Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma
Phase: PHASE2
Conditions: Glioblastoma, Recurrent Adult Brain Neoplasm, Malignant Glioma, WHO Grade III Glioma
Sponsor: Virginia Commonwealth University

NCT01817751
Phase II Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High 
Grade Glioma
04/22/2021

Virginia Commonwealth University Massey Cancer Center 
Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent 
High-Grade Glioma 
MCC Protocol #: MCC-14816 (CTC-11-011) 
Principal Investigator: 
Mark Malkin, MD 
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 SCHEMA 
Recurrent or progressive high-grade 
glioma; unselected patients 
• Sorafenib 400 mg orally
twice a day;
• Valproic acid (to levels ≥
LLN) orally twice a day;
• Sildenafil 50 mg orally
twice a day.
Titrate valproic acid to level 
≥ LLN for the laboratory 
Hold after enrollment of 16 
patients for interim analysis 
to determine the number of 
patients with 6-month 
progression-free survival 
(PFS). 
If there are 4 or more 
patients with 6-month PFS: 
continue to enroll unselected 
patients and complete 
enrollment onto the study.  
If there are 3 or fewer 
patients with 6-month PFS: 
close accrual to unselected 
patients, continue study and 
enroll only patients with 
PDGFRα-positive tumors. 
Accrue to a total of 16 
evaluable patients (inclusive 
of patients with PDGFRα-
positive tumors in the first 
interim analysis) for second 
interim analysis.  
Hold after enrollment of 16 
PDGFRα-positive patients for 
interim analysis to determine the 
number of patients with 6-month 
PFS. 
If there are 4 or more 
patients with 6-month PFS: 
continue to enroll PDGFRα-
positive patients and 
complete enrollment onto 
the study.  
If there are 3 or fewer 
patients with 6-month PFS: 
close study due to failure to 
meet prespecified efficacy 
criteria in both unselected 
and selected cohort. 

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TABLE OF CONTENTS 
 SCHEMA ..................................................................................................................................... II 
 ................................................................................................................... III 
LIST OF ABBREVIATIONS ......................................................................................................... 1 
1 
BACKGROUND ............................................................................................................. 2 
1.1 
RECURRENT OR PROGRESSIVE HIGH-GRADE GLIOMA ....................................................... 2 
1.2 
SORAFENIB ...................................................................................................................... 2 
1.3 
VALPROIC ACID ................................................................................................................ 2 
1.4 
SILDENAFIL ...................................................................................................................... 3 
1.5 
SORAFENIB + VALPROIC ACID PRECLINICAL DATA ............................................................. 4 
1.6 
RATIONALE ...................................................................................................................... 6 
1.7 
CLINICAL CONSIDERATIONS .............................................................................................. 6 
1.8 
CORRELATIVE STUDIES BACKGROUND .............................................................................. 9 
1.9 
RATIONALE FOR ADAPTIVE DESIGN ................................................................................... 9 
2 
OBJECTIVES ................................................................................................................ 9 
2.1 
PRIMARY OBJECTIVE ........................................................................................................ 9 
2.2 
SECONDARY OBJECTIVES ................................................................................................. 9 
2.3 
EXPLORATORY OBJECTIVE ............................................................................................. 10 
3 
STUDY DESIGN .......................................................................................................... 10 
3.1 
GENERAL DESCRIPTION .................................................................................................. 10 
3.2 
PRIMARY ENDPOINT ....................................................................................................... 10 
3.3 
SECONDARY ENDPOINTS ................................................................................................ 10 
3.4 
EXPLORATORY ENDPOINT ............................................................................................... 11 
4 
PATIENT SELECTION ................................................................................................ 11 
4.1 
INCLUSION CRITERIA ...................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ..................................................................................................... 12 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ............................................... 14 
5.1 
REGISTRATION PROCEDURES ......................................................................................... 14 
5.2 
STUDY DISCONTINUATION PROCEDURES ......................................................................... 14 
6 
TREATMENT PLAN .................................................................................................... 15 
6.1 
BASELINE TESTS AND PROCEDURES ............................................................................... 15 
6.2 
SCHEDULE ..................................................................................................................... 15 
6.3 
RADIOGRAPHIC EVALUATIONS ......................................................................................... 16 
6.4 
TOXICITY ASSESSMENTS ................................................................................................ 16 
7 
DOSE MODIFICATIONS ............................................................................................. 17 
7.1 
SORAFENIB .................................................................................................................... 17 
7.2 
SILDENAFIL .................................................................................................................... 24 
7.3 
VALPROIC ACID .............................................................................................................. 24 
7.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................... 26 
7.5 
LABORATORY MONITORING AND CLINICAL EXAM .............................................................. 28 
7.6 
DURATION OF THERAPY .................................................................................................. 29 
7.7 
MONITORING PATIENT COMPLIANCE ................................................................................ 29 
7.8 
DURATION OF FOLLOW UP .............................................................................................. 29 

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ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .............. 30 
8.1 
DEFINITIONS................................................................................................................... 30 
8.2 
ADVERSE EVENT CHARACTERISTICS ............................................................................... 31 
8.3 
KNOWN AE LIST ............................................................................................................. 32 
8.4 
TIME PERIOD AND GRADE OF AE CAPTURE ..................................................................... 32 
8.5 
PROCEDURES FOR RECORDING AES, SAES, QUALIFYING TOXICITIES, AND UPS .............. 32 
8.6 
EXPEDITED REPORTING PROCEDURES FOR SAES, UPS, AND QUALIFYING TOXICITIES ..... 33 
9 
PHARMACEUTICAL INFORMATION ......................................................................... 33 
9.1 
SORAFENIB .................................................................................................................... 33 
9.2 
VALPROIC ACID .............................................................................................................. 42 
9.3 
SILDENAFIL .................................................................................................................... 49 
9.4 
DRUG PROCUREMENT AND ACCOUNTABILITY .................................................................. 55 
10 
MEASUREMENT OF EFFECT .................................................................................... 55 
10.1 
DEFINITIONS................................................................................................................... 55 
10.2 
RESPONSE CRITERIA ...................................................................................................... 56 
10.3 
CONSIDERATIONS FOR PATIENTS WITH MULTIFOCAL DISEASE .......................................... 57 
10.4 
TIMING OF IMAGING STUDIES .......................................................................................... 57 
11 
CORRELATIVE STUDIES ........................................................................................... 58 
11.1 
PDGFRΑ EXPRESSION IN PRIMARY TUMOR SAMPLES ..................................................... 58 
11.2 
TIMING OF SAMPLE COLLECTION AND ANALYSIS .............................................................. 58 
11.3 
COLLECTION OF SPECIMENS ........................................................................................... 59 
11.4 
HANDLING OF SPECIMENS .............................................................................................. 60 
11.5 
IMMUNOSTAINING OF SPECIMENS .................................................................................... 60 
11.6 
INTERPRETATION OF CORRELATIVE STUDY ...................................................................... 60 
11.7 
OTHER POTENTIAL PHARMACODYNAMIC MARKERS ......................................................... 60 
12 
STUDY CALENDAR .................................................................................................... 61 
13 
STATISTICAL CONSIDERATIONS ............................................................................ 64 
13.1 
STUDY DESIGN ............................................................................................................... 64 
13.2 
SAMPLE SIZE/ACCRUAL RATES ....................................................................................... 64 
13.3 
GENERAL STATISTICAL ANALYSIS .................................................................................... 65 
13.4 
ANALYSIS OF PRIMARY ENDPOINTS ................................................................................. 65 
13.5 
ANALYSIS OF SECONDARY ENDPOINTS ............................................................................ 65 
13.6 
SAFETY LEAD-IN, AND SAFETY STOPPING RULE .............................................................. 66 
13.7 
EVALUABILITY FOR QUALIFYING TOXICITY, TOXICITY, RESPONSE ..................................... 67 
14 
DATA AND SAFETY MONITORING PLAN (DSMP) .................................................. 67 
14.1 
STUDY TEAM .................................................................................................................. 67 
14.2 
MONITORING AND AUDITING ............................................................................................ 68 
15 
REGULATORY COMPLIANCE AND ETHICS ............................................................ 68 
15.1 
ETHICAL STANDARD ....................................................................................................... 68 
15.2 
REGULATORY COMPLIANCE ............................................................................................ 68 
15.3 
INFORMED CONSENT PROCESS ...................................................................................... 68 
15.4 
PATIENT CONFIDENTIALITY ............................................................................................. 69 
16 
DATA COLLECTION AND MANAGEMENT ............................................................... 69 

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16.1 
CRFS AND DATA COLLECTION ........................................................................................ 69 
16.2 
STUDY RECORD RETENTION ........................................................................................... 69 
17 
REFERENCES ............................................................................................................. 70 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ............................................................... 73 
APPENDIX 2. COCKCROFT-GAULT EQUATION .................................................................... 74 
APPENDIX 3. NYHA CLASSIFICATION OF HEART FAILURE ............................................... 75 

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LIST OF ABBREVIATIONS 
ABC 
ATP-binding cassette 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BBB 
Blood brain barrier 
BP 
Blood pressure 
CBC 
Complete blood count 
cGMP 
Cyclic guanosine monophosphate 
CrCL 
Creatinine clearance 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRL 
Clinical and Translational Research Laboratory 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group  
EGFR 
Epidermal growth factor receptor 
EIAED 
Enzyme-inducing antiepileptic drug 
GBM 
Glioblastoma 
HDAC 
Histone deacetylase 
Hgb 
Hemoglobin 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
LLN 
Lower limit of normal 
MCC 
Massey Cancer Center 
NO 
Nitric oxide 
PDE5 
Phosphodiesterase type 5 
PDGFR 
Platelet-derived growth factor receptor 
PFS 
Progression-free survival 
PI3 
Phosphoinositide 3 
PRMC 
Protocol Review and Monitoring Committee 
RANO 
Response Assessment in Neuro-Oncology 
SAE 
Serious adverse event 
UP 
Unanticipated problem 
VCU 
Virginia Commonwealth University 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell count 
WNL 
Within normal limits 
 

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1 BACKGROUND 
1.1 Recurrent or Progressive High-Grade Glioma 
High-grade gliomas are the most common malignant primary brain tumors in adults (2) and 
are associated with poor prognosis. Despite optimal therapy, nearly all high-grade gliomas 
eventually recur. The median survival following recurrence is only 25 to 30 weeks for World 
Health Organization (WHO) grade IV gliomas and 39 to 47 weeks for WHO grade III 
gliomas (3, 4). GBMs account for approximately 60% to 70% of high-grade gliomas. 
Anaplastic astrocytomas comprise 10% to 15%. Anaplastic oligodendrogliomas and 
anaplastic oligoastrocytomas combined represent 10% of high-grade gliomas. Less 
common tumors such as anaplastic ependymomas and anaplastic gangliogliomas make 
up the rest (5). 
Many targeted agents against these aberrant pathways or affecting glioma stem cell 
growth are under investigation in recurrent high-grade glioma. Bevacizumab (Avastin; 
Genentech, South San Francisco, CA), a monoclonal antibody against VEGF, has been 
studied extensively in this patient population. In a randomized, multicenter, 
noncomparative phase 2 trial, the estimated 6-month progression-free survival (PFS) rates 
for patients with recurrent GBM were 42.6% for bevacizumab alone and 50.3% for 
bevacizumab plus irinotecan (6). Additional therapies are urgently needed. 
1.2 Sorafenib 
Sorafenib is a multi-targeted protein kinase inhibitor that was originally developed as an 
inhibitor of RAF-1, a component of the ERK1/2 pathway. Sorafenib was subsequently 
shown to inhibit multiple other kinases, including class III tyrosine kinase receptors such as 
platelet-derived growth factor receptors (PDGFRs), vascular endothelial growth factor 
receptors (VEGFRs), c-Kit, and FLT3. VCU investigator Dr Paul Dent and collaborators 
have shown in vitro that sorafenib, through its effects on the PDGFRs, can activate Src 
non-receptor tyrosine kinases, and that this effect plays a role in the activation of death 
receptors resulting in tumor cell death (7, 8). Lethality of sorafenib in cancer cells is 
enhanced by concomitant histone deacetylase (HDAC) inhibitor exposure (9, 10). Cell 
death is through the extrinsic pathway of apoptosis. 
In the USA, sorafenib is approved for the treatment of differentiated thyroid carcinoma 
refractory to radioactive iodine treatment, and renal cell and hepatocellular carcinomas. 
Ongoing studies in GBM have investigated sorafenib as a single agent and in combination 
with mTOR inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and 
bevacizumab. To date, there are no studies combining sorafenib with HDAC inhibitors in 
high-grade glioma.  
1.3 Valproic Acid 
Valproic acid (sodium valproate, valproate) is an anti-seizure medication in common 
medical use, and is referred to as a non-enzyme-inducing antiepileptic drug (non-EIAED). 
It is frequently used in chemotherapy regimens due to the fact that it does not modulate the 
cytochrome p450 system; thus, valproic acid does not have many of the drug-drug 
interactions with standard chemotherapy agents that are common for other antiepileptic 
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(11). Valproic acid has been demonstrated at clinically relevant concentrations to inhibit 
class I (HDAC 1, 2, and 3, along with HDAC 8) and class II, subclass I HDACs (HDAC 4,5, 
and 7) (11).  
HDAC inhibitors are a class of drugs that inhibit the enzymes that deacetylate histones 
(12). By regulating histone acetylation, chromatin condensation is changed and the levels 
of transcription may be altered. Many other proteins, including those that are cytosolic, are 
also acetylated and it is probable that the actions of HDAC inhibitors involve both the 
regulation of gene expression (eg, FAS-ligand), as well as regulating acetylation of other 
cytosolic proteins (eg, HSP90) (13). In previously published work in GI tumor cells by Dent 
and colleagues, HDAC inhibitors were shown to increase the levels of FAS-ligand, as well 
as its receptor CD95, both of which played a role in HDAC inhibitor toxicity (7, 8). His 
group has more recently demonstrated that knockdown of CD95 protected CNS tumor 
cells from the combination of sorafenib and valproic acid (14).  
Valproic acid in combination with temozolomide and radiotherapy is currently under 
investigation in the treatment of newly diagnosed GBM. There are over 10 studies, ongoing 
or recently completed, that have evaluated HDAC inhibitors in the treatment of CNS 
tumors, none of which are combined with sorafenib.  
1.4 Sildenafil  
Sildenafil is FDA approved for the treatment of both erectile dysfunction and pulmonary 
hypertension, and has been administered to men, women, and children on a chronic daily 
basis.  
Intracellular cyclic guanosine monophosphate (cGMP) levels reflect the balance of 
synthesis by guanylate cyclases and degradation by phosphodiesterases. Nitric oxide (NO) 
activates guanylate cyclase in diverse tissues including vasculature, and cGMP is the 
second messenger that induces smooth muscle relaxation and vasodilation. Sildenafil 
increases intracellular cGMP and induces vasodilation. This activity is generally attributed 
to selective inhibition of cGMP-specific phosphodiesterase type 5 (PDE5). Sildenafil and 
PDE5 inhibitors may also have other functions that relate to anticancer therapy, specifically 
relating to blood brain barrier (BBB) interactions and drug efflux mechanisms. PDE5 
inhibitors have been shown to increase chemotherapy delivery to brain tumors in animal 
models, through increased tumor cGMP levels (15). ATP-binding cassette (ABC) proteins 
transport various molecules across extra- and intracellular membranes. Sildenafil has also 
been shown to inhibit the ABCB1 and ABCG2 drug efflux pumps, and reverse ABCB1 and 
ABCG2 mediated chemotherapeutic drug resistance (16). The ABCG2 transporter has 
recently been shown to be the dominant transporter that limits transport of sorafenib into 
the brain (17). This is clinically relevant as GBM is considered to be a diffuse disease, with 
many areas of tumor residing in areas of the brain with an intact BBB. Inhibition of the 
ABCG2 transporter with sildenafil may increase sorafenib drug concentrations in the brain, 
improving sorafenib anti-tumor efficacy.  
To date, there are no CNS tumor studies utilizing drug efflux pump modulators, like 
sildenafil, in conjunction with sorafenib.  

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1.5 Sorafenib + Valproic Acid Preclinical Data 
Dent and colleagues have tested the combination of sorafenib and HDAC inhibitors in 
multiple GBM isolates. These studies have included: GBM cells expressing mutant active 
forms of the EGFR (GBM6, EGFR vIII; GBM12, mutant active full-length EGFR), GBM 
cells lacking PTEN function (GBM14), GBM cells expressing a mutant active 
phosphoinositide 3 (PI3)-kinase and PDGFRα (GBM5), or GBM cells with low levels of 
growth factor receptors (GBM15). There appear to be differences in drug combination 
sensitivity based on the molecular phenotype of the GBM cell line. Sorafenib toxicity was 
enhanced by valproate in the GBM6 EGFR mutant variant III cells in a dose-dependent 
fashion (Figure 1). This mutation in EGFR leads to a truncated EGFR that is constitutively 
active, but does not bind ligand. GBM15 and GBM14 were both sensitive to the drug 
combination, similar to GBM6 (data not shown).  
In the following figures, valproic acid (VAL) was the HDAC inhibitor used in combination 
with sorafenib (SOR).  
Percentage cell death
0
20
40
60
80
24h
48h
GBM6
*
*
*
*
Figure 1
VEH
SOR 3
VEH
SOR 6
VAL (1)
VEH
SOR 3
SOR 6
VEH
SOR 3
SOR 6
VEH
SOR 3
SOR 6
VEH
VAL (1)
 
Figure 1. GBM6 cells were treated with vehicle or sodium valproate (1 mM). Thirty minutes later cells 
were treated with vehicle or sorafenib (3 µM; 6 µM). Cells were isolated 24 h and 48 h later. Viability was 
determined by trypan blue exclusion (n=3, +/- SEM) * p<0.05 greater than corresponding vehicle-control 
treated cells. 
GBM12 full-length EGFR mutant cells appear to be more resistant to the drug combination 
than GBM6 truncated EGFR mutant cells (Figure 2). 

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The cells that were clearly most sensitive to the sorafenib and valproic acid drug 
combination were GBM5 cells; cells that express one of the growth factor receptor targets 
of sorafenib, PDGFRα (Figure 3).  
 
Figure 3. GBM5 cells were treated with vehicle or sodium valproate (1 mM). Thirty minutes later cells 
were treated with vehicle or sorafenib (1, 2, 3, or 6 µM). Cells were isolated 24 and 48 h later. Viability 
was determined by trypan blue exclusion (n = 3, +/- SEM) * p < 0.05 greater than corresponding vehicle-
control treated cells. 
Collectively, this data suggests that the combination of sorafenib and valproic acid is worth 
investigating in GBM. It appears from the preclinical data that different molecular 
phenotypes may have different sensitivities to the drug combination, and this will be 
investigated during the study.  
Percentage cell death
0
20
40
60
80
SOR 1
SOR 2
GBM5, 24h
GBM5, 48h
*
*
*
*
Figure 3 
VEH
SOR 3
VEH
SOR 6
VAL (1)
VEH
VAL (1)
SOR 1
SOR 2
VEH
SOR 3
SOR 6
SOR 1
SOR 2
VEH
SOR 3
SOR 6
SOR 1
SOR 2
VEH
SOR 3
SOR 6
Figure 2. GBM12 cells were 
treated with vehicle or sodium 
valproate (1 mM). Thirty minutes 
later cells were treated with 
vehicle or sorafenib (3 µM; 6 µM). 
Cells were isolated 48 h later. 
Viability was determined by trypan 
blue exclusion (n=3, +/- SEM) * 
p<0.05 greater than 
corresponding vehicle control 
treated cells. 

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1.6 Rationale  
Promising single agent in vitro activities and potentially complementary mechanisms of 
action suggest that the combination of sorafenib, valproic acid, and sildenafil may have 
therapeutic potential for the treatment of 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. 
1.7 Clinical Considerations 
One dose level of sorafenib will be tested in this phase 2 study. Sorafenib will be dosed at 
the FDA approved dose of 400 mg orally twice daily, which is well established as the 
maximum tolerated dose for continuous dosing. This dose of sorafenib has been tested in 
recurrent GBM in 5 separate phase 2 studies in combination with temozolomide (18, 19), 
temsirolimus (20), erlotinib (21), and bevacizumab (22).  
In the study by Reardon et al (18), 12 patients were taking CYP3A EIAEDs, 10 patients 
were taking non-EIAEDs, and 10 patients were not taking any medication to prevent 
seizures (valproic acid is a non-EIAED). Overall, 4 patients (13%) required dose 
modification or discontinuation of sorafenib for grade 3 or 4 elevation of amylase/lipase, 
and 3 patients (9%) required dose modification or discontinuation of sorafenib for grade 3 
PPE. Only 2 of the 4 patients with elevated amylase/lipase were symptomatic and in 1 of 
those 2 patients, underlying gallstones were the likely etiology. Of note, 5 out of 10 patients 
on the non-EIAED arm who underwent pharmacokinetic sampling required sorafenib dose 
interruption or modification during cycle 1 of therapy. For patients not on EIAEDs, day-28 
sorafenib AUC 0-24 was significantly higher compared to day 1. This increase may also 
have been mildly augmented by the discontinuation of dexamethasone (a mild CYP3A 
inducer) in 3 patients. 
In the study by Zustovich et al (19), all patients (n=43) received oxcarbazepine, a hepatic 
CYP3A inducer (EIAED). Grade 3-4 toxicity was observed in 4 patients (9%) with PPE, 1 
patient (2%) with diarrhea and 1 patient (2%) with lipase elevation. It is possible that if 
these patients had been taking non-EIAEDs the toxicity ascribed to sorafenib would have 
been higher. 
In the study by Lee et al (20), patients receiving EIAEDs were excluded. In the phase 1 
component of the trial, 1/6 (17%) developed grade 3 diarrhea. In the phase 2 component of 
the trial, 1/19 patients (5%) developed grade 3 lipase elevation and 1/19 patients (5%) 
experienced grade 3 diarrhea. The frequency of these toxicities is well below the threshold 
of 35% that is proposed in the current study. 
Similarly, in the study by Peereboom et al (21), patients receiving EIAEDs were excluded. 
Grade 3 or 4 events felt to be possibly, probably or definitely related to sorafenib or 
erlotinib ranged from 2% (elevated transaminases, PPE, diarrhea) to 7% (elevated lipase) 
to 9% (fatigue). The elevations of lipase were asymptomatic. The frequency of these 
toxicities is well below the threshold of 35% that is proposed in the current study. There 
were no unexpected toxicities. 

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In the study by Galanis et al (22), 3/19 patients (16%) experienced grade 4 non-
hematologic toxicity and a 42% discontinuation rate. Fatigue (which could be ascribed to 
sorafenib and/or bevacizumab) and hypertension (due to bevacizumab) were the 2 most 
commonly observed toxicities. Decrease of the starting sorafenib dose from 200 mg twice 
daily to 200 mg daily resulted in improved treatment tolerance. 
Unfortunately, in none of these 5 studies was notable efficacy seen. Partial response rates 
of 3-12%, 6-month PFS of 0-26% and overall survival of 5.6-9.6 months were reported. It is 
our hypothesis that the addition of valproic acid with its HDAC activity, coupled with 
sildenafil with its drug efflux pump inhibitory activity, could synergistically increase the 
likelihood of GBM tumor cell kill without concomitant unacceptable sorafenib (or valproic 
acid) toxicity. 
Since the accepted and expected rate of grade 3+ toxicities of sorafenib alone is 35%, the 
safety component in this trial will focus on identifying a measurable increase in that rate of 
overall toxicities. The safety lead-in component of this study will serve to screen for an 
increase in early toxicities. The safety stopping rule will permit monitoring of both early and 
late toxicities, but practically speaking only becomes applicable if early toxicities are 
deemed not excessive. Note that grade 5 (fatal) toxicity was not seen in any of the 5 
studies cited above. 
If toxicity is observed that could be ascribed to sorafenib, then the sorafenib dose will be 
modified according to Section 7. Likewise, if toxicity is observed that could be ascribed to 
valproic acid, then the valproic acid dose will be modified according to Section 7, which 
simply follows Good Clinical Practice principles. Total and free serum valproate levels can 
be obtained on a same-day basis from the clinical laboratory to help guide the investigator 
to the appropriate dose modification. If toxicity is observed that could be ascribed to 
sildenafil, then the sildenafil dose will be modified according to Section 7. If sorafenib or 
valproic acid toxicity is observed, it is important to first modify the dose of sorafenib or 
valproic acid and maintain the sildenafil dose constant, since reducing the sildenafil dose 
may result in decreases of tumor tissue levels of both sorafenib and valproic acid, 
abrogating the therapeutic effect that this phase 2 trial is designed to achieve. If dose 
modification of sorafenib or valproic acid does not reverse drug toxicity attributable to those 
agents, then subsequent sildenafil dose reductions may also be needed to accomplish that 
goal. We believe this is a rational approach to optimize tumor cell kill while minimizing risk 
to study patients. 
The FDA recommended initial dose of valproic acid is 10-15 mg/kg per day in divided 
doses; for the purposes of this study valproic acid will generally be dosed twice daily, to 
allow for ease of administration of all 3 agents at the same time. After initiation of therapy 
at 10-15 mg/kg/day, escalation of the dose over approximately 1 week to ≥ lower limit of 
normal (LLN) will be performed. Prior research with valproic acid suggests that therapeutic 
concentrations of valproic acid can inhibit histone deacetylation (11, 23, 24). For patients 
with a seizure disorder being treated with valproic acid, serum levels should be checked 1 
week after the initial dose; therapeutic concentrations are usually in the 50-150 mcg/mL 
range. For patients who develop neurologic deterioration, valproic acid levels will be 
checked to make sure that supratherapeutic drug concentrations are not the source of the 
neurologic deterioration. 
It is generally accepted that patients with GBM and seizures should be treated with a non-
EIAED to minimize CYP3A-mediated drug interactions and, more specifically, to avoid 

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inadvertent lowering of cytotoxic drug concentrations in GBM tumor cells. Which non-
EIAED to choose is a matter of personal preference for the treating physician; there is no 
published practice parameter or “standard of care”. That said, there is a growing body of 
evidence that valproic acid is a logical first choice in this setting 1) because it is an 
effective AED and 2) because of its HDAC activity. Weller et al (25) showed that GBM 
patients receiving valproic acid appeared to derive more survival benefit from 
temozolomide/radiotherapy than patients receiving an EIAED or not receiving any AED. 
Guthrie et al (26) and Barker et al (27) came to a similar conclusion. Felix et al (28) 
corroborated this observation in 94 children with a variety of primary CNS tumors. 
Furthermore, Kerkhof et al (29) demonstrated that valproic acid monotherapy conferred 
equivalent freedom from seizures (78%) as did levetiracetam (70%) in patients with GBM. 
Therefore, we do not believe that patients in this trial will be placed at any seizure control 
disadvantage when treated with valproic acid and, indeed, may benefit from the associated 
HDAC activity directed against their tumor. 
Of note, there is a single case report describing the use of sorafenib plus valproic acid in 
an infant with a spinal GBM (30). Marked clinical and radiographic improvement was 
shown, and no side effects of the combination were observed.  
Sildenafil will be dosed at 50 mg orally twice daily, at the time of sorafenib dosing. The 
purpose of twice daily dosing is to have maximal sildenafil concentrations at the time of 
sorafenib dosing, to maximize inhibition of ABC transport system and to try to maximize 
increases in sorafenib transport across the BBB. This dosing schedule is less frequent 
than some dosing schedules used in pulmonary hypertension studies and heart failure 
studies. One study evaluating pulmonary hypertension in heart failure dosed sildenafil at 
50 mg, 3 times a day, for a period of 12 months, and did not report significant toxicities 
(31).  
There are no major overlapping toxicities relating to valproic acid, sorafenib, or sildenafil 
that suggest that the combination would be subject to higher rates of toxicity. There is a 
low incidence of diarrhea in patients treated with sorafenib that may be exacerbated with 
valproic acid; this will be monitored closely. There is an early stopping rule in place should 
there be unexpected significant toxicities from the combination. It is expected from clinical 
experience that a fraction of patients will not tolerate full dose sorafenib in the chronic 
setting, and these patients may continue therapy at reduced dose levels. 
One previously published study has evaluated sorafenib in combination with sildenafil (32). 
This study was a non-cancer study, which treated patients with pulmonary hypertension 
with sorafenib and prostanoid therapy, half of whom were also on chronic sildenafil. No 
grade 3 or 4 drug-related toxicities were reported.  
Children under the age of 18 will be excluded from study. There are no published reports 
regarding the safety of sorafenib at the fixed dose of 400 mg orally, twice a day, in the 
pediatric population, and evaluating the safety of full dose sorafenib in the pediatric 
population is beyond the scope of the study. 
In patients with progressive high-grade glioma, survival time is generally short. Six-month 
PFS will be used as the primary endpoint in the study. This endpoint has been accepted by 
the FDA as a reasonable endpoint in recurrent or progressive GBM, and a positive 6-
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1.8 Correlative Studies Background 
Molecular profiling has identified various phenotypes of GBM. It has already been shown 
that the methylation status of the MGMT promoter is an important prognostic factor in 
predicting survival with alkylating therapy (33). More recently, The Cancer Genome Atlas 
(TCGA) Network catalogued recurrent genetic abnormalities in GBM, and established the 
existence of 4 subtypes (proneural, neural, classical, and mesenchymal) (34). Aberrations 
and gene expression of EGFR, NF1, and PDGFRα/IDH1 each define classical, 
mesenchymal, and proneural, respectively. Gene signatures of normal brain cell types 
showed a strong relation between subtypes and different neural lineages. Additionally, 
response to aggressive therapy differs by subtype with greatest benefit in classical and no 
benefit in proneural (34). Given the differences in sensitivity to the combination of sorafenib 
and valproic acid in preclinical models, it will be important to characterize patient tumors, 
as this combination may be effective in one subtype of GBM but ineffective in another. 
PDGFRα is a target of sorafenib, and expression of this protein may predict drug efficacy. 
This study will evaluate PDGFRα levels in tumor specimens by immunohistochemistry 
(IHC), and correlate this sorafenib drug target to response. Consideration will be given to 
gene expression profiling at the conclusion of the study, based on responses to therapy. 
This may help to further characterize the patient population to be targeted in a phase 3 
study.  
1.9 Rationale for Adaptive Design 
All patients with recurrent or progressive high-grade glioma will be eligible for the study. 
Sorafenib is a multikinase inhibitor, with a wide variety of cellular effects. Not enough is 
known about the in vivo mechanisms of action and resistance to the drug to justify initial 
exclusion of molecular subtypes of high-grade glioma. There will be an interim analysis, 
however; at which point the decision will be made whether or not to continue with all 
subtypes of high-grade glioma, based on pre-specified efficacy criteria. If efficacy criteria 
are not met for the combined group, the study will continue with only patients who have 
PDGFRα expressing tumors, since PDGFRα is a target of sorafenib and this is the most 
promising subgroup in preclinical models. A second interim analysis will be performed 
once enough patients with PDGFRα expressing tumors have been accrued, to determine if 
the drug combination is worth pursuing in this specific patient population. 
2 OBJECTIVES 
2.1 Primary Objective 
2.1.1 Determine the efficacy of the combination of sorafenib, valproic acid, and sildenafil, 
in terms of 6-month PFS in high-grade glioma. 
2.2 Secondary Objectives 
2.2.1 Determine the efficacy of the combination of sorafenib, valproic acid, and sildenafil, 
in terms of 6-month PFS in high-grade glioma patients who are evaluable for 
response and who have tumors that express PDGFRα. 
2.2.2 Evaluate the overall response rate, based on Response Assessment in Neuro-
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who are evaluable for response (those who express PDGFRα and those who do 
not). 
2.2.3 Evaluate the overall response rate, based on RANO or Macdonald criteria, to the 
drug combination in PDGFRα expressing tumors in patients who are evaluable for 
response. 
2.2.4 Determine the efficacy of the drug combination, in terms of 12-month survival and 
median overall survival in patients who are evaluable for response (those who 
express PDGFRα and those who do not). 
2.2.5 Determine the efficacy of the drug combination, in terms of 12-month survival and 
median overall survival in high-grade glioma patients who are evaluable for 
response and who have tumors that express PDGFRα.  
2.2.6 Evaluate the safety and toxicity of the drug combination. 
 
 
 
 
  
3 STUDY DESIGN 
3.1 General 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 
(35) incorporating an interim analysis for efficacy. If efficacy endpoints are not reached, the 
trial focus will be narrowed to include only the subgroup of patients whose tumors express 
PDGFRα. The trial will continue with this cohort in a second Simon’s mini-max 2-stage 
design, with an additional interim efficacy analysis of this subgroup.  
3.2 Primary Endpoint 
Proportion of patients evaluable for response, regardless of tumor PDGFR status, 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.  
3.3 Secondary Endpoints 
3.3.1 Proportion 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.  
3.3.2 Overall response rate (CR+PR), using RANO or Macdonald criteria, in patients 
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3.3.3 Overall response rate (CR+PR), using RANO or Macdonald criteria, in patients who 
are evaluable for response and who have tumors that express PDGFRα. 
3.3.4 Proportion 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. OS 
defined as the time from the first day a patient receives study treatment until death 
by any cause. 
3.3.5 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. OS 
defined as the time from the first day a patient receives study treatment until death 
by any cause. 
3.3.6 AEs using NCI Common Terminology Criteria for Adverse Events, Version 4.0 
(CTCAE v4.0). 
 
 
 
 
. 
4 PATIENT SELECTION 
4.1 Inclusion Criteria  
A patient must meet all of the following inclusion criteria to be eligible to participate in the 
study: 
4.1.1 Pathologically confirmed high-grade glioma (WHO grade 3 or 4), with documented 
CT or MRI progression or recurrence. Biopsy is also an acceptable method of 
confirming progression. 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 PDGFRα-positive tumors), patients will be pre-
registered for PDGFRα analysis and registered to the combination treatment 
schema only if PDGFRα-positive and all other enrollment criteria are met. 
4.1.2 Measurable or evaluable disease by RANO (MRI) or Macdonald (CT) criteria (see 
Section 10.2). 
4.1.3 Fixed or decreasing dose of corticosteroids (or no corticosteroids) for at least 1 
week prior to cycle 1 day 1. 
4.1.4 Age ≥ 18 years. 
4.1.5 At least 12 weeks since the completion of radiation therapy to a total of ≥ 50 Gy.  

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4.1.6 ECOG performance status of 0, 1, or 2 (Appendix 1). 
4.1.7 Clinical laboratory parameters: 
• 
WBC ≥ 3,000/mm3 
• 
ANC ≥ 1,500/mm3 
• 
Platelets ≥ 100,000/mm3 
• 
Hgb ≥ 8.5 g/dL 
• 
AST, 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 the standard 
Cockcroft-Gault equation (Appendix 2) 
4.1.8 Women of childbearing potential must have a negative serum pregnancy test 
performed within 7 days prior to the start of treatment.  
4.1.9 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. 
4.1.10 Ability to understand and the willingness to sign a written informed consent 
document. 
4.2 Exclusion Criteria 
A patient who meets any of the following exclusion criteria is ineligible to participate in the 
study: 
4.2.1 Investigational agent within 4 weeks of first dose of study treatment. 
4.2.2 Prior bevacizumab or tyrosine-kinase inhibitor.  
4.2.3 History of allergic reactions or intolerance to any of the required agents on the 
study. 
4.2.4 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). See Section 6.2.7 for details on valproic acid titration prior to initiation of 
study therapy. 
4.2.5 Seizure disorder necessitating the use of 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.  
4.2.6 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 (CTCAE v4.0) within 4 weeks 
or less prior to first dose of study treatment. 

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• 
Radiological evidence of any intracranial hemorrhage within the 4 weeks or 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. 
4.2.7 Major surgery within 2 weeks of the start of study treatment, or ongoing 
complications from surgeries performed previously.  
4.2.8 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 (Appendix 3), ventricular arrhythmias 
requiring anti-arrhythmic therapy, recent (within 6 months) myocardial infarction or 
unstable coronary artery disease. 
4.2.9 Systolic blood pressure (BP) > 160 mm Hg or diastolic pressure > 100 mm Hg 
despite optimal medical management. 
4.2.10 History of priapism. 
4.2.11 Known history of retinitis pigmentosa. 
4.2.12 Known mitochondrial disorder caused by mutations in mitochondrial DNA 
polymerase γ. 
4.2.13 Arterial thromboembolic or embolic events such as myocardial infarction, 
cerebrovascular accident, including transient ischemic attacks within 6 months prior 
to first study treatment. 
4.2.14 Serious uncontrolled infection > grade 2 (CTCAE v4.0).  
4.2.15 Known HIV positivity. 
4.2.16 Unable to swallow medication or suspected malabsorption. 
4.2.17 Patients on chronic nitrate therapy or alpha-blockers. 
4.2.18 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: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm093664.htm 
4.2.19 Women who are pregnant or nursing. 
4.2.20 Persistent heart rate (HR) < 50 or > 120 beats per minute (bpm). 
4.2.21 QTc > 480 ms (grade 2 or greater) on screening ECG*. 

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* 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 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. 
4.2.22 Other condition(s) that in the opinion of the investigator might compromise the 
objectives of the study. 
5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Registration Procedures 
To register a patient, the study team will provide the following to the registrar at VCU 
Massey Cancer Center 
  
• 
Registration cover sheet  
• 
Completed eligibility checklist  
• 
Signed & dated informed consent form  
The registrar will complete the registration process by assigning a study ID number and 
forwarding the “Confirmation of Registration” form to the registering study team.  
No patient may begin study treatment until the Confirmation of Registration assigning a 
study ID number has been received from the registrar. The registering study team will 
enter into the OnCore database the patient’s initial enrollment data (demographics, 
consent, eligibility, on study, treatment assignment) within 24 hours of registration and 
before treatment begins. 
5.2 Study Discontinuation Procedures 
5.2.1 A patient may decide to withdraw from study participation at any time. 
5.2.2 Patients will be removed from study treatment and enter into the follow-up phase 
when any of the criteria listed in Section 7.6 “Duration of Therapy” applies.  
5.2.3 A patient may be removed from the study follow-up phase and be taken off study for 
any of the following reasons: 
• 
Investigator determination that discontinuation is in a patient’s best medical 
interest  
• 
Withdrawal of support of study sponsor 

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5.2.4 The reason for study removal and the date the patient was removed must be 
documented in the source documents and the OnCore case report forms (CRFs). 
6 TREATMENT PLAN 
6.1 Baseline Tests and Procedures 
Refer to Section 12, Study Calendar, for the screening tests and procedures that are 
required prior to treatment and/or registration, and for the timing of these events relative to 
the start of combination treatment. 
6.2 Schedule 
The treatment schedule is combined sorafenib, valproic acid, and sildenafil, administered 
orally, twice daily continuously. A cycle consists of 4 weeks. The first cycle begins once 
therapy begins with all 3 agents—after, if necessary, titration of valproic acid dosage, 
described in Section 6.2.7. Titration of valproic acid may occur as a matter of clinical 
preference, prior to study enrollment. 
Study drug therapy is taken on an empty stomach, that is, at least 1 hour before or 2 hours 
after eating, due to absorption characteristics of sorafenib.  
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) 
and patients will undergo weekly evaluations for qualifying toxicities (Section 6.4.2) during 
the first 4 weeks of combination therapy.  
6.2.1 Initiation of sorafenib and sildenafil will not take place until valproic acid levels are ≥ 
LLN for the laboratory, which generally takes 5-7 days after initiation.  
6.2.2 Valproic acid will be administered orally, generally twice daily. The tablets or 
capsules should be swallowed without chewing to avoid local irritation of the mouth 
and throat. Patients who experience gastrointestinal irritation may benefit from 
administration of the drug with food or by slowly building up the dose from an initial 
low level. 
6.2.3 If a patient is already on valproic acid and blood levels are ≥ LLN for the laboratory, 
no further titration is necessary. 
6.2.4 If a patient presents for evaluation for this study and are at risk for seizures, the 
patient may be started on valproic acid. 
6.2.5 If a patient is already on non-valproic acid antiepileptic therapy, they may be 
transitioned to valproic acid, as a matter of clinical preference, prior to enrollment to 
obtain levels ≥ LLN for the laboratory prior to discontinuing the original antiepileptic 
therapy.  
6.2.6 Patients with disease recurrence require routine maintenance on antiepileptic 
therapy. If a patient presents for study evaluation before initiation of antiepileptic 

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medication, patient may start valproic acid titration to ≥ LLN for the laboratory as a 
matter of clinical care.  
6.2.7 Valproic acid titration: Titration to levels ≥ LLN for the laboratory generally takes 5-7 
days. The FDA recommends that valproic acid doses start at 10-15 mg/kg/day. If a 
patient is already on a stable dose of valproic acid, the drug does not need to be 
titrated unless the dose is less than the LLN. 
6.2.8 Sorafenib is dosed at 400 mg orally, twice daily, continuously. Subsequent dose 
modifications are allowed based on toxicity assessment. 
6.2.9 Sildenafil is dosed at 50 mg orally, twice daily, continuously. Subsequent dose 
modifications are allowed based on toxicity assessment. 
6.3 Radiographic Evaluations 
6.3.1 MRI of the brain obtained within 3 weeks prior to entry into the protocol can be used 
as baseline staging evaluation. In the event that MRI scans cannot be performed, 
contrast-enhanced CT scans can be used. If scans were obtained from another 
institution, copies should be obtained and maintained in the research files.  
6.3.2 A reasonable dose of corticosteroids will be determined on clinical grounds for each 
patient. An effort will be made to keep the patient on this steroid dose for at least 5 
days prior to the next MRI or contrast-enhanced CT scan. If it is not possible to keep 
the steroid dose constant for 5 days then the MRI scan will be delayed until the dose 
has been stable for 5 days.  
6.4 Toxicity Assessments 
6.4.1 Toxicity Grading 
Adverse events (AEs) will be characterized and graded according to NCI CTCAE 
version 4.0. See Section 8. 
6.4.2 Qualifying Toxicities for the Safety Lead-In and Safety Stopping Rule 
Qualifying toxicities for the safety lead-in are evaluated weekly during the first 4 
weeks of combination treatment for each of the first 6 patients deemed evaluable for 
qualifying toxicity for the safety lead-in (see Section 10.1). 
Qualifying toxicities for the safety stopping rule are evaluated regularly during the 
first 4-week cycle of combination treatment for patients deemed evaluable for the 
early stopping rule (see Section 10.1). 
Qualifying toxicities are defined as any of the following that are possibly, probably, 
or definitely related to drug therapy: 
Any grade ≥ 3 toxicity, except the following: 
• 
nausea, vomiting, or diarrhea in the absence of adequate prophylaxis and/or 
responsive to medical management 
• 
grade 3 thromboembolic event 

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• 
grade 3 hyperglycemia 
• 
grade 3 PPE (hand-foot syndrome) 
• 
fatigue responsive to medical management 
• 
grade 3 hypertension 
• 
electrolyte abnormalities that, once corrected, can be maintained with oral 
repletion 
• 
grade 3 anemia, platelets, neutrophils, WBC, lymphocytes, febrile neutropenia 
6.4.3 See Section 8.5 for AE and qualifying toxicity reporting procedures. 
7 DOSE MODIFICATIONS 
If the toxicity is not covered in Table 1, Table 2, Table 3, or Table 4, use the following 
general guidelines: 
• 
Option to modify for grade ≥ 1 toxicity 
• 
Recommendation to consider modification for grade ≥ 2 non-hematologic toxicity, 
other than PPE (see sorafenib dose-modification guidelines below) 
• 
Requirement to modify for grade ≥ 3 non-hematologic toxicity 
• 
Requirement to modify for grade 4 toxicity 
Study treatment modification consists of dose omission and/or schedule adjustment of 1 or 
more agents as clinically appropriate and as described below. In general, agent(s) should be 
omitted pending resolution of toxicity to ≤ grade 1 and then resumed at the same or a lower 
dose or frequency.  
Should the occasion arise that one or more of the study agents need to be discontinued due 
to dose modification requirements, patients may continue on study at investigator discretion, 
taking single- or dual-agent study drug treatment, with the following exception: if both 
valproic acid and sorafenib must be permanently stopped, study treatment will be 
discontinued. 
Patients are not required to be removed from study treatment for a qualifying toxicity 
(Section 6.4.2). Removal from the study treatment for safety reasons may be considered at 
the treating physician’s discretion, based on the severity/type of toxicity. 
7.1 Sorafenib 
Sorafenib dose reductions (to be followed decrementally in this order):  
• 
400 mg twice daily  
• 
400 mg daily  
• 
200 mg daily  
• 
200 mg twice daily dosed every other day 
• 
If cannot tolerate lowest sorafenib dose, discontinue sorafenib 

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If toxicities leading to modification resolve to ≤ grade 1, the sorafenib dose may be 
escalated in increments of 200 mg per day after cycle 1 but not beyond a patient’s 
enrollment dose. 
7.1.1 Sorafenib Dose Modifications 
Table 1. Sorafenib Dose Modifications 
Toxicity 
Sorafenib Modification 
Cardiac 
Grade ≥2 acute coronary 
syndrome (myocardial 
ischemia) or Grade ≥2 
myocardial infarction 
Discontinue sorafenib permanently. 
Heart failure 
Grade 3 
• Interrupt until ≤ grade 1; upon resumption, decrease by 1 dose 
level. 
• If no recovery after 30 day interruption, discontinue sorafenib 
permanently unless patient is deriving clinical benefit; confer 
with PI. 
Grade 4 
Discontinue sorafenib permanently. 
Skin and Subcutaneous Disorders 
Palmar-plantar 
erythrodysesthesia 
syndrome (PPE) (hand-foot 
syndrome) 
See Table 2 ‘Sorafenib Dose Reduction Guidelines for PPE 
(Hand-Foot Syndrome).’ 
Grade 2 rash acneiform 
At investigator’s discretion, consider holding and/or reducing 
sorafenib to the next lower dose. 
Grade 3 or grade 4  
rash acneiform 
Hold sorafenib. 
• Re-evaluate at least weekly until resolution to ≤ grade 1 or 
tolerable grade 2. 
• Re-start sorafenib at one dose reduction. 
• If toxicity persists > 14 days, discontinue sorafenib. 
• Patients with grade 4 acneiform rash related to sorafenib may 
be taken off sorafenib at investigator’s discretion. 
Stevens-Johnson syndrome 
or toxic epidermal 
necrolysis 
Discontinue sorafenib if Stevens-Johnson Syndrome or toxic 
epidermal necrolysis are suspected. 
Gastrointestinal Disorders 
Perforation (esophageal, 
gastric, colonic, duodenal, 
ileal, jejunal, rectal, or small 
intestine) 
Discontinue sorafenib permanently.  

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Investigations 
Grade ≥ 3 ALT increase in 
the absence of another 
cause 
or 
 
AST or ALT >3x ULN with 
bilirubin >2xULN in the 
absence of another cause; 
 
or 
 
Grade ≥ 1 Alkaline 
phosphatase in the 
absence of known bone 
pathology with grade ≥ 
grade 2 bilirubin increase; 
 
or  
 
any 1 of the following 
INR ≥ 1.5, ascites and/or 
encephalopathy in the 
absence of underlying 
cirrhosis or other organ 
failure related to drug-
induced liver injury 
 
Discontinue sorafenib permanently. 
 
Lab abnormalities - not 
clinically significant 
 
Note: For clinically 
significant lab abnormalities 
follow the dose modification 
guidelines for “All Other 
Non-Hematologic  
Toxicities.” 
Continue sorafenib and institute supportive measures. At 
investigator’s discretion, consider holding and/or reducing 
sorafenib to the next lower dose. 

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Grade 3 electrocardiogram 
QT corrected interval 
prolonged  
See also Section 7.4.8 
Hold sorafenib  
• Check and immediately administer potassium to achieve 
levels of ≥ 4 and magnesium to levels of ≥ 2. 
• Consider chronic oral supplementation of potassium and/or 
magnesium.  
• Review with principal investigator prior to patient’s next 
scheduled treatment, considering the following options: 
o 
STOP sorafenib until QTc recovers to pre-study 
treatment baseline (grade 1 or less, or ≤ 480ms). 
o 
When QTc returns to baseline, reinitiate 
sorafenib cautiously, with additional QTc 
monitoring at earliest possible follow-up 
opportunity, but no more than 8 days from 
reintroduction of sorafenib. 
o 
If QTc prolongation event felt attributable to 
sorafenib, reduce sorafenib to the next lower 
dose. 
• For recurrent QTc grade 3 felt attributable to sorafenib despite 
dose reduction, consider permanent discontinuation of 
sorafenib. 
Grade 4 electrocardiogram 
QT corrected interval 
prolonged  
Discontinue sorafenib. Do not restart. 
Nervous System Disorders (potentially reflective of cardio-toxicity) 
Grade 2 pre-syncope or 
grade 3 syncope 
See also Section 7.4.8 
• 
Obtain ECG for cardiology review/consultation. 
• 
Check and immediately administer potassium to achieve 
level of ≥ 4 and magnesium to level ≥ 2. 
• 
If ECG shows new dysrhythmia or QTc ≥ grade 2 (> 480ms), 
hospitalize for monitoring with Cardiology consultation.   
• 
STOP sorafenib until any potassium and magnesium 
abnormalities are corrected, symptoms resolved and QTc 
returns to grade 1 or less (≤ 480ms). 
• 
Reintroduce sorafenib cautiously, with input from Cardiology 
and with additional QTc evaluation, either concurrent with 
reintroduction or at earliest possible follow-up opportunity 
and no more than 8 days from reintroduction. 
• 
If event felt attributable to sorafenib, reduce sorafenib to the 
next lower dose. 
• 
Consider chronic oral supplementation of potassium and/or 
magnesium. 
• 
For recurrent syncope or near-syncope felt attributable to 
sorafenib, consider permanent discontinuation of sorafenib. 
Vascular Disorders 
Hypertension 
See Table 3 ‘Management of Hypertension.’ 
All Other Non-Hematologic Toxicities 
Grade ≥2 hemorrhage 
(requiring medical 
intervention) 
Discontinue sorafenib permanently. 

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Any grade 2 non-
hematologic toxicity that is 
persistent, intolerable, or 
unresponsive to optimal 
management 
At the treating investigator’s discretion, consider holding or 
continuing treatment at 1 dose reduction. 
Grade 3  
1st occurrence: 
• 
Hold sorafenib until resolution to ≤ grade 2 or baseline. 
• 
When resuming sorafenib, decrease the sorafenib dose 
by one dose reduction. 
• 
 If toxicity persists >14 days of treatment delay, 
discontinue sorafenib. 
No improvement within 7 days; or 2nd or 3rd occurrence: 
• 
Hold sorafenib until resolution to ≤ grade 2 or baseline. 
• 
When resuming sorafenib, decrease the sorafenib dose 
by 2 dose reductions. 
• 
 If toxicity persists >14 days of treatment delay, 
discontinue sorafenib 
4th occurrence: 
• 
Hold sorafenib until resolution to ≤ grade 2 or baseline. 
• 
When resuming sorafenib, decrease the sorafenib dose 
by 3 dose reductions. 
• 
 If toxicity persists >14 days of treatment delay, 
discontinue sorafenib 
Grade 4 
Discontinue sorafenib permanently. 

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7.1.2 Sorafenib Dose Modification Guidelines and Management for PPE (Hand-Foot 
Syndrome)  
Table 2. Sorafenib Dose Reduction Guidelines for PPE 
Grade 
Occurrence 
Action 
Grade 1 
1st occurrence or 
recurrence 
Continue sorafenib and institute 
supportive measures for 
symptomatic relief.* 
Grade 2: Moderate and painful 
skin changes of hands and/or 
feet such as peeling, blisters, 
bleeding, hyperkeratosis, 
erythema, swelling; and/or any 
such changes that are limiting 
instrumental activities of daily 
living (preparing meals, 
shopping for groceries, using the 
telephone, managing money, 
etc). 
1st  occurrence 
Decrease sorafenib dose by one 
dose level and institute or continue 
supportive measures for 
symptomatic relief.*  
 
If no improvement within 7 days, see 
below. 
No improvement 
within 7 days  
Stop sorafenib treatment until toxicity 
resolves to grade 0-1. When 
resuming treatment, continue at 
ongoing dose reduction.  
Institute or continue supportive 
measures for symptomatic relief.* 
Recurrence beyond 
1st occurrence 
Stop sorafenib treatment until toxicity 
resolves to grade 0-1. When 
resuming treatment, decrease 
sorafenib by 1 dose level.  
Institute or continue supportive 
measures for symptomatic relief.* 
Grade 3: Severe and painful skin 
changes of the hands and/or 
feet, such as moist 
desquamation, ulceration, 
blistering, bleeding, 
hyperkeratosis, erythema, 
swelling; and/or any such severe 
changes or pain that are limiting 
self-care activities of daily living 
(bathing, dressing, feeding self, 
using toilet, taking medications 
or becoming bedridden). 
1st or 2nd occurrence  
Stop sorafenib treatment until toxicity 
resolves to grade 0-1. When 
resuming treatment, decrease 
sorafenib by one dose level. 
Institute or continue supportive 
measures for symptomatic relief.* 
3rd occurrence 
Discontinue sorafenib treatment. 
*See also Section 7.4.7. 
7.1.3 Sorafenib Dose Modification Guidelines and Management for Hypertension 
The management of hypertension related to sorafenib, including the choice of 
antihypertensive medication, will be performed according to the treating physician’s 
usual practice. 
Every effort should be made to control BP by medical means other than sorafenib 
dose modification. If necessary, follow the sorafenib dose reduction instructions in 
Table 3. 

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Table 3. Management of Hypertension Related to Sorafenib 
Grade 
Antihypertensive Therapy 
Sorafenib Dosing 
Grade 1 
Prehypertension 
Systolic BP 120-139 mmHg 
or  
Diastolic BP 80-89 mmHg 
None 
• Continue sorafenib 
• Consider increasing BP 
monitoring 
Grade 2 
Asymptomatic and diastolic 
BP 90-99 mmHg 
Treat with the aim to 
achieve diastolic BP < 90 
mmHg 
• If BP previously WNL, 
start antihypertensive 
• If patient is already on 
antihypertensive 
medication, increase the 
dose 
Continue sorafenib and 
increase BP monitoring 
Grade 2 
Symptomatic or persistent 
 
or 
 
Grade 2  
Symptomatic increase in 
diastolic BP by > 20 mmHg 
(diastolic) or > 140/90 
mmHg if previously within 
normal limits 
 
or 
 
Grade 3 
Systolic BP ≥ 160 mmHg 
or 
Diastolic BP ≥ 100 mmHg 
or 
More than one 
antihypertensive medication 
or indication for more 
intensive therapy than 
previously used 
Treat with the aim to 
achieve diastolic BP < 90 
mmHg 
Start antihypertensive 
medication 
and/or 
Increase current 
antihypertensive medication 
and/or 
Add additional hypertensive 
medications 
• Omit sorafenib until 
diastolic BP ≤ 90 mmHg, 
and if symptomatic, until 
symptoms resolve 
• When sorafenib is 
restarted, resume at 1 
dose reduction step 
Grade 4 
Life-threatening 
consequences (eg, 
malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per treating physician 
Discontinue sorafenib 
permanently. 
* If BP remains controlled for at least one cycle, dose escalation, up to the enrolled dose 
level, is permitted at the investigator’s discretion. 

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7.2 Sildenafil 
Sildenafil dose reductions (to be followed decrementally in this order): 
• 
50 mg twice daily 
• 
25 mg twice daily 
• 
25 mg once daily  
• 
If cannot tolerate lowest sildenafil dose, discontinue sildenafil 
Sildenafil may be omitted for short periods at the treating physician’s discretion, if it is 
believed that sildenafil is contributing to excess toxicity. If toxicities resolve to ≤ grade 1, 
the sildenafil dose may be escalated at the treating physician’s discretion but not beyond a 
patient’s enrollment dose. 
The following toxicities require immediate discontinuation of sildenafil therapy: 
• 
Prolonged erection for more than 4 hours 
• 
Sudden loss of vision in one or both eyes 
• 
Sudden decrease or loss of hearing 
7.3 Valproic Acid 
If toxicity is observed that is thought to be due to valproic acid then serum valproate levels 
should be obtained. If supratherapeutic valproate levels are observed (as described in 
Section 1.7) temporary interruption of valproate may be indicated until toxicity resolves to 
grade 1 or less. Upon resolution of toxicity, a repeat serum valproate level should be 
obtained. Resumption of valproic acid at a reduced dose to achieve a lower serum 
valproate level should be considered. In the setting of hypoalbuminemia, the serum 
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Table 4. Vaproic Acid Dose Modifications 
Toxicity 
Valproic Acid Modification 
General Disorders: Hypothermia 
Lethargy, confusion, coma, 
significant alterations in major 
organ systems (cardiovascular 
and respiratory) may signal 
hypothermia 
Consider holding valproic acid while evaluating serum 
valproic acid levels. Blood ammonia level may be evaluated 
at investigator discretion.  
Grade 2 or greater hypothermia 
Consider discontinuing valproic acid. Discuss with principal 
investigator.  
Investigations: Other – Hyperammonemia 
Symptomatic elevated 
ammonia level. Ammonia 
measured only as clinically 
indicated for clinical findings of 
unexplained lethargy, vomiting 
or changes in mental status. 
Consider holding valproic acid while measuring serum 
valproic acid and ammonia levels. Consider evaluation for 
underlying urea cycle disorder and discontinuing valproic acid 
for elevated ammonia level. Discuss with principal 
investigator.  
If liver toxicity is suspected: 
• 
Discontinue valproic acid 
• 
Consider supplementation with L-carnitine 
Investigations: Hepatotoxicity 
Grade 3 or grade 4  
AST or ALT increase 
Consider holding valproic acid while under evaluation to rule 
out hepatic dysfunction.   
Consider liver ultrasound, hepatology consult, tests of hepatic 
function (such as bilirubin, INR, GGT, ammonia). 
Consider supplementation with L-carnitine. 
If no alternative explanation for transaminitis can be 
determined (such as viral hepatitis, progressive underlying 
malignancy), discontinue valproic acid. 
Gastrointestinal Disorders 
Abdominal pain, nausea, 
vomiting and/or anorexia that 
are not attributable to other 
causes can signal pancreatitis 
and require prompt medical 
evaluation 
Consider holding valproic acid while under evaluation and 
ruling out pancreatitis. 
Pancreatitis 
Discontinue valproic acid.  
 
Note: Elevations in lipase are very common in patients taking 
sorafenib. A diagnosis of pancreatitis should not be made 
solely based on abnormal laboratory values. 
Valproic acid should be immediately discontinued in the presence of significant hepatic 
dysfunction, suspected or apparent. 
Patients should be monitored for the emergence or worsening of depression, suicidal 
thoughts or behavior, and/or unusual changes in mood or behavior. 
Significant bleeding or coagulopathy is an indication for reduction of the dosage or 
discontinuation of valproic acid. 

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7.4 General Concomitant Medication and Supportive Care Guidelines 
(see also Section 9) 
7.4.1 Fluids should be administered as indicated to prevent/treat dehydration. Maintain 
appropriate electrolyte balance including correction of hypokalemia and 
hypomagnesemia, and hypophosphatemia, if possible, prior to and during study 
treatment. In those patients who demonstrate electrolyte abnormalities, oral 
supplementation should be considered as a standard supportive measure to keep 
magnesium levels at ≥ LLN for the laboratory, potassium levels at ≥ LLN for the 
laboratory, and phosphorus levels at or above 2.4 mg/dL. 
7.4.2 Clinically significant diarrhea should be managed aggressively to prevent electrolyte 
abnormalities and dehydration.  
7.4.3 Concurrent administration of other anti-neoplastic agents with the study combination 
regimen is prohibited. 
7.4.4 Concurrent administration of organic nitrates or alpha-blockers with the study 
combination regimen is prohibited. 
7.4.5 Cautionary statements about other concurrent medications: 
Addition of any STRONG CYP inhibitors and/or inducers per examples on the FDA 
website 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/D
rugInteractionsLabeling/ucm093664.htm) during study participation should prompt 
treating investigator awareness of possible interactions. Specifically: 
• Caution should be observed if sorafenib is to be coadministered with CYP3A4 
inducers such as rifampin, rifampicin, St. John’s wort, phenytoin, carbamazepine, 
phenobarbital, and dexamethasone (for reference see 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources
/DrugInteractionsLabeling/ucm093664.htm) may increase metabolism of 
sorafenib, decreasing sorafenib plasma concentrations 
• Caution should be observed if sildenafil is to be coadministered with CYP3A4 or 
CYP2C9 inhibitors (for reference see 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources
/DrugInteractionsLabeling/ucm093664.htm) 
7.4.6 Caution should be observed if valproic acid is to be coadministered with any of 
the following: aspirin, carbapenem antibiotics (ertapenem, imipenem, 
meropenem), rifampin. 
7.4.7 PPE (hand-foot syndrome)  
Biopsy specimens of patients with PPE secondary to tyrosine kinase inhibition show 
hyperkeratosis, keratinocyte necrosis, and dermal inflammation. Recommended 
management strategies for skin toxicities consistent with PPE are summarized in 
the following sections: 

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7.4.7.1 PPE Prevention 
• Before initiating treatment with sorafenib, check the condition of the 
patient’s hands and feet. Suggest a manicure/pedicure, when indicated. 
Recommend use of a pumice stone for callus or rough spot removal. 
During sorafenib treatment, instruct patients to avoid pressure points 
and items that rub, pinch, or create friction. 
• Instruct the patient to apply moisturizing lotions to their hands and feet 
twice a day throughout treatment. 
7.4.7.2 PPE Treatment 
• Treatment may begin at the first clinical signs of PPE. At first 
occurrence, independent of grade, supportive measures should be 
promptly initiated.  
• Tender areas should be protected as follows: 
- 
Use socks/gloves to cover moisturizing creams 
- 
Wear well-padded footwear; use insole cushions or inserts. 
- 
Foot soaks with tepid water and Epson salts. 
• Creams may be used as follows: 
- 
Non-urea based creams may be applied liberally. 
- 
Keratolytic creams (eg, urea-based creams 10%, salicylic acid 6%) 
may be used on affected (hyperkeratotic) areas 3 times per day. 
- 
Alpha hydroxyl acids (AHA)-based creams may be applied liberally 
2 times a day. Approximately 5% to 8% provides gentle chemical 
exfoliation. 
- 
Topical analgesics (eg, lidocaine 2%) may be used for pain control. 
- 
Topical corticosteroids like clobetasol 0.05% should be considered 
for patients with grade 2 or 3 PPE. Systemic steroids should be 
avoided. 
Use of Celecoxib  
A meta-analysis of PPE prevention strategies concluded that celecoxib, 
with statistically significant results, was the most promising agent (1). 
Therefore, celecoxib is recommended to reduce the severity of 
sorafenib-related PPE as follows: 
- 
Celecoxib 200 mg once daily should begin at the first clinical signs 
or symptoms of grade 2 PPE. 
Guidelines for sorafenib dosing modifications are listed in Section 7. 

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7.4.8 QT Prolongation Considerations  
7.4.8.1 ECGs will be evaluated for QTc prolongation prior to next scheduled 
treatment 
7.4.8.2 Any time QTc is evaluated during the course of the study:  
• 
When HR is between 60-100 bpm, no manual read of QT required 
• 
When HR < 60 or > 100 bpm, manual read of QT by cardiologist is 
required, using Fridericia correction  
Any questions or concerns about ECG readings will be reviewed with a 
cardiologist. 
7.4.8.3 To the extent possible, concurrent use of drugs known to cause 
clinically significant QT prolongation should be avoided. Such drugs 
may be identified at the Credible Meds website 
(http://crediblemeds.org/login). The Credible Meds website requires free 
user registration to view the list of clinically relevant QT prolonging 
drugs, eg, those known to carry a risk of causing Torsades de Pointes 
(TdP). QT prolonging drugs to be avoided during this trial are shown in 
the Credible Meds list of “drugs with known TdP risk.”  
7.4.8.4 When concurrent use of sorafenib and any drug on the Credible Meds 
list of “drugs with known TdP risk” cannot be avoided, review QTc prior 
to concurrent use. If pre-concuurent use QTc is: 
• 
grade 0 (< 450 ms), follow-up QTc evaluation should be done at the 
next scheduled follow-up visit. 
• 
grade 1 ( 450-480 ms), follow-up QTc evaluation should be done 
within 8 days after concurrent use starts. 
• 
grade 2 (481-500 ms), withhold sorafenib until follow-up ECG at 
next possible opportunity shows QTc grade 1 or less (≤ 480 ms); 
evaluate QTc within 8 days after reintroduction of sorafenib. 
7.4.8.5 Any new onset of dysrhythmia on ECG during study treatment phase will 
be reviewed and managed with input from cardiology. 
7.4.8.6 For any episode of syncope (grade 3) or near syncope (pre-syncope 
grade 2) or QTc grade 3 or greater (> 500 ms on 2 ECGs), see Section 
7.1.1. 
7.5 Laboratory Monitoring and Clinical Exam 
Patients in the safety lead-in cohort (for qualifying toxicity assessment) will be seen weekly 
for the first 4 weeks of combination study therapy, then every 2 weeks for the next 4 
weeks, and then monthly. Visits for subsequently enrolled patients are required every 2 
weeks for the first 8 weeks, then monthly. Assessments to be done at each visit are as 
shown in the Study Calendar. Serum valproic acid levels will be monitored every 2 weeks, 
or more frequently as clinically indicated through the end of cycle 2. After cycle 2 they will 
be checked as clinically indicated. Determination of steroid dose will be made at least 

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every 2 weeks (weekly in the safety lead-in cohort) and steroid dose may be tapered at the 
treating physician’s discretion if the patient demonstrates a stable to improved neurologic 
exam. 
In the event that a patient complains of abdominal pain, serum amylase and lipase will also 
be checked. Severe abdominal pain warrants a CT scan of the abdomen to rule out 
visceral perforation and pancreatitis.  
7.6 Duration of Therapy 
A cycle is defined as 4 weeks. Treatment will continue for the duration of response or 
stable disease. 
Study treatment continues until one of the following: 
• 
Investigator determination that discontinuation is in a patient’s best medical 
interest  
• 
Progression 
• 
Withdrawal of support of study sponsor 
The reason for study treatment discontinuation and the date treatment was discontinued 
must be documented in the OnCore CRF. 
7.7 Monitoring Patient Compliance 
A drug diary will be provided to each patient to use to track study drug administration. The 
diary will be reviewed by the study team periodically (see Study Calendar). Patient reports 
of self-administration, review of medication diary and pill counts will be used to assess 
study medication compliance. Concurrent medication assessments will be used to capture 
corticosteroid use and supportive care medications. 
7.8 Duration of Follow Up 
Patients who discontinue treatment for any reason other than death or their choice to 
withdraw from all study follow-up remain on study in follow-up status for an initial 30-
day AE evaluation period following the last dose of study agent(s). This 30-day post-
treatment follow-up period is meant to capture resolution or stabilization of ongoing 
treatment-related AEs or evolution of new treatment-related AEs.  
The initial AE follow-up period may be extended if new or worsening treatment-related AEs 
require longer observation. Similarly, the initial AE follow-up period may end early in the 
event of death, patient request to withdraw from follow-up, or initiation of new anti-cancer 
therapy. 
After the initial AE follow-up period, patients who are not evaluable for objective response 
(see Section 10.1) are off study. Patients who are evaluable for objective response enter 
an extended follow-up period for progression and/or survival outcomes. 
Patients who discontinue treatment with an ongoing response (PR or CR) or with ongoing 
stable disease (SD) are followed until the first evidence of progression after coming off 
treatment or until other anti-cancer therapy is initiated. At the onset of progression or 

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initiation of new therapy, whether this occurs during the initial or extended follow-up period, 
patients are followed only for survival. 
The primary reasons for a patient’s discontinuation from study treatment and from follow-
up status are to be recorded in the source documents and the CRFs. 
Certain late-occurring AEs may be subject to reporting during the extended follow-up 
period (eg, secondary malignancies). 
8 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
8.1.2 Serious Adverse Event (SAE) 
An AE is considered “serious” if in the view of the investigator, it results in any of the 
following outcomes: 
• 
death, 
• 
a life-threatening AE (An AE is consider “life-threatening” if, in the view of either 
the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.), 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions, or 
• 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment; they may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
8.1.3 Unanticipated Problem (UP) 
UPs include any incident, experience, or outcome that meets all of the following 
criteria: 
• 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents; such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 

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• 
related or possibly related to participation in the research (ie, there is a 
reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research; and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
8.2 Adverse Event Characteristics 
8.2.1 CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI CTCAE version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4 can be downloaded from the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
8.2.2 Expectedness: AEs can be ‘Unexpected’ or ‘Expected’. 
Unexpected AEs are those AEs occurring in one or more subjects participating in 
the research protocol, the nature, severity, or frequency of which is not consistent 
with either: 
• 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) the protocol-related document, such as 
the IRB-approved research protocol, any applicable investigator brochure, and 
the current IRB-approved informed consent document, and (b) other relevant 
sources of information, such as product labeling and package inserts; 
or 
• 
The expected natural progression of any underlying disease, disorder, or 
condition of the subject(s) experiencing the AE and the subject’s predisposing 
risk factor profile for the AE. 
See Sections 9.1.9 (sorafenib), 9.2.8 (valproic acid), and 9.3.10 (sildenafil).  
8.2.3 Attribution of the AE: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 

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8.3 Known AE List  
Expected AEs are those AEs, the specificity and severity of which is consistent with the 
listings for valproic acid, sorafenib or sildenafil in Section 9 or those documented in the 
informed consent document. 
8.4 Time Period and Grade of AE Capture 
All AEs, regardless of grade, will be recorded from the beginning of the study procedures 
through 30 days following the end of the study treatment. 
8.5 Procedures for Recording AEs, SAEs, Qualifying Toxicities, and UPs 
All AEs, SAEs, qualifying toxicities, and UPs will be recorded in MCC’s OnCore database 
program. 
In certain instances, it may be acceptable to record in OnCore only the highest grade of a 
toxicity occurring during a particular study segment when an event has serial fluctuations in 
grade over time. 
SAE’s will be entered into the OnCore SAE domain. UPs will be entered into the OnCore 
Deviations domain. An SAE that is both an SAE and a UP will be entered in both domains. 
For all SAEs, a corresponding entry should be made in the routine AE record to match the 
event entries in the SAE domain.

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8.6 Expedited Reporting Procedures for SAEs, UPs, and Qualifying Toxicities 
Table 5. Expedited Reporting Requirements (Events, Report Recipients, and Time Frames) 
SAEs 
UPs  
 
Qualifying Toxicities1 
Principal Investigator, Co-
Investigator (as listed 
below), and Coordinating 
Study Team2, 3  
Principal Investigator, Co-
Investigator (as listed below), 
and Coordinating Study 
Team2, 3 
 
Principal Investigator, Co-
Investigator (as listed 
below), and Coordinating 
Study Team2 
 
DSMC4 
DSMC4 
 
IRB5 
 
1 See Section 6.4.2. 
2 Report event within 1 business day of becoming aware of the occurrence.  
3 A de-identified PDF of an OnCore SAE or deviation record may be used for expedited 
reporting purposes. 
4 Report event within 2 business days of becoming aware of the occurrence. A de-identified 
PDF of an OnCore SAE or deviation record may be used for expedited reporting purposes. 
5 Each UP must be reported to the VCU IRB within 5 business days of becoming aware of 
the occurrence.  
Principal Investigator: 
Mark Malkin, MD 
 
 
 
 
 
 
Coordinating Study Team: 
 
 
Massey Cancer Center DSMC: 
 
9 PHARMACEUTICAL INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
 

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10 MEASUREMENT OF EFFECT 
10.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with sorafenib and/or valproic acid and/or sildenafil. 
Evaluable for qualifying toxicities for the safety lead-in. Only those patients who have 
completed the first cycle of therapy (or have experienced a qualifying toxicity prior to the 
end of the first cycle) will be evaluable for the safety lead-in. Qualifying toxicities will be 
defined in the first cycle only. Patients must have completed twice-daily sorafenib dosing 
for at least 21 out of the first 28 days to be considered to have had sufficient exposure to 
the regimen for qualifying toxicity evaluation. Patients who are not evaluable for the 
qualifying toxicity assessment for the safety lead-in will be replaced.  
Evaluable for qualifying toxicities for the early stopping rule after the safety lead-in. 
Patients who have initiated the first cycle of therapy will be considered evaluable for the 
early stopping rule. Qualifying toxicities will be defined in the first cycle only. Patients who 
are not evaluable for the qualifying toxicity assessment for the early stopping rule will not 
be replaced unless they were included in the safety-lead in. 
Evaluable for objective response. Patients who have been treated with the combination 
of twice-daily sorafenib and valproic acid for a minimum of 28 days, and have had their 
disease re-evaluated, will be considered evaluable for response. These patients will have 
their response classified according to the definitions stated below. Patients who do not 
complete study dosing for at least 28 days, or those who do not have their disease re-
evaluated following initiation of the combination of sorafenib and valproic acid, will be 
replaced to ensure that a sufficient number of patients will be available for response 
evaluation. 
 
 

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10.2 Response Criteria 
The neurologic examination and the MRI or contrast-enhanced CT at each evaluation will 
be scored as follows: 
10.2.1 Neurologic Exam Status 
10.2.2 MRI Assessment: Based on Response Assessment in Neuro-Oncology working 
group (RANO) criteria (37). 
Table 13. RANO Criteria 
Response 
Criteria 
Complete 
Response 
 
Requires all of the following: Complete disappearance of all enhancing 
measurable and non-measurable disease sustained for at least 4 weeks; no new 
lesions; stable or improved non-enhancing (T2/FLAIR) lesions; and with patient 
off corticosteroids or only on physiological replacement doses. Requires repeat 
MRI in 4 weeks for confirmation.  
Partial 
Response 
Requires all of the following: ≥ 50% decrease, compared with baseline, in the 
sum of products of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks; no progression of non-measurable disease; no 
new lesions; stable or improved non-enhancing (T2/FLAIR) lesions on the same 
or lower dose of corticosteroids compared to baseline scan; and with patient on a 
dose corticosteroids not greater the dose at the time of baseline scan, and is 
stable or doing better clinically. Requires repeat MRI in 4 weeks for confirmation. 
Stable 
Disease 
Stable disease occurs if the patient does not qualify for complete response, 
partial response, or progression, and requires the following: Stable non-
enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids 
compared with baseline scan and clinically stable status. 
 
In the event that the corticosteroid dose was increased for new symptoms and 
signs without confirmation of disease progression on neuroimaging, and 
subsequent follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to show stable 
disease will be the scan obtained when the corticosteroid dose was equivalent to 
the baseline dose. 
Progressive 
Disease 
Progression is defined as any of the following: ≥ 25% increase in the sum of the 
products of perpendicular diameters of enhancing lesions, on stable or increasing 
doses of steroids; a significant increase in non-enhancing (T2/FLAIR) on stable 
or increasing dose of steroids compared with baseline scan or best response 
after initiation of therapy; the appearance of new lesions; clear progression of 
non-measurable lesions; definite clinical deterioration not attributable to other 
causes apart from tumor or to decreases in corticosteroid dose. 
Table 12. Neurologic Exam Status as Compared to Pre-Treatment Exam 
Status 
Criteria 
Better 
No new neurologic deficits. Must be on stable or decreasing dose of steroids, 
with stable to improved ECOG performance status 
Worse 
New neurologic deficits, declining ECOG performance status, or requiring 
increasing dose of steroids to remain stable 

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10.2.3 Contrast-enhanced CT Assessment: Based on Macdonald Criteria (38).  
Table 14. Macdonald Criteria    
Response 
Criteria 
Complete 
Response 
Requires all of the following: complete disappearance of all enhancing measurable 
and non-measurable disease sustained for at least 4 weeks; no new lesions; no 
corticosteroids; and stable or improved clinically.  
Partial 
Response 
Requires all of the following: ≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained 
for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and 
stable or improved clinically.  
Stable 
Disease 
Requires all of the following: does not qualify for complete response, partial 
response, or progression; and stable clinically. 
Progression 
Defined by any of the following: ≥ 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions; any new lesion; or clinical 
deterioration.  
*Table from (37) 
10.3 Considerations for Patients with Multifocal Disease 
For patients with multifocal disease, progressive disease is defined as ≥ 25% increase in 
the sum of the products of perpendicular diameters of enhancing lesions compared with 
the smallest tumor measurements after the initiation of therapy. The appearance of a new 
lesion or unequivocal, progression of non-target lesions will also be considered 
progression.  
Partial response is defined as a ≥ 50% decrease, compared with baseline, in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks, with stable or decreasing corticosteroid dose and with stable neurologic 
exam. 
10.4 Timing of Imaging Studies 
For the purposes of this study, patients will be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following 
initial documentation of objective response (PR or CR).  
Evaluation of neurologic imaging can be confounded by factors such as edema and subtle 
variances in imaging parameters. In the event that imaging meets objective progression 
criteria, but the patient‘s clinical status is stable or improving, with a stable or decreasing 
steroid dose, and, in the opinion of the investigator, the aggregate patient assessment is 
not definitive for progression, study therapy can continue at investigator’s discretion with 
repeat imaging at time of next scheduled assessment. If subsequent imaging again meets 
objective progression criteria, regardless of clinical and/or steroid dosing status, then 
progression criteria will have been met, and the date of progression will be noted as the 
earliest imaging date that was consistent with objective progression. 
If clinical conditions raise the concern for progressive disease in between regularly 
scheduled interval scans, repeat imaging may be performed at the treating physician’s 
discretion. 

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10.4.1 Duration of Response 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for a complete response or a partial response 
(whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement 
criteria are first met for complete response until the first date that progressive 
disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
10.4.2 PFS 
PFS is defined as the duration of time from start of treatment to time of symptomatic 
and/or radiographic progression or death, whichever occurs first. 
11 CORRELATIVE STUDIES 
11.1 PDGFRα Expression in Primary Tumor Samples 
Analysis will take place on archived tissue. Patients being considered for enrollment onto 
this study will have had primary therapy for their high-grade glioma, which includes 
resection, when possible, with a minimum of a core needle biopsy of the tumor for patients 
with unresectable disease. Some patients will also have had a biopsy of recurrent disease. 
Other patients will have had progression from a lower grade glioma, and multiple biopsies 
will be available to choose from. The preferred tumor specimen is from the primary 
resection specimen at the time of initial treatment for high-grade glioma. 
11.2 Timing of Sample Collection and Analysis  
In the initial PDGFRα-unselected cohort, archived samples may be obtained and submitted 
for initial processing any time after study consent is obtained, preferably within the first few 
weeks of study therapy. Analysis/interpretation of these samples may be done without 
regard to participant initiation of study treatment. Samples may be held for batch 
processing, staining, and analysis until such time as it is determined whether the study will 
proceed to enrollment of only patients known to have PDGFRα-positive tumors.  
If the study continues to enrollment of a PDGFRα-positive cohort, archived samples will 
need to be collected, processed, and scored as part of the screening process to determine 
eligibility.  
After the first interim analysis for 6-month PFS: 
• If the study continues with enrollment of PDGFRα-unselected patients only, tissue 
collection, processing, and analysis may continue, with the understanding that samples 
may be processed and/or analyzed for PDGFRα status in a non-CLIA-certified setting. In 

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this case, samples will be deparaffinized in VCU Anatomic Pathology, immunostained in 
the VCU Massey Cancer Center Clinical and Translational Research Laboratory (VCU 
MCC CTRL) and scored in VCU Anatomic Pathology.   
• If the study continues with enrollment of PDGFRα-selected patients (only those who 
have PDGFRα-positive tumors), results of PDGFRα immunostaining will need to be 
available PRIOR TO enrollment. Immunostaining for the PDGFRα-positive cohort will be 
performed in a CLIA-certified setting. In this case, for consistency, all previously 
collected samples from the PDGFRα-unselected patient cohort will also undergo staining 
and analysis in the CLIA-certified setting. 
11.3 Collection of Specimens 
A total of 5 unstained slides, each with specimen 4-microns thick, should be obtained. All 
slides will have PHI removed before submission for correlative testing and will be labeled 
with:  
• 
Study Number 
• 
Subject ID# 
• 
Surgical pathology accession #   
VCU MCC CTRL and VCU Anatomic Pathology will maintain logs of samples handled for 
correlative testing keyed by those 3 identifiers.  
To obtain a biopsy specimen from VCU archives, contact VCU Anatomic Pathology 
 and reference surgical pathology 
specimen number and block number. Provide a copy of protocol specifications for sample 
collection and signed informed consent. 
• 
For the PDGFRα-unselected cohort, make arrangements for de-identified slides to 
be obtained and submitted to the VCU MCC CTRL to be stored until a 
determination is made about where the slides will be processed and analyzed.  
• 
For the PDGFRα-selected cohort, make arrangements for de-identified slides to be 
obtained and submitted to the VCU Anatomic Pathology for pre-enrollment 
processing and analysis to determine PDGFRα-status 
VCU Anatomic Pathology 
 
 
 
  
  
 
 
 
  
 
To obtain an archived biopsy specimen from outside hospital, request that a tissue block 
be sent to Anatomic Pathology at the above address, Attention 
 and 

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notify 
 to expect the specimen for research testing. The study team should 
coordinate with 
 to transfer the prepared slides from outside tissue blocks to the 
VCU MCC CTRL.  
If the outside hospital does not transfer blocks of tissue, request delivery of 5 unstained 
slides, each with specimen 4-microns thick, directly to the study team. Blank slides from an 
outside hospital do not need to be sent to pathology for preparation, and may be submitted 
directly to the VCU MCC CTRL for immunostaining. 
11.4 Handling of Specimens 
Five unstained slides, each with specimens 4 microns thick, will be submitted for 
immunostaining.  
11.5 Immunostaining of Specimens 
Immunostaining and analysis will be done in either the VCU MCC CTRL or in a CLIA-
certified setting, per Section 11.2.  
11.6 Interpretation of Correlative Study 
 
 
 
 
 
 
 
 
11.7 Other Potential Pharmacodynamic Markers 
The laboratory of 
 at MCC will analyze the samples for the pharmacodynamic 
marker studies.  

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12 STUDY CALENDAR 
Table 15. Study Calendar 
Event 
BaselineA 
On TreatmentB 
Follow UpC 
Cycle 1 
Cycle 2 
Cycle 
3+ 
Initial    
30-Day 
Period 
Extended 
Period 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
Informed Consent 
XD 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Height 
XD 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam 
including Performance Status, 
Dermatologic and Neurologic 
Assessments 
X 
XE 
XF 
X 
XF 
X 
 
X 
 
X 
 
 
Vital Signs, Weight 
X 
X 
XF 
X 
XF 
X 
 
X 
 
X 
 
 
Baseline Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
 
X 
XF 
X 
XF 
X 
 
X 
 
X 
XC 
 
Concurrent Medications, 
Including Steroid Dosing 
Review 
X 
X 
XF 
X 
XF 
X 
 
X 
 
X 
 
 
Study Medication Diary Review 
and Pill 
Count 
 
X 
XF 
X 
XF 
X 
 
X 
 
X 
 
 
Pregnancy Test, Counseling 
XG 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
XH 
 
 
 
 
 
XH 
 
 
Tumor Imaging 
XI 
XJ 
Survival, Alternative Therapies 
 
 
 
 
 
 
 
 
 
 
XC 
XK 
Archived Tumor Tissue 
XL 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential, Platelets 
X 
XB 
XF 
X 
XF 
X 
 
X 
 
X 
 
 
Basic Metabolic Panel,M,N 
Hepatic Panel,O Magnesium,N 
PhosphorusN 
X 
XB 
XF 
X 
XF 
X 
 
X 
 
X 
 
 
PT, INRP 
X 
X 
 
 
Serum Valproic Acid LevelQ 
X 
X 
 
 
Serum Ammonia 
X 
 
 
 
Valproic Acid 
Initiate, titrate, and/or maintain level ≥ LLN for the laboratory and dose per Sections 6 
and 9. 
 
 
Sorafenib 
 
Initiate on C1D1, provided valproic acid level is ≥ LLN for the laboratory; 
continue dosing per Sections 6 and 9. 
 
 
Sildenafil 
 
 
 

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A. Within 2 weeks prior to enrollment unless otherwise noted.  
B. C1D1 labs do not need to be repeated on C1D1 if done within 7 days prior to initiation of study treatment. Other C1D1 
assessments may be performed within 3 days prior to day 1 dosing. In cycle 1, weekly assessments must be done within +/- 1 
day of required time point. In cycle 3 and subsequent cycles, assessments must be done within +/- 3 days of scheduled time 
point; greater variations in timing may be permitted after cycle 2, with prior principal investigator/designee notification. For 
patients who are still on study for longer than 36 months, assessments may be done every other cycle (approximately every 8 
weeks). 
C. See Section 7.8: The 30-day post-treatment follow-up period is meant to capture resolution or stabilization of ongoing 
treatment-related AEs or evolution of new treatment-related AEs.  
D. Within 4 weeks prior to initiation of study treatment. 
E. If baseline history and physical exam is performed on a day other than C1D1, a brief visit to determine neurologic stability on 
current dose of steroids is also required on day 1 or day before.  
F. Only patients in the safety lead-in cohort. 
G. For women capable of pregnancy: pregnancy test at baseline; subsequently, review pregnancy risks and offer pregnancy test 
H. First “on-treatment” ECG is done approximately C1D8-C1D15 to evaluate acute changes relative to the study drug 
combination; the second is done approximately C3D1 to evaluate changes after a more chronic dosing of study drug 
combination. 
I. 
MRI or contrast-enhanced CT within 3 weeks prior to enrollment. An MRI is the preferred modality in all patients without a 
contraindication to MRI. Baseline and follow-up scans must be performed using the same modality. 
J. Imaging to be done to assess response every 2 months from initiation of treatment until off-study due to patient withdrawal, 
progression, or death. If MRI or contrast-enhanced CT shows response then repeat after 1 month to confirm response and 
then follow every 2 months from time of confirmatory MRI or CT. Patients with symptoms suggestive of progression may have 
imaging done between regularly scheduled scans, any time there is clinical concern for progressive disease. See also Section 
10.4. 
K. See Section 7.8: After stopping study treatment, capture initiation of new therapy, first new progression date, and/or survival 
status since last observation approximately every 2 months during extended follow-up.  
L. Obtain and analyze archived tumor tissue per Section 11. During enrollment of the initial PDGFRα-unselected subgroup (prior 
to first interim analysis), archived tumor tissue must be obtained and analyzed, but analysis does not need to be performed 
prior to enrollment. After the first interim analysis, if the study proceeds to include only PDGFRα-positive patients, archived 
specimen analysis for PDGFRα will be required, and results must be known, prior to enrollment. 
M. Sodium, potassium, carbonate, chloride, glucose, calcium, BUN, creatinine. 
N. Additional assessments may be done at investigator discretion in patients with congestive heart failure, bradyarrhythmias, 
those on drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. 
O. ALT, AST, ALP, total bilirubin, direct bilirubin, albumin, total protein. 
P. In patients taking warfarin: at baseline and then as clinically indicated. 

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Q. Initial level approximately 5 days after starting valproic acid. Once on study treatment, check level at least every 2 weeks, or 
more frequently if clinically indicated, through the end of cycle 2. After cycle 2, check only as clinically indicated. 

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13 STATISTICAL CONSIDERATIONS 
13.1 Study Design  
This is a single-arm phase 2 study of sorafenib, valproic acid, and sildenafil in the 
treatment of patients with recurrent high-grade glioma. The primary objective is to 
determine the efficacy of the drug combination in terms of 6-month PFS. This study will be 
conducted through an adaptive design potentially including 2 Simon’s two-stage mini-max 
designs. Initially, recurrent high-grade glioma patients will be enrolled, regardless of tumor 
molecular subtype, to determine the efficacy of the drug combination. If efficacy criteria are 
not met in patients inclusive of all molecular subtypes, then only patients with tumors that 
express PDGFRα will be enrolled. Therefore, 2 Simon’s designs may be included; the first 
is for patients in the entire cohort and the second is for patients with PDGFRα expressing 
tumors only if efficacy criteria are not met in the entire cohort. Details on the rationale of 
the adaptive design can be found in Section 1.9.  
The total expected sample size is estimated to be 44, with a range from 32 to 66 patients.  
Both a safety lead-in and a safety stopping rule are provided to monitor whether there are 
“too many” unexpected toxicities related to the drug combination, as patients continue 
being enrolled in the study. To ensure safety with respect to any interaction toxicity effects 
among the 3 drugs, we provide a safety lead-in rule for the first 6 qualifying toxicity-
evaluable patients—like a “3+3” phase 1 design. Once a dose has been identified wherein 
< 2 of 6 qualifying toxicity-evaluable patients develop a qualifying toxicity during the first 4 
weeks of therapy, then that dose will be used for expansion. Qualifying toxicities are 
defined in Section 6.4.2.  
Once the dose for expansion to the full cohort is identified, then an early sequential safety 
stopping rule which is based on the occurrence rate of qualifying grade 3 or greater 
toxicities is provided to monitor safety for any toxicities in the expansion. The safety lead-in 
rule is designed for a “3+3” study and is used to enhance safety analysis for the first 6 
qualifying toxicity-evaluable patients on the study, whereas the sequential stopping rule for 
subsequent enrollment has considered the variability of toxicity rate by confidence intervals 
based on observed data and scenarios where unacceptable toxicity could occur prior to 
study suspension. More details on the clinical rationale are in Section 1.7. Details on the 
safety lead-in and safety stopping rule are in Section 13.6. 
13.2 Sample Size/Accrual Rates 
The sample size and power are calculated based on Simon’s two-stage mini-max design 
which minimizes the expected maximum sample size (35). The primary outcome, 6-month 
PFS, is considered as a binary variable, ie, a patient either has 6-month PFS or not. Per 
the previous studies of second-line therapy in GBM, we assume that the null hypothesis, 
the proportion of patients who have 6-month PFS, is ≤ 20%, ie, p0 ≤ 0.2, which is 
unacceptably low, and the true proportion is p1=0.4. With a one-sided type I error of 5% 
and power of at least 80%, the first stage will enroll 16 response-evaluable patients. If 
there are 3 or less response-evaluable patients who have 6-month PFS, then the trial in 
the unselected patient population will end. If 4 or more response-evaluable patients have 
6-month PFS, then the trial will enroll an additional 17 response-evaluable patients into the 
second stage. If 11 or more out of the total of 33 response-evaluable patients have 6-

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month PFS, the drug combination meets efficacy criteria and further studies can be 
pursued.  
As mentioned in Section 13.1, the study will be conducted through an adaptive design 
possibly with 2 Simon’s two-stage designs. Both of these Simon’s designs will share the 
same parameters/settings, assumptions for sample size, and power calculations. The total 
sample size may range from 32 to 66. We expect that it is very likely that the study will 
enroll 16 response-evaluable patients inclusive of all molecular subtypes, and then a total 
of 16 response-evaluable patients with PDGFRα-expressing tumors in the first stage 
(inclusive of patients with PDGFRα-positive tumors in the first interim analysis), and an 
additional 17 response-evaluable patients with PDGFRα-expressing tumors in the second 
stage. Per previous studies, PDGFRα is the third most common gene event identified in 
GBM, and about 30-40% patients have positive PDGFRα expression among all GBM 
patients , with a higher percentage in patients with transformed GBM from lower grade 
glioma (39). Therefore, we expect that the total sample size for the adaptive design is 
about 44 response-evaluable patients. Based on previous recruitment at the Massey 
Cancer Center, it is estimated that 8-12 patients will be enrolled per year, and therefore, it 
is estimated that the study will complete enrollment in approximately 4 years and be closed 
in approximately 5 years. It is likely that the accrual rate for the PDGFRα expression cohort 
will be slower than for the entire population and the study team will invite more clinical sites 
to increase the accrual rate.   
13.3 General Statistical Analysis 
Patient demographics, AEs and SAEs, disease status, treatment dosing level, treatment 
status, clinical response, time-to-event intervals etc. will be recorded and summary 
descriptive statistics will be calculated. The clinical response rates will also be summarized 
using descriptive statistics for each cohort, along with their corresponding 95% confidence 
intervals. 
13.4 Analysis of Primary Endpoints 
The primary endpoint is whether a patient has a 6-month PFS or not. The proportion of 
response-evaluable patients who have 6-month PFS in the entire cohort and in PDGFRα 
expressing tumor and their confidence intervals will be calculated, respectively. 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 (40), for the entire 
population and for PDGFRα expression, respectively. Cox regression analysis will be used 
to evaluate baseline characteristics and any potential covariates. 
13.5 Analysis of Secondary Endpoints 
The overall best response rate to the drug combination will be estimated for the entire 
study population and for the PDGFRα-expressing high-grade glioma cohort, along with the 
95% confidence intervals.  
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 PDGFRα expression, respectively. Cox 
regression analysis will be used to evaluate baseline characteristics and any potential 
covariates. 

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13.6 Safety Lead-in, and Safety Stopping Rule 
13.6.1 Safety Lead-in 
The first 6 patients will be treated as a single dose-level safety lead-in prior to 
continuation of accrual of the entire study cohort. The lead-in rule is designed for a 
“3+3” study and is used to enhance safety analysis for the first 6 patients on the 
study, wherein the sequential stopping rule has considered the variability of toxicity 
rate by confidence intervals based on observed data and scenarios where 
unacceptable toxicity could occur prior to study suspension. Patients will be 
evaluated for qualifying toxicities as defined in Section 6.4.2. If < 2 of 6 qualifying 
toxicity-evaluable patients complete the first 4 weeks of therapy without a qualifying 
toxicity, then the dose is considered safe for expansion to the remainder of the 
entire study cohort. If ≥ 2 of 6 qualifying toxicity-evaluable patients experience a 
qualifying toxicity during the first 4 weeks of therapy, doses will be modified and an 
additional 6 patients enrolled for qualifying toxicity evaluation. In this case, the 
protocol will be placed on hold until the protocol is amended to specify the modified 
doses. Once a dose has been identified wherein < 2 of 6 patients develop a 
qualifying toxicity during the first 4 weeks of therapy, then that dose will be used for 
enrollment of the entire study cohort. In the event that toxicity develops late, the 
stopping rule below will remain in effect to trigger review by the DSMC.  
13.6.2 Sequential Safety Stopping Rule after the Safety Lead-in 
In addition to the safety lead-in described above, a formal sequential stopping 
guideline, which is based on the occurrence rate of qualifying toxicities, is designed 
for a phase 2 study, with a relatively looser threshold than the safety lead-in rule. If 
the stopping guideline is reached, accrual is stopped and a thorough review of the 
safety data is completed by the DSMC. The stopping guideline indicates a level of 
concern based on the occurrence rate of qualifying toxicities. However, the stopping 
guideline is not an indicator that an insurmountable safety problem exists. Likewise, 
the fact that a stopping guideline is not reached does not provide assurance that the 
drug combination is safe. Qualifying toxicity is defined in Section 6.4.2. 
Previous studies of sorafenib have shown the acceptable occurrence rate for grade 
3 or greater toxicities is ≤ 35% (41). Using a binomial probability calculation, values 
of “m” (number of patients with qualifying toxicities) and "n" (number of qualifying 
toxicity-evaluable patients that have been treated) are selected such that the two-
sided 95% confidence interval of the sequential observed occurrence toxicity rate 
keeps containing the prefixed acceptable occurrence rate ≤ 35%. 
More specifically, the following values of m/n apply to those patients who are 
qualifying toxicity evaluable: 5/7, 6/8-9, 7/10-11, 8/12-13, 9/14-15, 10/16-17, 11/18-
19, 12/20-21, 13/22-23, 14/24-25, 15/26-28, 16/29-30, 17/31-32, 18/33-34, 19/35-
37, 20/38-39, 21/40-41, 22/42-44, 23/45-46, 24/47-48, 25/49-51, 26/52-53, 27/54-
56, 28/57-58, 29/59-61, 30/62-63, 31/64-65, 32/66. If, at any time, m/n reaches the 
values shown, accrual to the study protocol is stopped and the accumulated safety 
data is submitted to the DSMC for evaluation. Please refer to Section 6.4.2 for a list 
of qualifying toxicities. 

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13.6.3 Summary of Safety Monitoring Plan 
As mentioned in Section 13.6.1, once a dose has been identified wherein < 2 of 6 
patients develop a qualifying toxicity during the first 4 weeks of therapy, then the 
study will be conducted through a Simon’s two-stage design (Section 13.1) at that 
dose for the entire population first and then for the PDGFRα-expressing population. 
As mentioned in Sections 13.1-13.2, 16 patients will be enrolled for the first stage for 
the entire population. The monitoring plan for the 16 patients is summarized in the 
table below. Subsequent patients will be monitored as described in Section 13.6.2.  
Table 16. Summary of Safety Monitoring Plan 
Number of 
qualifying toxicity-
evaluable patients 
Cumulative safety monitoring plan 
The first 6 patients  
Must have < 2/6 qualifying toxicity-evaluable patients as 
indicated by the safety lead-in rule in Section 13.6.1 
The next 6 patients  
Of the 7-12 qualifying toxicity-evaluable patients, must have 
< 5-8 patients who develop qualifying toxicities, as indicated 
in the sequential safety stopping rule in Section 13.6.2 
The next 4 patients  
Of the 13-16 qualifying toxicity-evaluable patients, must 
have < 8-10 patients who develop qualifying toxicities, as 
indicated in the sequential safety stopping rule in Section 
13.6.2 
Further patients  
Continue monitoring of qualifying toxicity-evaluable patients 
as in Section 13.6.2  
13.7 Evaluability for Qualifying Toxicity, Toxicity, Response  
Each registered patient will be deemed as evaluable for toxicity, qualifying toxicities and 
response as per Section 10.1: 
For response evaluability, the patients are coded as having a response or not. 
• Responders - Best response assessment is complete response or partial response 
• Non-Responders - Best response assessment is stable disease or progressive 
disease or those patients who were not assessed or not evaluable  
• The coding of patients as responders or non-responders will be made by the study 
team with the concurrence of the biostatistician. 
14 DATA AND SAFETY MONITORING PLAN (DSMP) 
14.1 Study Team 
The study team, consisting of physicians, research nurses, clinical research associates, 
study statistician, and regulatory personnel, will have primary responsibility for study 
conduct. The study team will maintain a study summary and meet at least monthly while 
patients are on study treatment. The study statistician will meet with the study team at least 
quarterly. Meetings will include, but not be limited to, reportable AEs and UPs, and an 
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schema. The appropriateness of further patient enrollment and the specific intervention for 
a next patient enrollment are addressed. All meetings including attendance are 
documented. 
14.2 Monitoring and Auditing 
14.2.1 MCC Compliance Office 
Compliance specialists in the MCC Compliance Office will provide ongoing 
monitoring and auditing for this trial.  
14.2.2 Data and Safety Monitoring Committee 
The study will be reviewed by the MCC Data and Safety Monitoring Committee 
(DSMC) initially according to the risk level specified by the MCC Protocol Review 
and Monitoring Committee (PRMC) and then according to a schedule based on 
study status and quality indicators. The DSMC reviews reports of the sponsor-
investigator/study team and the MCC Compliance Office focusing on data integrity 
and patient safety. 
15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (US National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research, April 18, 1979). 
15.2 Regulatory Compliance 
This study will be conducted in compliance with the protocol and applicable regulatory 
requirements. 
15.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
patients and their families. Consent forms describing in detail the study 
interventions/products, study procedures, and risks are given to the patient and written 
documentation of informed consent is required prior to starting intervention/administering 
study product. Consent forms will be IRB-approved and the patient will be asked to read 
and review the document. Upon reviewing the document, the investigator will explain the 
research study to the patient and answer any questions that may arise. The patient will 
sign the informed consent document prior to any procedures being done specifically for the 
study. The patients should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate. The patients may withdraw consent at any 
time throughout the course of the trial. A copy of the informed consent document will be 
given to the patients for their records. The rights and welfare of the patients will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 

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15.4 Patient Confidentiality 
Patient confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biologic samples and genetic tests in addition to the clinical information relating to 
participating patients. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor-investigator. 
The study monitor or other authorized representatives of the sponsor may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the patients 
in this study. The clinical study site will permit access to such records. 
16 DATA COLLECTION AND MANAGEMENT 
16.1 CRFs and Data Collection 
Data Massey Cancer Center OnCore data management will provide standard CRFs and 
create study-specific CRFs to be able to capture all information required by the protocol. 
The CRFs will be approved by the study team to ensure the most effective data 
acquisition.  
The investigator(s) and study coordinator(s) must maintain source documents for each 
patient in the study. All information on CRFs will be traceable to these source documents, 
which are generally maintained in the patient’s file. 
All CRFs should be completed and available for collection within a timely manner, 
preferably no more than 14 days after the patient’s visit. 
16.2 Study Record Retention 
The investigator will maintain all study records according to applicable regulatory 
requirement(s).  

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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (eg, light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed < 50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 

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Appendix 2. Cockcroft-Gault Equation  
Calculated Creatinine Clearance (Cockcroft and Gault) 
 
Creatinine Clearance (mL/min) = {(140 - Age) × Wt in kg × 
G} / (Creat × 72) 
G = 1 (males); G=0.85 (females) 
 

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Appendix 3. NYHA Classification of Heart Failure 
Class Description 
I 
No symptoms. Ordinary physical activity such as walking and climbing stairs does not 
cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, in cold weather, in wind or when under 
emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity. Walking 1 to 2 blocks on the level 
and climbing more than one flight of stairs in normal conditions causes undue fatigue or 
dyspnea. 
IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea.