinnitus	1/47 (2.1%)	1
vertigo	1/47 (2.1%)	1
Endocrine disorders
cushingoid	1/47 (2.1%)	1
endocrine disorders-other, specify	1/47 (2.1%)	1
hyperthyroidism	1/47 (2.1%)	1
Eye disorders
blurred vision	8/47 (17%)	9
eye disorders-other, specify	5/47 (10.6%)	6
eye pain	1/47 (2.1%)	1
watering eyes	1/47 (2.1%)	1
Gastrointestinal disorders
abdominal distension	2/47 (4.3%)	2
abdominal pain	8/47 (17%)	12
bloating	2/47 (4.3%)	2
constipation	7/47 (14.9%)	8
diarrhea	21/47 (44.7%)	34
dry mouth	3/47 (6.4%)	3
dyspepsia	4/47 (8.5%)	4
dysphagia	4/47 (8.5%)	4
fecal incontinence	7/47 (14.9%)	10
flatulence	3/47 (6.4%)	3
gastroesophageal reflux disease	6/47 (12.8%)	9
Gastrointestinal disorders - Other, specify	6/47 (12.8%)	7
Gastrointestinal pain	1/47 (2.1%)	3
Hemorrhoidal hemorrhage	1/47 (2.1%)	1
mucositis oral	2/47 (4.3%)	2
nausea	11/47 (23.4%)	12
oral dysesthesia	2/47 (4.3%)	2
oral hemorrhage	1/47 (2.1%)	1
toothache	1/47 (2.1%)	1
vomiting	7/47 (14.9%)	8
gait disturbance	13/47 (27.7%)	14
General disorders
edema face	1/47 (2.1%)	1
edema limbs	6/47 (12.8%)	9
fatigue	26/47 (55.3%)	34
fever	1/47 (2.1%)	1
General disorders and administration site conditions - Other, specify	3/47 (6.4%)	3
Generalized edema	1/47 (2.1%)	2
irritability	1/47 (2.1%)	1
malaise	4/47 (8.5%)	4
non-cardiac chest pain	1/47 (2.1%)	1
pain	6/47 (12.8%)	11
Immune system disorders
allergic reaction	2/47 (4.3%)	3
Infections and infestations
eye infection	1/47 (2.1%)	1
infections and infestations-other, specify	3/47 (6.4%)	3
mucosal infection	2/47 (4.3%)	2
nail infection	1/47 (2.1%)	1
otitis media	1/47 (2.1%)	1
papulopustular rash	1/47 (2.1%)	1
pharyngitis	1/47 (2.1%)	1
prostate infection	1/47 (2.1%)	1
skin infection	3/47 (6.4%)	4
soft tissue infection	1/47 (2.1%)	3
urinary tract infection	2/47 (4.3%)	2
Injury, poisoning and procedural complications
bruising	11/47 (23.4%)	16
wound complication	1/47 (2.1%)	1
wound dehiscence	1/47 (2.1%)	1
fall	12/47 (25.5%)	22
fracture	1/47 (2.1%)	2
injury, poisoning and procedural complications- other, specify	3/47 (6.4%)	3
Investigations
Activated partial thromboplastin time prolonged	2/47 (4.3%)	2
Alanine aminotransferase increased	17/47 (36.2%)	23
alkaline phosphatase increased	3/47 (6.4%)	4
aspartate aminotransferase increased	16/47 (34%)	21
blood bilirubin increased	4/47 (8.5%)	6
cholesterol high	3/47 (6.4%)	3
creatinine increased	3/47 (6.4%)	3
GGT increased	1/47 (2.1%)	1
hemoglobin increased	1/47 (2.1%)	1
investigations - other, specify	8/47 (17%)	17
lymphocyte count decreased	22/47 (46.8%)	36
neutrophil count decreased	20/47 (42.6%)	32
platelet count decreased	32/47 (68.1%)	48
weight gain	2/47 (4.3%)	4
weight loss	6/47 (12.8%)	13
white blood cell decreased	22/47 (46.8%)	36
Metabolism and nutrition disorders
anorexia	13/47 (27.7%)	16
dehydration	4/47 (8.5%)	4
glucose intolerance	1/47 (2.1%)	1
hyperglycemia	4/47 (8.5%)	5
hyperkalemia	10/47 (21.3%)	12
hypermagnesemia	4/47 (8.5%)	4
hypernatremia	3/47 (6.4%)	4
hypertriglyceridemia	2/47 (4.3%)	2
hypoalbuminemia	20/47 (42.6%)	26
hypocalcemia	26/47 (55.3%)	41
hypoglycemia	4/47 (8.5%)	7
hypokalemia	13/47 (27.7%)	28
Hypomagnesemia	7/47 (14.9%)	10
hyponatremia	14/47 (29.8%)	19
hypophosphatemia	35/47 (74.5%)	63
Metabolism and nutrition disorders - Other, specify	1/47 (2.1%)	2
Musculoskeletal and connective tissue disorders
arthralgia	2/47 (4.3%)	3
back pain	4/47 (8.5%)	7
buttock pain	1/47 (2.1%)	1
chest wall pain	1/47 (2.1%)	1
generalized muscle weakness	9/47 (19.1%)	13
joint range of motion decreased	1/47 (2.1%)	2
muscle weakness left-sided	2/47 (4.3%)	2
muscle weakness lower limb	4/47 (8.5%)	4
muscle weakness right-sided	2/47 (4.3%)	3
muscle weakness upper limb	1/47 (2.1%)	1
Musculoskeletal and connective tissue disorder - Other, specify	4/47 (8.5%)	7
myalgia	3/47 (6.4%)	3
pain in extremity	2/47 (4.3%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	2/47 (4.3%)	2
Nervous system disorders
cognitive disturbance	3/47 (6.4%)	4
concentration impairment	3/47 (6.4%)	3
depressed level of consciousness	4/47 (8.5%)	4
dizziness	5/47 (10.6%)	6
dysarthria	2/47 (4.3%)	2
dysesthesia	1/47 (2.1%)	1
dysgeusia	7/47 (14.9%)	8
dysphasia	7/47 (14.9%)	8
edema cerebral	1/47 (2.1%)	1
encephalopathy	1/47 (2.1%)	1
facial muscle weakness	1/47 (2.1%)	1
headache	12/47 (25.5%)	19
hypersomnia	2/47 (4.3%)	2
intracranial hemorrhage	3/47 (6.4%)	3
ischemia cerebrovascular	1/47 (2.1%)	2
lethargy	7/47 (14.9%)	11
memory impairment	7/47 (14.9%)	8
nervous system disorders- other, specify	8/47 (17%)	9
paresthesia	4/47 (8.5%)	4
peripheral sensory neuropathy	1/47 (2.1%)	1
presyncope	1/47 (2.1%)	1
seizure	5/47 (10.6%)	5
sinus pain	1/47 (2.1%)	1
somnolence	5/47 (10.6%)	6
spasticity	2/47 (4.3%)	2
tremor	4/47 (8.5%)	4
Psychiatric disorders
Agitation	6/47 (12.8%)	7
anxiety	5/47 (10.6%)	5
confusion	15/47 (31.9%)	18
delusions	1/47 (2.1%)	1
depression	2/47 (4.3%)	2
hallucinations	3/47 (6.4%)	3
insomnia	8/47 (17%)	9
personality change	1/47 (2.1%)	1
psychiatric disorders- other, specify	1/47 (2.1%)	1
suicidal ideation	1/47 (2.1%)	1
Renal and urinary disorders
hematuria	5/47 (10.6%)	5
proteinuria	4/47 (8.5%)	5
renal calculi	1/47 (2.1%)	1
urinary frequency	6/47 (12.8%)	7
urinary incontienence	9/47 (19.1%)	11
urinary retention	2/47 (4.3%)	2
urinary tract pain	1/47 (2.1%)	1
urinary urgency	3/47 (6.4%)	3
Reproductive system and breast disorders
genital edema	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
allergic rhinitis	1/47 (2.1%)	1
atelectasis	1/47 (2.1%)	1
cough	8/47 (17%)	8
dyspnea	6/47 (12.8%)	7
epistaxis	3/47 (6.4%)	3
hiccups	1/47 (2.1%)	1
hoarseness	5/47 (10.6%)	6
nasal congestion	3/47 (6.4%)	3
pleural effusion	2/47 (4.3%)	2
postnasal drip	1/47 (2.1%)	1
sleep apnea	1/47 (2.1%)	1
sore throat	4/47 (8.5%)	7
Skin and subcutaneous tissue disorders
alopecia	7/47 (14.9%)	8
body odor	1/47 (2.1%)	1
dry skin	8/47 (17%)	9
pain of skin	1/47 (2.1%)	1
palmar-plantar erythrodysesthesia syndrome	20/47 (42.6%)	55
pruritus	5/47 (10.6%)	5
purpura	2/47 (4.3%)	2
rash acneiform	3/47 (6.4%)	3
rash maculo-papular	17/47 (36.2%)	22
scalp pain	4/47 (8.5%)	4
skin and subcutaneous tissue disorders- other, specify	10/47 (21.3%)	24
skin ulceration	1/47 (2.1%)	1
Vascular disorders
flushing	17/47 (36.2%)	18
hematoma	1/47 (2.1%)	1
hypertension	19/47 (40.4%)	44
hypotension	3/47 (6.4%)	3
thromboembolic event	2/47 (4.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.