A Phase 2 Clinical Trial Testing the Safety and Efficacy of Voronistat in Pediatric Patients With Drug Resistant Epilepsy
Phase: PHASE2
Conditions: Refractory Epilepsy
Sponsor: University of Calgary

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
1 | P a g e  
 
 
 
 
 
 
TITLE: A Phase II Pilot Clinical Trial Testing the Safety and Efficacy of Vorinostat in 
Pediatric Patients with Medically Intractable Epilepsy  
 
PROTOCOL NO.: VOR-17-2471 
 
PRINCIPAL INVESTIGATORS:  Dr. Jong Rho 
Department of Pediatrics, Department of Physiology and 
Pharmacology, Department of Clinical Neurosciences, 
Cumming School of Medicine, University of Calgary 
Department of Pediatrics, Alberta Children’s Hospital, 
Alberta Health Services 
 
Dr. Deborah Kurrasch 
Department of Medical Genetics  
Cumming School of Medicine 
University of Calgary 
 
CO-INVESTIGATORS:         Dr. Luis Bello-Espinosa 
Dr. JP Appendino 
Department of Pediatrics, Cumming School of Medicine,  
University of Calgary 
Department of Pediatrics, Alberta Children’s Hospital,  
Alberta Health Services 
  
 
VERSION 2: 2018-07-18 
  
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
2 | P a g e  
 
 
TABLE OF CONTENTS 
 
GLOSSARY OF ABBREVIATIONS .............................................................................................................................. 5 
SECTION 1.0: BACKGROUND AND RATIONALE ...................................................................................................... 7 
1.1 BACKGROUND ................................................................................................................................. 7 
1.1.1. DISEASE .......................................................................................................................... 7 
1.1.2 STUDY DRUG RATIONALE ............................................................................................. 7 
1.1.3 TOLERABILITY OF VORINOSTAT ................................................................................ 10 
1.1.4 TOLERABILITY OF VORINOSTAT IN PEDIATRIC EPILEPSY PATIENTS ................... 15 
1.2 RATIONALE FOR THE STUDY ...................................................................................................... 23 
SECTION 2.0: OBJECTIVES ...................................................................................................................................... 25 
2.1 PRIMARY OBJECTIVES ................................................................................................................. 25 
2.2 SECONDARY OBJECTIVES ........................................................................................................... 25 
SECTION 3: STUDY DESIGN ..................................................................................................................................... 26 
3.1 OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN .......................................................... 26 
3.1.1 DOSAGE ........................................................................................................................... 26 
3.1.2 PHASES OF STUDY ......................................................................................................... 27 
3.1.2 END OF STUDY ................................................................................................................ 28 
3.2 RATIONALE FOR STUDY DESIGN ................................................................................................ 28 
3.3 NUMBER OF SUBJECTS ............................................................................................................... 28 
SECTION 4: STUDY POPULATION ........................................................................................................................... 29 
4.1 OVERVIEW ..................................................................................................................................... 29 
4.2 INCLUSION CRITERIA ................................................................................................................... 29 
4.3 EXCLUSION CRITERIA .................................................................................................................. 29 
4.4 DIAGNOSTIC CRITERIA FOR MEDICALLY INTRACTABLE EPILEPSY ....................................... 30 
4.5 CONCOMITANT MEDICATIONS AND TREATMENTS .................................................................. 30 
4.5.1 PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS ........................... 30 
4.5.2 PERMITTED CONCOMITTANT MEDICATIONS .............................................................. 31 
4.6 CONTRACEPTION PROTECTION ................................................................................................. 32 
4.7 CRITERIA FOR PREMATURE WITHDRAWAL .............................................................................. 32 
4.8 REPLACEMENT POLICY................................................................................................................ 32 
SECTION 5: SCHEDULE OF ASSESSMENTS AND PROCEDURES ....................................................................... 34 
5.1 PROCEDURES ............................................................................................................................... 34 
5.1.1 SCREENING EXAMINATION AND ELIGIBILITY SCREENING FORM – VISIT 1 ............ 35 
5.1.2 ENROLLMENT VISIT – VISIT 2 ........................................................................................ 36 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
3 | P a g e  
 
5.1.3 ASSESSMENTS AND PROCEDURES DURING THE TREATMENT PERIOD ................ 37 
5.1.4 SAFETY FOLLOWUP ....................................................................................................... 38 
5.2 OUTCOMES ASSESSMENTS ........................................................................................................ 38 
5.2.1 SAFETY AND TOLERABILITY ASSESSMENT ................................................................ 38 
5.2.2 EFFICACY ASSESSMENTS ............................................................................................. 38 
5.3 SAFETY MONITORING .................................................................................................................. 38 
5.3.1 ADVERSE EVENTS .......................................................................................................... 39 
5.3.2 SAFETY MONITORING .................................................................................................... 39 
SECTION 6: INVESTIGATIONAL MEDICINAL PRODUCT ........................................................................................ 41 
6.1 FORMULATION, PACKAGING AND LABELING ............................................................................ 41 
6.1.1 FORMULATION ................................................................................................................ 41 
6.1.2 PACKAGING & LABELING ............................................................................................... 41 
6.1.3 STORAGE ......................................................................................................................... 41 
6.2 DOSE AND SCHEDULE OF STUDY MEDICATION ....................................................................... 41 
6.2.1 DOSAGE RATIONALE ...................................................................................................... 41 
6.2.2 DOSAGE ........................................................................................................................... 41 
6.2.3 DOSE INTERRUPTIONS .................................................................................................. 42 
6.3 ASSESSEMENT OF COMPLIANCE ............................................................................................... 42 
6.4 DESTRUCTION OF STUDY MEDICATION .................................................................................... 42 
SECTION 7: SAFETY INSTRUCTION AND GUIDANCE ........................................................................................... 43 
7.1 ADVERSE EVENTS AND LABORATORY ABNORMALITIES ........................................................ 43 
7.1.1 CLINICAL ADVERSE EVENTS ......................................................................................... 43 
7.1.2 LABORATORY TEST ABNORMALITIES .......................................................................... 44 
7.1.3 TREATMENT AND FOLLOW UP OF AEs ........................................................................ 45 
7.2 HANDLING OF SAFETY PARAMETERS ....................................................................................... 46 
7.2.1 REPORTING OF SERIOUS ADVERSE EVENTS ............................................................ 46 
7.2.2 EXEMPTION OF PROJECT SPECIFIC SERIOUS AEs FROM IMMEDIATE REPORTING 
TO HEALTH AUTHORITIES AND IRBs.......................................................................... 47 
7.2.3. PREGNANCY ................................................................................................................... 47 
SECTION 8: STATISTICAL CONSIDERATION AND ANALYTICAL PLAN .............................................................. 48 
8.1 PRIMARY AND SECONDARY STUDY ENDPOINTS ..................................................................... 48 
8.1.1 PRIMARY ENDPOINTS .................................................................................................... 48 
8.1.2 SECONDARY ENDPOINT ................................................................................................ 48 
8.2 STATISTICAL AND ANALYTICAL METHODS................................................................................ 48 
8.2.1 SAMPLE SIZE ................................................................................................................... 48 
8.2.2 ANALYSIS ......................................................................................................................... 48 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
4 | P a g e  
 
SECTION 9: DATA COLLECTION & MANAGEMENT ............................................................................................... 50 
SECTION 10: ETHICAL ASPECTS ............................................................................................................................ 51 
SECTION 11: STUDY DOCUMENTATION, RECORD KEEPING, AND CONFIDENTIALITY OF TRIAL 
DOUCMENTS AND PARTICIPANT RECORDS ................................................................................... 52 
11.1 INVESTIGATOR’S FILES/RETENTION OF DOCUMENTS .......................................................... 52 
11.2 CONFIDENTIALITY OF TRIAL DOUCMENTS AND PARTICIPANT RECORDS ......................... 52 
SECTION 12: REFERENCES ..................................................................................................................................... 54 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
5 | P a g e  
 
GLOSSARY OF ABBREVIATIONS 
 
13 cRA 
13-cis-retinoic acid 
ACH 
Alberta Children’s Hospital 
AE 
Adverse Event 
AED 
Anti-epileptic drug 
ALL 
Acute lymphoblastic leukemia 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate transaminase 
BOR 
bortezomib 
BSA 
Body surface area 
BVC 
Brivaracetam 
CBZ 
carbamezapine 
CHREB  
Conjoint Health Research Ethics Board 
CRF 
Case report form 
CTCAE 
Common Terminology criteria for adverse events 
CTCL 
Cutaneous T-cell lymphoma 
DCF 
Data collection form 
DEC 
decitabine 
DLT 
dose-limiting toxicity 
DVT 
deep vein thrombosis 
ECG 
Electrocardiogram  
EDC 
Electronic data capture 
eDCF 
Electronic data capture form 
EOT 
End of treatment 
ESF 
Eligibility screening form 
ETSP 
Epilepsy therapy screening program 
ETX 
Ethosuximide 
FBM 
Felbamate 
FDA 
Food and Drug Administration 
GBP 
Gabapentine 
GCP 
Good Clinical Practice 
HDAC 
Histone deacetylase 
HDACi 
Histone deacetylase inhibitor 
ICH 
International Conference on Harmonisation  
ILAE 
International League Against Epilepsy 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
KD 
Ketogenic diet 
LCM 
Lacosamide 
LEV 
Levetiracetam 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
6 | P a g e  
 
LTG 
Lamotrigine 
MIBG 
metaiodobenzylguanidine 
MO 
Morpholino oligonucleotide 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIH 
National Institutes of Health 
OXC 
Oxcarbazepine 
PK 
pharmacokinetics 
PMP 
Perampanel 
PTT 
Prothrombin time 
PTZ 
pentylenetetrazol 
QoL 
Quality of life 
QTc 
QT corrected 
REB 
Research ethics board 
SAE 
Serious adverse event 
SFU 
Safety Follow-up  
TEM 
Temozolomide 
TPM 
Topiramate 
ULN 
Upper limit of normal 
vEEG 
Video EEG 
VNS 
Vagal nerve stimulator 
VOR 
Vorinostat 
VPA 
 
Valproic acid 
wt 
wild type 
ZNS 
Zonisamide 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
7 | P a g e  
 
SECTION 1.0: BACKGROUND AND RATIONALE 
 
1.1 BACKGROUND 
 
1.1.1. DISEASE  
 
Epilepsy is defined as the occurrence of two or more unprovoked seizures, caused by abnormal, excessive discharge 
of neurons, usually accompanied by behavioral or sensorimotor manifestations1. An estimated 15,500 new patients 
are diagnosed with epilepsy each year in North America alone2.  
 
Several therapies are available for the treatment of seizures, including over 10 pharmaceutical agents, as well as 
surgical, neurostimulation, diet, and immunomodulatory interventions, with the goals of complete seizure remission, 
minimal or no adverse effects (AEs), and best quality of life (QoL)3, 4. Despite these numerous available therapies, 
attainment of treatment goals continues to be elusive. Approximately 85% of patients are prescribed an anti-epileptic 
drug (AED) within one year of the first unprovoked seizure5; of those only 30 - 50% achieve seizure freedom5, 6, and 
30–60% experience drug-related AEs7. About a third have medically intractable epilepsy 5, 8, which is defined by the 
International League Against Epilepsy (ILAE) 2010 task force as “failure of adequate trials of two tolerated, 
appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve 
sustained seizure freedom”9.    
 
Uncontrolled seizures in children can impose a deleterious impact on development, increase the risk of medical 
complications and injuries, contribute to poor QoL10, and significantly increase mortality rate (1.59% per year) 10, 11. 
Almost half of the children with medically intractable epilepsy may evolve some intellectual dysfunction or decline in 
cognitive function over the years12-14. Children with epilepsy are at particular risk for impaired QoL and psychological 
problems, and are among those with the poorest QoL and worst psychological adjustment during infancy and 
adolescence, compared to other chronic conditions not involving central nervous system conditions15, 16. The risk of 
death in children with epilepsy is several-fold higher over the subsequent 10-20 years of life17; and lack of seizure 
freedom is the greatest risk factor for premature death in this population18. Furthermore, the associated medical care 
costs of sub-optimal control of seizures is exorbitant: while the direct and indirect costs of epilepsy are estimated to be 
$9.6 billion (US data)19-21, the health care costs of patients with uncontrolled seizures or AEs are estimated to be twice 
as high22.  
 
The incidence of medically intractable epilepsy remains unacceptably high and an unmet medical need exists for 
patients with uncontrolled seizures. Newly identified treatment targets to control seizures are clearly required, however 
typical drug development processes take greater than a decade to avail new treatment options. A strategy which 
identifies potential therapies that can be rapidly tested in the clinical setting is paramount. 
 
1.1.2 
STUDY DRUG RATIONALE  
 
Vorinostat (VOR), a histone deacetylase (HDAC) inhibitor has been identified as a potential viable therapy for the 
treatment of seizures in epilepsy, via a metabolism based discovery platform by researchers at the University of 
Calgary. Dr. Kurrasch et al. have developed a novel, metabolism-based discovery platform, modelled on the 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
8 | P a g e  
 
mechanistic underpinnings and therapeutic efficacy of the ketogenic diet (KD), to rapidly identify potential therapies 
and therapeutic targets. 
  
The KD is a high-fat, low-carbohydrate treatment for patients who fail to respond to anti-seizure medications23-25. 
Although the underlying mechanisms of the KD remain unclear26, proof of clinical efficacy has been demonstrated23. A 
link appears to exist between the KD and alterations in bioenergetics, since patients who respond to the KD 
demonstrate underlying respiratory changes27, 28. Derangements in cellular metabolism have been linked in part to the 
underlying aetiology of epilepsy, therefore it is possible that restoration of mitochondria-mediated bioenergetics may 
have disease-modifying effects29. For this reason, alterations and restoration of cellular bioenergetics can serve as a 
framework for investigation of target identification and drug development, where pharmacological agents that exert 
similar neurometabolic effects might prove efficacious in controlling seizures. 30 Dr. Kurrasch et al. developed such a 
platform, which utilizes a combination of zebrafish genetics and in vivo bioenergetics functional readout assays to 
screen for therapeutic agents that improve mitochondrial health in single gene knockdown models of epilepsy. 
Efficacious compounds can be identified via this platform by screening commercially available chemical libraries of 
approved drugs.  
 
The metabolism based discovery platform includes a multi-step process for screening and identifying potential viable 
drug therapies: behavioral assay screen; metabolic assay screen; and validation of positive compounds with 
spontaneously epileptic Kcna1-null mice (see Figure 1).  
 
 
 
Figure 1: Schematic representation of the workflow for the 2-step drug screen.  
 
1. Behavioral assay 
First, a behavioral assay is conducted using a zebrafish genetic model of epilepsy to screen compounds from chemical 
libraries. Zebrafish are simple vertebrates that are highly amenable to genetic manipulation and share >70% genetic 
similarity with humans31-33, thereby conserving many biological pathways common to zebrafish and humans. As such, 
zebrafish have rapidly become a key tool in epilepsy research and experimental therapeutics34-37. Two zebrafish models 
of ‘epileptic’ zebrafish were developed and validated for this purpose, the first was a pharmacological induction model 
utilizing pentylenetetrazol (PTZ), termed the ‘PTZ induction model’. The second, termed the ‘kcna1-MO model’ is a 
knockdown approach targeting the zebrafish orthologue of the human and murine potassium channel gene (KCNA1 
and Kcna1 respectively), which encodes for the delayed rectifier potassium channel protein Kv1.1. This was done using 
a morpholino oligonucleotide (MO) that targeted the kcna1a ATG initiation site. The models were validated to 
demonstrate neuronal hyperexcitability consistent with a seizure model, and elevated basal, total mitochondrial and 
ATP-linked respiration. Compounds which reduced total locomotor activity by 40% or more in populations of these 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
9 | P a g e  
 
models, without toxic effects, moved forward to the metabolic screen step. 870 compounds were screened in the 
behavioural assay; 120 compounds went on the next step. 
2. Metabolic screen assay 
To assess the efficacy of the compounds identified in the behavioral screen for improved bioenergetics, wild-type (wt) 
and kcna1-MO zebrafish were exposed to PTZ and/or drug identified in the behavioral assay. Compounds that reversed 
basal & mitochondrial respiration by >40% in both zebrafish models were considered ‘active’.  
 
The active compounds identified via the metabolic screen assay were then assessed to determine if the compound 
functions as an effective anti-epileptic compound. This includes a 3-pronged approach: i. extracellular field recordings 
in zebrafish; ii. video EEG (vEEG) recording in spontaneously epileptic Kcna1-null mice and; iii. acutely induced 
approaches in mice in collaboration with the United States National Institutes of Health-sponsored Epilepsy Therapy 
Screening Program (ETSP), which is the pre-eminent epilepsy screening program that, since 1975, has tested and 
made important contributions to nearly every anti-seizure drug developed over the past forty years. ETSP tested 
compounds across two mouse models of epilepsy – the 6Hz psychomotor and Maximal Electroshock Seizure (MES) 
models, which represent therapy resistant limbic seizures and tonic-clonic seizures respectively38, 39  
 
Of the compounds screened through this process, VOR was identified as a potent anti-epileptic compound. When 
measuring the extracellular field potentials from kcna1-MO zebrafish brains, repetitive high-frequency large amplitude 
spikes, indicative of hyperexcitability, were nearly completely abolished with VOR perfusion (Fig 2). Additionally, when 
Kcna1-null mice were treated with VOR, seizure frequency was significantly reduced by 60% (see Fig 3). Lastly, when 
the acute effect of VOR administration was tested on seizures in the 6 Hz psychomotor and MES models, mice form 
the 6 Hz model responded to all doses when dosed 30 minutes prior to the 6Hz test. However VOR was far less 
efficacious in the MES test, with only 2 animals responding when treated 2 hours prior to MES stimulation. These data 
suggests that VOR may not possess a broad-spectrum anti-seizure profile. However, anti-epileptic compounds that 
are principally effective in the MES model are voltage-gated sodium channel blockers with restricted efficacy in focal 
onset seizures. Furthermore, valproic acid (VPA), a commonly utilized anti-epileptic with known HDAC inhibitor activity, 
is considered a broad spectrum drug.  
 
 
 
Figure 2: Figure shows representative extracellular field recordings obtained from the optic tectum of 
6- days-post fertilization wild-type and kcna1-MO zebrafish larvae + VOR treatment 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
10 | P a g e  
 
 
 
Figure 3: Representative electrographic seizure recorded in Kcna1-null mice. Bar graph of the mean 
number of seizures per day recorded from six Kcna1-null mice + VOR treatment. VOR 
treatment significantly reduced the number of seizures (two way ANOVA, F=27.7, P<0.01). 
 
 
VOR is a potent inhibitor of histone deacetylases. These enzymes catalyze the removal of acetyl groups from the lysine 
residues of proteins, including histones and transcription factors 40. HDACs control various cellular functions by altering 
the dynamics of chromatin structure, which thereby affects gene transcription and can contribute to the pathogenesis 
of various diseases. The potential for HDAC inhibitors for the treatment of epilepsy was first proposed with the discovery 
of VPA’s HDAC activity. VPA is broad anti-epileptic drug used as a first-line treatment in various seizures and 
epilepsies. It was originally thought to block voltage-dependent sodium channels and increase brain levels of γ-
aminobutyric acid. However, more recently, VPA has been shown to also inhibit HDACs, and it is through this action 
that VPA is thought to offer its neuroprotective effects. VPA inhibits both Class I and Class IIa enzymes41, whereas 
VOR inhibits Class I, IIa, IIb, IV enzymes42, 43.  
 
Currently, VOR is approved by Health Canada for the treatment of cutaneous manifestations in patients with advanced 
cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease subsequent to prior systemic 
therapies40. The anti-neoplastic effect of VOR is attributed to the inhibition of HDAC activity and subsequent 
accumulation of acetylated proteins, including histones. Histone acetylation results in transcriptional activation of 
genes, including tumor suppressor genes, whose expression leads to induction of differentiation, apoptosis and/or 
inhibition of tumor growth40. 
 
 
1.1.3 
TOLERABILITY OF VORINOSTAT 
 
In Phase 1 studies, VOR has been generally well-tolerated with drug limiting toxicities (DLTs)44-47.  
• 
According to the VOR product monograph40, AEs reported at greater than 10% incidence at a dose of 400 mg/day 
were: fatigue (45.3%), diarrhea (46.5%), nausea (38.4%), thrombocytopenia (25.5%), dysgeusia (23.3%), 
anorexia (23.3%), weight decrease (19.8%), dry mouth (16.3%), alopecia (16.3%), muscle spasms (16.3%), 
anemia (12.8%), blood creatinine increase (12.8%), vomiting (11.6%), decreased appetite (11.6%), 
constipation (10.5%), chills (10.5%).  

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
11 | P a g e  
 
• 
Of these AEs, the following occurred with a severity of Grade 3-4 (moderate – life threatening): 
thrombocytopenia (5.8%), nausea (3.5%), muscle spasms (2.3%), anemia (2.3%), fatigue (2.3%), anorexia 
(2.3%), weight decrease (1.2%), decreased appetite (1.2%), chills (1.2%), dizziness (1.2%), and abdominal 
pain (1.2%). 
• 
SAEs outlined included events of pulmonary embolism (4.7%) and anemia (2.3%), as well as single 
experiences (1% incidence rate each) of thrombocytopenia, death of unknown cause, ischemic stroke, deep vein 
thrombosis (DVT), gastrointestinal hemorrhage, streptococcal bacteremia, dehydration and syncope, increased 
serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, and vomiting. There were 
a total of 5 deaths in these studies, which included disease progression, untreated sepsis, ischemic stroke and 
unknown cause; these were all considered unrelated to VOR. 
• 
Regarding dose modification, 10.5% of patients required a dose modification due to AEs. AEs included: increased 
serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia, and 
vomiting. 10.5% of patients discontinued VOR due to AEs, these included: anemia, angioneurotic edema, 
asthenia, chest pain, death, DVT, ischemic stroke, lethargy, pulmonary embolism and skin lesions. 
 
It is recommended by the product monograph that patients on VOR be closely monitored for several particular events, 
namely, thromboembolic events, QT/QTc prolongation, increased heart rate, hyperglycemia, dehydration, and 
hematologic events. In addition, VOR should be used with caution in special populations.  
• 
Thromboembolic events: a greater incidence of thromboembolic events appears to be associated with the use in 
VOR in adult patients with malignancies48. In the pivotal study in patients with CTCL, the incidence rate of 
pulmonary embolism and DVT was 4.7%, and 1.2%, respectively49. In all completed and ongoing studies in 
patients with CTCL, the proportion of patients with a venous thromboembolic event was 6.8%48. In greater than a 
1000 patients with hematologic malignancies and solid tumors who have been treated with VOR as monotherapy, 
or in combination with other chemotherapy agents, in completed and ongoing clinical studies, the proportion of 
patients that experienced a venous thromboembolic events was approximately 5.0%48. In a double-blind study of 
patients with advanced non-small cell lung cancer who received VOR in combination with chemotherapy, there 
was an increase in the incidence of venous thromboembolic events as compared to patients who received 
chemotherapy alone; DVT and/or pulmonary embolism was reported in 6.5% (8/124) of patients in the 
VOR/chemo arm compared to 2.4% (3/124) in the placebo arm48. 
• 
QT/QTc prolongation: Use of VOR is reported to be associated with QT/QTc interval prolongation, which may 
lead to torsade de pointes; particular care should be exercised in patients with increased risk of experiencing 
torsade de pointes and patients on medications known to increase QT/QTc interval48. 
• 
Increased heart rate: Use of VOR is reported to be associated with increases in heart rate, which may lead to 
worsening of cardiac conditions in patients with history of cardiac problems48. 
• 
Hyperglycemia: Hyperglycemia is reported at an incidence rate of 4.7%48 when using VOR.  
• 
Dehydration: Reported as a common serious drug-related AE in clinical trials48 with VOR. 
• 
Hematologic events: Use of VOR is associated with dose-related thrombocytopenia and anemia48.  
• 
Special populations: VOR should with caution in patients with mild hepatic impairment; it is not recommended in 
patients with moderate hepatic impairment, and is contraindicated in patients with severe hepatic impairment. 
 
The pivotal VOR studies reviewed above did not include a pediatric population, and currently VOR is not approved for 
use in children. As the proposed study design involves a pediatric population, it was elected to examine the tolerability 
profile of VOR in pediatric patients. Five Phase 1 studies utilizing VOR in a pediatric population were reviewed. These 
studies sought to investigate the efficacy, tolerability, and maximum tolerated dose (MTD) of VOR as a single agent 
and/or in combination therapy in pediatric populations with various malignancies. The first report reviewed was a Phase 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
12 | P a g e  
 
1 trial investigating the use of VOR alone and in combination with 13-cis-retinoic acid (13 cRA), an antiangiogenic 
agent, in children with recurrent or refractory malignancies, namely solid tumors and leukemia50. The second study 
was a Phase 1 trial investigating VOR in combination with Temozolomide (TEM) (an oral imidazotetrazine prodrug that 
undergoes spontaneous hydrolysis to the active metabolite MTIC, which methylates DNA at O6‐guanine and other 
sites), in children with recurrent or refractory brain or spinal cord tumors51. The third was a Phase I trial investigating 
VOR in combination with bortezomib (BOR), (a selective inhibitor of the ubiquitin‐proteasome pathway, which is 
essential for the degradation of most regulatory intracellular proteins), in children with recurrent or refractory solid 
tumors, including CNS tumors52. The fourth study was a pilot study investigating the combination of VOR and decitabine 
(DEC) (a cytidine anti-metabolite analogue that acts as a demethylating agent by incorporating itself into cellular DNA 
and covalently trapping DNA methyltransferase as a protein-DNA adduct), followed by standard re-induction 
chemotherapy to test the feasibility, tolerability and efficacy in patients with relapse or refractory acute lymphoblastic 
leukemia (ALL)53. The final study was a Phase 1 trial to determine the MTD of VOR and 131I-metaiodobenzylguanidine 
(MIBG) (a systemic radiopharmaceutical), when used in combination in children with relapsed or refractory 
neuroblastoma.54 
 
There were a total of 110 patients with ages ranging from 12 months to 60 years of age with median age being 11.4 
years of age. Three dosage levels of VOR were utilized in these studies, 180 mg/m2/d, 230 mg/m2/d; and 300 mg/m2/d. 
These dosages were utilized as single agents or in combination therapy with 160 mg/m2/d of 14cRA; 150 mg/m2 – 200 
mg/m2 TEM; 1.3 mg/m2/d BOR; 15 mg/m2 DEC; or 8 - 18 mCi/kg MIBG.  
 
Adverse events 
As these were oncology studies, with the majority attempting to determine MTD, AEs were typically graded according 
to the National Institutes of Health Common Terminology Criteria for Adverse Events (CTCAE) 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf). 
Therefore the prevalence of reported AEs are presented utilizing this grading system. Briefly, Grade 1 refers to mild, 
asymptomatic; Grade 2 refers to moderate events, which may require non-invasive interventions; Grade 3 refers to 
events that are severe but not life-threatening; or required hospitalization or prolongation; Grade 4 refers to life-
threatening events, and Grade 5 refers to events that lead to death.  
 
The AE prevalence given below is for all patients in all reviewed studies evaluable for toxicity, at all doses of treatment 
for cycle 1 of treatment: (See Table 1 for all AEs reported)  
 
• 
Across the five studies, there were a total of 378 AEs reported in 110 patients.  
• 
Of the 378 AEs, 158 (42%) were rated as Grade 2; 145 (38%) as Grade 3; 72 (19%) as Grade; and 3 (0.8 %) 
were Grade.  
• 
Grade 2-3 events: 45% of all Grade 2-3 AEs were hematologic type AEs; 27% were non-hematologic; less than 
10% were laboratory abnormalities (see Table 1 for specific AEs); the most commonly reported Grade 2-3 AEs 
were leukopenia (38%); lymphopenia (23%); thrombocytopenia (17%); neutropenia (15%); and anemia 
(14%).  
• 
Grade 4 events: 66% of all Grade 4 events were hematological; 26% were non-hematological; 7% were laboratory 
abnormalities (see Table 1 for specific AEs); the most commonly reported Grade 4 AEs were: leukopenia (32%); 
lymphopenia (26%); thrombocytopenia (22%); nausea (19%); anemia (18%); neutropenia (14%). 
• 
Grade 5 events: there were 3 events that led to death: hemorrhage/bleeding event; hypoxia/acute respiratory 
distress, and CNS hemorrhage. 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
13 | P a g e  
 
• 
DLT AEs: there were 36 AEs (10%) that met the criteria for DLTs; the most common DLT was thrombocytopenia 
(4%); severe DLTs included thrombosis (n=1), neuropathy (n=1), and hemorrhage (oral, n=1; CNS, n=1). 
 
Severe and Serious AEs  
 
DLTs were pre-defined in study protocols; they were typically divided into hematologic/non-hematologic categories and 
had to meet a severity Grade of 3 or 4. There were 3 events, which were considered as severe DLTs. The first was a 
case in which the patient developed a DVT in the iliac vein while on VOR monotherapy at a dose of 180 mg/m2, the 
lowest dose group utilized in the study50. The authors indicated that this was most likely not related to therapy, given 
that the patient was on oral contraceptives and had a vascular anomaly50. The second was a case of Grade 2 sensory 
neuropathy at the highest dose level of the study (300 mg/m2/d VOR + 1.3 mg/m2/d BOR). The patient had stable 
disease but elected to stop therapy; the neuropathy progressed however to Grade 3, requiring intensive analgesia for 
pain and physical rehabilitation. This event was attributed to BOR therapy by the researchers since this is a known AE 
associated with BOR52. The third case involved Grade 3 oral bleeding in the setting of Grade 4 thrombocytopenia and 
evidence of platelet allosensitization54. 
 
There were 3 deaths during the course of these studies. The first involved a single toxic death which included a Grade 
5 hemorrhage/bleed. This was attributed to the chemotherapy cocktail given after VOR/DEC therapy (230 mg/m2 VOR 
+ 15 mg/m2 DEC)53. The second death occurred in the same study in a patient who experienced Grade 5 hypoxia/acute 
respiratory distress and then died on day 4; this was attributed to disease progression53. The third death involved Grade 
5 central nervous system hemorrhage, in the setting of ongoing thrombocytopenia and coagulopathy54. The patient 
was on the highest dose of the study 18 mCi/kg MIBG + 230 mg/m2 VOR. This occurred in the same study as the Grade 
3 oral bleeding event described above. The authors indicated these events were unanticipated, since bleeding is an 
unusual event for both VOR and MIBG when used as single agents and that perhaps this event was the result of an 
unanticipated interaction between VOR and MIBG.  
 
There are similarities and differences between the adult studies (pivotal studies for FDA approval) to the reviewed 
pediatric studies. Comparing the Grade 3-4 events, it appears that children experience more hematologic events. For 
example, the incidence rate of thrombocytopenia in the pediatric studies was 29.1%, as compared to 5.8% in the adult 
studies; anemia was 12.7% in the pediatric studies, as compared to 2.3% in adults. Other hematologic events seen 
frequently in the pediatric studies were lymphopenia (34.5%), and leukopenia (29.1%); these were not reported in the 
adult studies. The highest non-hematologic event in children was nausea (24.5%), whereas in adults nausea was 
reported at 3.5%. Regarding serious adverse events (SAEs), DVT and bleeding/hemorrhage were reported in both 
adults and children, however in the pediatric studies, all SAEs were not attributed to VOR therapy. Discontinuation 
rates were higher in the pediatric studies than the adult studies (32.7% vs. 10.5%). Regarding the special cautionary 
AEs recommended for special monitoring in the product monograph, increased QT interval, hyperglycemia and 
dehydration had incidence rates of <1% each in the pediatric studies and there were no cases of increased heart rate. 
It is important to note that comparison of the adult studies and pediatric studies should be approached with the context 
that in the pediatric studies: patients with refractory/relapsed solid tumors, CNS tumors and leukemia also made up 
the tested population, in addition to refractory/relapsed CTCL patients; patients were heavily pre-treated prior to VOR 
treatment; and lastly the majority of patients were treated with a combination that included VOR as part of treatment.  

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
14 | P a g e  
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
15 | P a g e  
 
 
1.1.4 
TOLERABILITY OF VORINOSTAT IN PEDIATRIC EPILEPSY PATIENTS 
 
AS VOR has not been tested in a population with epilepsy, it is not possible to give the tolerability of VOR within this 
population. Further, findings from the reviewed VOR studies cannot be extrapolated to a population with epilepsy, due 
the severity of illness and heavy pre-treatment of the populations of patients enrolled. However, as indicated previously, 
VPA – a widely utilized AED - has been shown to be in the same class of drug as VOR. VPA is a broad-spectrum AED 
used as a first-line agent for both generalized and partial seizures. A wealth of data exists for VPA as a result of length 
of time on the market and widespread utilization. It was first used in Europe in 1968 and in the United States in 197855. 
VPA is one of the most widely-used AEDs in different regions of the world, being the most frequently prescribed AED 
in children in several European countries56, 57, and the second most frequently prescribed AED for children in the United 
States in the 1990’s58. VPA can be administered as monotherapy, however it is commonly administered as part of 
polytherapy regimens comprising several AEDs59. Therefore, although safety of VOR in a pediatric population is not 
known since the data is not available; the safety/tolerability of VOR can be taken in context of the safety data of VPA - 
a commonly utilized AED with HDAC inihibitor activity in pediatric populations of children with seizures/epilepsy, 
combined with that of commonly utilized AEDs, to inference the safety of VOR in a currently untested pediatric 
population with seizures. 
 
 
1.1.4.1 TOLERABILITY OF VPA IN POPULATIONS WITH EPILEPSY 
 
The safety/tolerability profile of VPA is generally positive in relation to efficacy, however there are several AEs, some 
potentially serious, reported with the use of VPA. For instance, the product monograph lists pancreatitis and 
hepatotoxicity, as known SAEs. Fatal hepatotoxicity has an estimated occurrence of 1:10,000 exposed patients and 
young children on polytherapy are a special group at risk60. Other potential SAEs listed in the product monograph 
include hyperammonemia and thrombocytopenia. Other less serious AEs, commonly associated with treatment 
discontinuation are also reported. However, reported rates vary greatly and prevalence and associated risk are difficult 
to assess. For example, thrombocytopenia, the most commonly reported AE for VPA is reported to occur in 5-60%61 
of treated patients. Weight gain, one of the most commonly reported reasons for drug discontinuation is reported to 
occur between 4-44% of patients62-65. Reasons for wide margins of reported prevalence of AEs include: variability in 
study design; number of participants; dosage; rate of titration; monotherapy vs polytherapy; and duration of follow up. 
Therefore a review of several large, multi-centered studies utilizing VPA for the treatment of epilepsy was conducted 
to gain context regarding the wide incidence rates of AEs, severity, and relationship to drug discontinuation with VPA.  
 
A total of 17 studies were reviewed, however one study was the 12-month follow up of the original study, and another 
study was an analysis of the pediatric sub-population of the original study. The studies comprised of large multi-national 
studies within the last 25 years. The range of participants treated with VPA in these studies was 78 – 1192 in each 
study, for a total of 3,777 participants. Participants were followed between 4 weeks – 6.6 years. 3 studies included 
adult participants only; 9 studies included adult and pediatric participants, and 5 studies included pediatric patients 
only. 3 studies allowed for polytherapy. Patient populations included newly diagnosed patients; therapy-resistant 
patients; and those who attained remission but had relapsed. All studies with the exception of one were multi-centered. 
12 studies were AED comparative studies, of these - 10 were randomized; 7 were double-blind; and 5 were open-label. 
2 studies were dose concentration studies, where patients were randomized to a low or high concentration dose. 3 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
16 | P a g e  
 
studies investigated various formulations of VPA only. Dosage ranged from 987 mg/day – 4114 mg/day for adult studies 
and combined adult/pediatric studies, and 17 mg/kg/day – 68.86 mg/kg/day for pediatric studies.  
 
In general, most treatment emergent AEs considered related were generally rated as mild to moderate in severity; 
occurred early in therapy, were transient, and rarely required discontinuation; most SAEs were not considered related 
to study medication66-69. Rates of overall AEs with VPA ranged from 23% to 88% in the 6 studies that reported overall 
rates of AEs70-75 the other 11 studies did not report overall rates66-69, 76-81. 13 studies reported 25 AE types that 
demonstrated a prevalence of > 10%66, 69-74, 76, 77, 79-82; 4 studies had no specific AE types that presented with a 
prevalence of > 10%67, 68, 75, 78. 
 
Adverse Events 
The most commonly reported AEs are shown in Table 2 below, only AEs with greater than > 10% prevalence within 
each study have been included.  
 
 
 
Serious Adverse Events 
Overall reported SAE rates ranged from 0.8% - 10% in the 6 studies reporting an SAE rate or where the rate could be 
calculated67, 69, 74, 76, 80, 81. The SAEs presented in Table 3 were reported in studies reviewed; since the actual number 
of participants who had experienced an SAE was often not clear, it was elected to summarize the number of studies 
where specific SAEs were reported.  
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
17 | P a g e  
 
 
 
 
Therapy discontinuations due to intolerable AEs 
All studies reviewed reported a rate of therapy discontinuation due to intolerable AEs. The range of rates of 
discontinuation due to intolerable AEs was 0%-33%. AEs presented in Table 4 were reported as the reason for 
treatment discontinuation. Rates of prevalence for individual AEs resulting in discontinuation were mostly not given, 
therefore it was elected to report number of studies where a specific AE was given as the reason for discontinuation. 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
18 | P a g e  
 
 
 
1.1.4.2 TOLERABILITY OF AEDs IN POPULATIONS WITH EPILEPSY 
 
There are over 20 AEDs that have been approved in North America and Europe. AEDs are considered to be of “3 
generations”, based on the timeframe of their development - 1st generation includes: carbamazepine (CBZ); clobazam; 
clonazepam; ethosuximide (ETX); phenobarbital; phenytoin; sulthiame; and VPA; 2nd generation includes: felbamate 
(FBM); gabapentin(GBP); lamotrigine (LTG); levetiracetam (LEV); oxcarbazepine (OXC); pregabalin; tigabine; 
topiramte (TPM); vigabatrin; zonisamide (ZNS); and 3rd generation includes: brivaracetam (BVC) , eslicarbazepine 
acetate, lacosamide (LCM); perampanel (PMP); retigabine; rufinamide; and stiripentol83. Modern AEDs (2nd and 3rd 
generation) are generally considered less enzyme-inducing, or are not metabolized by the oxidative cytochrome p450 
system, and are therefore less likely to be involved in drug interaction based on enzyme induction84. However in various 
studies comparing 1st generation to subsequent generations of AED, the efficacy/tolerability profile was comparable or 
better. Additionally, most 2nd/3rd generation AEDs are listed as adjunctive treatment of epilepsy in adults, and therefore 
used off-label in pediatric populations83. In general, the safety/tolerability of VPA is comparable to other AEDs, based 
on AEs, SAEs, and discontinuation rates.  
 
CBZ and VPA are both 1st generation AEDs and have been compared substantially since they were approved over 40 
years ago. The overall prevalence of AEs is similar for the two AEDs [52% VPA vs 55% CBZ71; 49.4 % VPA vs 48.4% 
CBZ70; 52% VPA vs 55% CBZ76]. Treatment failure due to SAEs is also comparable, with treatment failing in 5% of 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
19 | P a g e  
 
patients on VPA vs. 3% of patients on CBZ over a period of 6 months – 3 years70. Lastly, 90% of patients on VPA 
remained on treatment at 6 months, as compared to 75% of CBZ patients70 
 
OXC is a 2nd generation AED. Safety profiles are also similar between the drugs, where the proportion of patients in 
the OXC group and VPA groups experiencing at least one AE, regardless of relationship to the trial drug, is similar 
(89.8 % VPA vs. 87.6% OXC)72. Further, there were no statistically significant differences between VPA and OXC with 
respect to the total number of premature discontinuations or those due to AEs72. 
 
TPM is also a 2nd generation AED, and like VPA is a broad-spectrum AED. In one study, the time to exit study for any 
reason did not differ between VPA, TPM, or CBZ66. However in the pediatric substudy, discontinuation due to AEs was 
32% for VPA, 14% for TPM, and 4% for CBZ77. However in another study, which included an adult and pediatric 
population, there was no significant difference in overall clinically important AEs (22.7% VPA vs 24.9% TPM)75. There 
was also no significant differences for treatment failure due to intolerable AEs75.  
 
LTG is also a 2nd generation AED. LTG has been suggested as an alternative to VPA, particularly for women of 
childbearing age, because of concerns about higher rates of teratogenicity and delayed cognitive development in 
children exposed to VPA in utero73. However for time to treatment failure, there were significant differences between 
drugs, where VPA was the best option, as compared to LTG and TPM73. Further, cumulative incidence analysis of 
treatment failure for intolerable AEs indicated that TPM is significantly inferior to both VPA and LTG73. Similarly, another 
study also indicated that there was no significant difference in AEs leading to withdrawals between VPA and LTG78. 
Another study compared VPA with LTG and ETX (another 1st generation AED). There were no significant differences 
among the treatment groups at 20 weeks in the frequency of treatment failures due to either intolerable AEs or 
withdrawal from the study80. Although certain side-effects occurred more frequently among children treated with ETX 
or VPA, as opposed to LTG, these side effects were transient and did not require discontinuation of treatment80. 
However by 12 months, the largest percentage of subjects discontinuing due to AEs were in the VPA group 9% vs 3% 
for LTG, and 1% for ETX81. Although VPA discontinuations were mostly due to weight increase after 20 weeks of 
therapy81. Another study also did not show statistical differences for treatment failure due to intolerable AEs between 
VPA, LTG and ETX67 
 
Other 2nd generation AEDs are GBP, LEV, ZNS, and FBM. Overall treatment emergent AEs was reported at 77.9% for 
patients treated with ZNS85 and 63%86 for FBM. Report of incidence of drug-related AEs was 39-55%87 for LEV, and 
77.9% with ZNS85. Report of intolerable AEs was 15.2%88, and 19.3%87 for GBP and ZNS respectively. For LEV, 
incidence of drug-related SAEs were reported between 0-4.7%87 , while for ZNS it was reported to be 16.4%85. Reported 
life-threatening SAEs, namely – aplastic anemia and hepatotoxicity have severely limited the widespread use of FBM. 
The risk of hepatic failure with FBM has been estimated to be 1:18,500-25,00089 and some cases have resulted in liver 
transplant or death. Aplastic anemia is estimated to be 1:300089. As a result of these SAEs, the manufacturer 
recommends that written consent be obtained before therapy is initiated. 
 
The most recent AEDs are termed 3rd generation AEDs; included in this grouping are LCM, BVC, and PMP. Reported 
AEs incidence was reported at 42%90 for LCM, 37%91 for BVC, and between 64.5-89%92 for PMP, depending on dose. 
Discontinuations due to AEs were reported at 11%93 for LCM, and 3% for BVC91. SAEs were reported at 3.5-8.2% for 
PMP, depending on dose92. 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
20 | P a g e  
 
1.1.4.3 COMPARISON OF SAFETY/TOLERABILITY PROFILES OF VOR, VPA, and AEDs 
 
As VOR has only been trialed in populations with malignancies, a population with a serious illness burden that is heavily 
pretreated, safety and tolerability findings from these studies are potentially not applicable to an epilepsy population. 
Therefore it was decided to compare the safety and tolerability findings of VOR to those of VPA, a widely utilized HDAC 
inhibitor for the treatment of seizures and epilepsy. In turn, these findings were compared to the general tolerability of 
commonly used AEDs. As VOR is not approved for use in children, the tolerability in a pediatric population was 
examined by reviewing five Phase 1 trials, which included only pediatric participants or a combination of adult/pediatric 
participants testing VOR for the treatment of various malignancies. As the reported margins of safety and tolerability 
for VPA were quite large, a review of sixteen large (~100 pediatric/adult patients or more on VPA per study), 
international, multi-centered trials, utilizing VPA for the treatment of seizures/epilepsy was conducted to determine 
context for the wide reporting margins.  
 
 
Adverse Events 
The rate of overall AEs reported in the adult studies of VOR were 324 AEs (all grades) in 86 patients; in the reviewed 
pediatrics studies for VOR, there were a total of 378 AEs reported (Grade 2-5) in 110 patients. In the adult VOR studies, 
the most common AEs were diarrhea, nausea and thrombocytopenia; most Grade 3-4 AEs consisted of 
thrombocytopenia and nausea. In the reviewed pediatric studies, the most common AEs were hematologic type, and 
included leukocytopenia, lymphopenia, thrombocytopenia, neutropenia, and anemia; and the most common non-
hematologic AE was nausea; this profile of AEs was the case regardless of grade. There was a higher prevalence of 
Grade 3-4 AEs in the reviewed pediatric studies than the adult studies.  
 
For VPA, incidence of reported AEs ranged from 23-88% in reviewed studies; for AEDs (all generations), this ranged 
from 14 -89%. The most commonly reported AEs for VPA are weight gain, fatigue, tremor, headache, alopecia, nausea, 
thrombocytopenia, dizziness and vomiting. Overall it appears that the incidence of AEs is higher in VOR than in VPA 
or AEDs. 
 
 
Serious AEs:  
In the adult studies for VOR, the reported incidence rate of SAEs was 7%, which included pulmonary embolism and 
anemia. However SAEs are defined as “any untoward medical occurrence that at any dose results in death, is life-
threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization”. According to this 
definition, Grade 4 events would qualify as SAEs, however in the adult VOR studies, Grade 3-4 AEs were grouped 
together. The incidence rate of Grade 3-4 events in these studies was 24%. In the reviewed pediatric studies for VOR, 
the rate of incidence of reported serious events (serious DLTs and death) was 5%, and included thromboembolic 
events, bleeding/hemorrhage, neuropathy, and hypoxic/acute respiratory distress, however none of these events were 
considered to be related to VOR therapy. The incidence of Grade 4 events (considered SAEs as per the standard SAE 
definition) in these pediatric studies was 65%, the majority of which included: lymphopenia, thrombocytopenia, 
leukopenia, and nausea.  
 
The rates of SAEs for VPA and AEDs were comparable with 0.8 -10% for VPA, and 4.7-8.2% for AEDs. The most 
commonly reported SAEs for VPA were pancreatitis, hospitalization (unspecified) and pneumonia. Overall the rates of 
SAEs appears to be comparable for VOR, VPA and AEDs. However, when considering Grade 4 events as SAEs, as 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
21 | P a g e  
 
per the standard definition of SAE, it appears that children on VOR therapy exhibit a much higher prevalence of serious 
events, comprised mostly of hematologic events.  
 
 
AEs resulting in death 
In the adult VOR studies, there was a total of 5 deaths, each of which were considered unrelated. In the reviewed 
pediatric VOR studies there were a total of 3 events leading to death all of which were also considered unrelated. 
Several deaths were reported in the VPA studies reviewed, however none were deemed related to therapy.  
 
 
Discontinuation of therapy due to Intolerable Adverse Events or Dose-Limiting Toxicities 
In the adult VOR studies, rate of discontinuation due to AEs was 10.5% and included anemia, angioneurotic edema, 
asthenia, chest pain, death, DVT, ischemic stroke, lethargy, pulmonary embolism and skin lesions. In the reviewed 
pediatric VOR studies, the prevalence of AEs meeting the criteria for DLT was 33 %, one-third of these discontinuations 
were due to thrombocytopenia. For VPA, reported incidence of discontinuation due to intolerable AEs was between 0 
- 33%, but the majority of studies reported rates of up to 15%. For AEDs, rates of discontinuation due to intolerable 
AEs was between 3-19%. In the VPA reviewed studies, the most common reasons for discontinuation reported was 
weight gain, alopecia, fatigue, psychiatric/behavioral type AEs, tremor, and nausea/vomiting. The rates of 
discontinuation due to AEs is comparable for the adult studies of VOR, and reviewed studies of VPA and AEDs (when 
the median of the ranges are taken). However three of the reviewed VPA studies69, 77, 80, 81 reported discontinuation 
rates similar to the pediatric VOR studies; all of these studies were either exclusively pediatric or included pediatric 
patients. 
 
 
Anticipated safety and tolerability of VOR in pediatric patients with medically refractory epilepsy 
Overall, VOR is considered to be tolerable in populations of patients with various malignancies, however VOR has not 
been trialed in a pediatric population with seizures, and the safety and tolerability are unknown in this population. The 
pivotal studies for approval of VOR were reviewed, however this patient population only included adult patients with 
CTCL. In order to gain a better understanding of safety and tolerability of VOR in a pediatric population, Phase 1 studies 
utilizing VOR in pediatric populations were reviewed. However the patient populations in these studies included various 
refractory and recurrent malignancies that were heavily pretreated, and nearly all treatment arms included combination 
therapy. Given these conditions, it is unlikely that these findings can be translated to the population in this proposed 
study. Therefore, it was elected to also review and compare the safety and tolerability profile of VPA, another HDAC 
inhibitor that has been commonly used as a broad spectrum AED for over 30 years; to better set the context for the 
use of an HDAC inhibitor in the proposed population. Additionally, this was compared to the overall tolerability of AEDs 
in general. Three metrics were examined: overall AEs, SAEs, and discontinuations due to intolerable AEs. Following 
this analysis, a reasonable assumption of the safety and tolerability of VOR in a pediatric population with seizures can 
be made.  
 
When comparing overall AEs for VOR, it appears that there is higher prevalence of Grade 3-4 AEs in the pediatric 
population than in the adult population, and the majority of these events in the pediatric population are hematologic 
events, as opposed to constitutional events found in the adult studies. This is most likely due to several factors 
including: the inclusion of various other refractory/recurrent malignancies (solid tumors, CNS tumors, leukemia) in the 
pediatric population in addition to CTCL patients; patients in the pediatric population were heavily pre-treated prior to 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
22 | P a g e  
 
commencing in the studies; study treatment included combination therapy in addition to VOR in nearly all treatment 
arms. Further, in the pediatric studies, patients were only required to demonstrate moderate hematologic function 
(platelet count > 100,000/µL; and absolute neutrophil count > 1000/ µL) and not be transfusion dependent, whereas 
in the adult studies, eligibility criteria required patients to demonstrate adequate hematologic function. It is likely that 
the pediatric population in the Phase 1 VOR studies were particularly susceptible to the adverse hematologic effects 
of VOR. Indeed, thrombocytopenia is also a known AE associated with VPA, which has been shown to be dosage 
dependent79. There is also a possibility that the immature systems of children are more susceptible to these effects, 
however in large dose-dependent study, it was found that female gender and increased dose were correlated with 
greater likelihood of thrombocytopenia, however age was not79. Aside from the noted hematologic events, which made 
up approximately two-thirds of all AEs, the most commonly reported AE in the VOR pediatric studies was nausea; 
similarly the most commonly reported AEs in the adult VOR studies were diarrhea, nausea, and thrombocytopenia, 
albeit at less prevalent rates. It also appears that overall, there is a greater prevalence of AEs reported with VOR than 
with VPA or other AEDs. Although, the interpretation of this comparison is limited since the margins of the reported 
incidence rates for VPA and AEDs are quite large. Given the generally stable health status of patients in the proposed 
population, incidence of overall AEs is anticipated within the range of that typically found for AEDs, although there is a 
possibility that there may be a higher prevalence of hematologic type AEs.  
 
The second metric reviewed was SAEs. The incidence of SAEs as reported for the adult VOR studies was 7%; 5% for 
the pediatric VOR studies, 0.8-10% for VPA studies, and 4.7-8.2% for AEDs. Given the differences in study designs 
and populations, the rates of SAEs are comparable. The most common SAEs reported in the adult VOR studies were 
thromboembolic events and anemia; in the pediatric VOR studies, SAEs consisted of thromboembolic events, 
bleeding/hemorrhage, neuropathy, and hypoxic/acute respiratory distress. Indeed the product monograph indicates 
that thromboembolic events maybe associated with VOR therapy with an overall incidence rate of 6.8%. However in 
the pediatric VOR studies, all SAEs were not considered to be related to VOR. Typically however, severity of events 
in cancer trials are graded using the National Institutes of Health CTCAE Grading system, whereas clinical trials 
typically utilize the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH)/ Good Clinical Practice Guidelines (GCP) for rating severity of events. Utilizing the ICH-GCP definitions, a 
“serious” AE includes events that are life-threatening. Events rated as Grade 4 using the CTCAE system are considered 
to be life-threatening. Given this, Grade 4 events using the CTCAE reporting could be considered to be “SAEs”. An 
analysis could not be carried out on the adult VOR studies because Grade 3 and 4 events were grouped together for 
reporting, however in the pediatric VOR studies, inclusion of the Grade 4 as SAEs caused the incidence rate of SAEs 
to jump to 65%, with again the most commonly reported events comprising hematologic events and nausea. Although 
this is an important consideration, it is also important to note that the term ‘life-threatening’ in the ICH/GCP definition 
of an SAE refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. It is not absolutely clear whether these 
Grade 4 events meet the ICH/GCP criteria for a serious event. However, the fact remains that Grade 4 hematologic 
events, which according to the CTCAE are platelets < 25 x 109/L; absolute neutrophil count < 0.5 x 109/L; and 
lymphocyte count < 0.2 x 109/L; are medically quite serious, regardless of whether they meet a pre-set definition. As 
discussed in the above section, it is unlikely that the rates of incidence found in the Phase 1 VOR pediatric studies are 
expected in an overall medically stable population; it is anticipated that incidence of SAEs in the proposed population 
will be that typically seen with VPA/AEDs. However potentially serious hematologic events cannot be ruled out and 
hematologic testing, in addition to other lab safety testing will be conducted every 2 weeks to monitor study patients. 
Patients will also be advised of signs of symptoms associated with these hematologic events and to contact the study 
team in the event of these signs and symptoms. Regarding the other events cautioned to require special monitoring in 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
23 | P a g e  
 
the product monograph, the incidences in the VOR pediatric studies were quite low, with only 1 event of prolonged 
QT/QTc (Grade 3); 3 events of hyperglycemia (2 – Grade 3; 1 – Grade 4); and 3 events of dehydration (1 – Grade 2; 
2 – Grade 3); incidence of these AE types are anticipated to be quite low. Deaths are not expected to occur in this 
study.  
 
The final metric investigated was rate of discontinuation due to intolerable AE/DLTs. The rate of discontinuation in the 
adult VOR studies was 10.5%; in the pediatric VOR studies the prevalence of patients meeting the criteria for a DLT 
was 33%; for VPA, rate of discontinuation was 0-33%, and for AEDs, this was reported as 3-19%. On first impression, 
the rate of discontinuation due to intolerable AEs appear similar for the VOR pediatric studies and VPA reviewed 
studies. However, the VPA discontinuation rate may be somewhat inflated since the majority of the VPA reviewed 
studies reported rates of up to 15% (11/15 studies); and the studies with the higher reported rates did not allow for 
dose de-escalation in their study designs, which is not typical in clinical practice. It is of interest to note however that 
three of the studies reporting higher discontinuation rates due to AEs were pediatric only studies or included pediatric 
patients The rate of discontinuation for the pediatric VOR studies may also be somewhat inflated, because in fact this 
rate actually represents DLTs. In our analysis, DLT events were counted as “discontinuations due to intolerable AEs” 
in order to allow for comparison. Furthermore, all DLT events regardless of dosage of VOR and dosage of the other 
combined therapies was included in our analysis for discontinuation. In reality however, the majority of DLTs occurred 
at doses higher than 230 mg/m2, which is why this was recommended as the MTD for pediatric patients with 
malignancies. It is of note however that over one-third of discontinuations was due thrombocytopenia, once again 
suggesting that adverse hematologic events are common, potentially serious and often are the cause for 
discontinuation. This is in contrast to VPA, in which the most common reasons for discontinuation are weight gain, 
fatigue, alopecia, and behavioral changes in children. Although it has been indicated that, in general, findings of the 
VOR pediatric studies are most likely not applicable, nor expected in a pediatric population with seizures, it is possible 
that rate of discontinuation may actually be similar given that rates of discontinuations for VPA are seen in the range 
of 33% particularly in pediatric studies. Therefore it can be expected that rate of discontinuations may be in the range 
of that seen in the Phase 1 VOR pediatric studies, and that seen in the pediatric VPA studies.  
 
Following a careful review of adult studies of VOR, pediatric studies with VOR and comparing the safety and tolerability 
to VPA and AEDs, it is anticipated that VOR in a population of pediatric patients with epilepsy will be well-tolerated. 
Given the stable health status of patients to be recruited in this study and treating with VOR at a dosage of 230 mg/m2, 
it is anticipated that the rates will not be more remarkable than at seen for normally prescribed AEDs and VPA in all 
three metrics reviewed. It is anticipated however that there may be a higher proportion of events that are hematological 
in nature, as compared to other AEDs. However, this is not a surprising event for the HDAC inhibitor class of drugs, 
since VPA is known to be associated with greater incidences of thrombocytopenia. Safety measures are in place to 
carefully monitor and identify such events, as well as other possible AEs.  
 
 
1.2 RATIONALE FOR THE STUDY 
 
A single centre, open-label, phase 2A/B pediatric epilepsy pilot study, evaluating safety, tolerability, and efficacy of 
VOR in a pediatric population with medically intractable epilepsy is proposed. Currently the incidence of medically 
refractory epilepsy remains unacceptably high and an unmet medical need exists for these patients. Newly identified 
treatment targets to control seizures are clearly required, however typically drug development takes greater than a 
decade to become available as a treatment option. Therefore, a strategy which rapidly identifies potential therapies 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
24 | P a g e  
 
that can be rapidly tested in the clinical setting is paramount. The metabolism based discovery platform, initiated by 
our group is such a platform in which potential targets can be rapidly escalated to clinical trials in an accelerated 
knowledge translation manner. Via this platform, Dr. Kurrasch et al30 identified VOR as a potential viable therapy for 
the treatment of seizures in epilepsy. The pre-clinical work described above indicates outstanding efficacy and supports 
the potential benefit for VOR in potentially reducing refractory seizures in children with medically intractable epilepsy. 
VOR is currently approved by Health Canada for the treatment of CTCL malignancies. VOR demonstrated good 
tolerability in pediatric patients with various malignancies. When reviewing the safety and tolerability of VOR in the 
context of that of VPA and other AEDs, it is anticipated that tolerability of VOR will not be worse than that normally 
seen with currently approved AEDs in pediatric patients with medically refractory epilepsy.  
 
To our knowledge – this proposed study is the first trial investigating VOR within a pediatric population with medically 
intractable epilepsy. In this proposed pilot trial, pediatric patients, aged 4 to 17 (inclusive) with medically intractable 
epilepsy will be given VOR, at a dose of 230 mg/m2/day for a duration of 6 weeks to determine safety, tolerability and 
efficacy at this dose in combination with standard of care anti-seizure medications.  
 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
25 | P a g e  
 
SECTION 2.0: OBJECTIVES 
 
2.1 PRIMARY OBJECTIVES 
 
Characterize the safety and tolerability of 230 mg/m2/day VOR, administered orally, in a pediatric population with 
medically intractable epilepsy in combination with standard of care anti-seizure drugs. 
 
 
2.2 SECONDARY OBJECTIVES 
 
Evaluate the efficacy of 230 mg/m2/day of VOR, administered orally, in reducing seizures in a pediatric population with 
medically intractable epilepsy in combination with standard of care anti-seizure drugs. 
 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
26 | P a g e  
 
SECTION 3: STUDY DESIGN 
 
3.1 OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN 
 
The study will consist of a single centre, open-label Phase 2A/B pilot study evaluating the safety, tolerability, and 
efficacy, of VOR in a pediatric population with medically intractable epilepsy. Participants will be administered 230 
mg/m2/day of VOR in addition to standard of care anti-seizure medication for a duration of 6 weeks. 
 
 
3.1.1 DOSAGE 
Participants will be administered 230 mg/m2/day of VOR in addition to standard of care anti-seizure medication for a 
duration of 6 weeks. The dosage was chosen based on the MTD of five Phase 1 trials, which included pediatric patients 
or were exclusively pediatric trials50-54.  
 
Briefly, in a Phase 1 study, Fouladi et al50, investigated VOR alone and in combination with 13 cRA in children with 
recurrent or refractory malignancies (Part A – solid tumors; Part B – leukemia). Three dose levels were utilized: 180 
mg/m2 VOR; 180 mg/m2 VOR +13cRA; 230 mg/m2 VOR; 300 mg/m2 VOR). In the solid tumors group at a dose of 180 
mg/m2 VOR, one patient suffered an SAE, however this was deemed to not related to treatment. At the 230 mg/m2/d 
VOR dose level, there were no DLT in the first three patients enrolled. At 300 mg/m2/d DLT occurred in 2 of 6 patients 
but since the AEs were of different classes, the cohort was expanded to six additional evaluable patients. At this dose, 
2 patients had DLT thereby exceeding the MTD, therefore three additional patients were subsequently enrolled at the 
230 mg/m2. In this cohort, only one experienced a DLT, defining 230 mg/m2/d as the MTD and recommended phase II 
dose for children with solid tumors. The recommended phase II dose was then trialed in the refractory leukemia group. 
Two of the first five patients experienced DLT, therefore this does did not appear tolerable in children with refractory 
leukemia; no other dose finding was attempted in this population. 
 
In a Phase 1 study, Hummel et al51 investigated VOR in combination with TEM in children with recurrent or refractory 
brain or spinal cord tumors. Three dose levels were tested: 230 mg/m2 VOR + 150 mg/m2 TEM; 300 mg/m2 VOR + 150 
mg/m2TEM; 300 mg/m2 VOR + 200 mg/m2 TEM. There were no DLTs at Dose level 1 or 2. At dose 3, 4 patients had 
DLTs, therefore the recommended phase 2 dose for the combination of VOR and TEM as 300 mg/m2 VOR + 150 
mg/m2TEM. 
 
In a Phase 1 study, Muscal et al52 investigated VOR in combination with BOR in children with recurrent or refractory 
solid tumors, including CNS tumors. Three dose levels were tested: 180 mg/m2 VOR + 1.3 mg/m2/d BOR; 230 mg/m2 
VOR + 1.3 mg/m2/d BOR; 300 mg/m2 VOR + 1.3 mg/m2/d BOR. At the third dose level, 2 patients experienced DLTs, 
thus dose level 2 (230 mg/m2 + 1.3 mg/m2/d BOR ) is the recommended phase 2 dose. 
 
Burke et al 53 performed a pilot study investigating the combination of DEC and VOR followed by standard re-induction 
chemotherapy in patients with relapse or refractory acute lymphoblastic leukemia. The only dosage tested was 230 
mg/m2 VOR + 15 mg/m2 DEC. The choice of this dosage was based on prior Phase 1 studies identifying the MTD for 
these agents. 12 patients completed the full 4 days of treatment and were evaluable for toxicity assessment; 8 patients 
completed full protocol therapy and end of course evaluation; the one patient who did not complete the 4 days died of 
progressive disease on Day 4; the other 4 patients did not complete protocol therapy due to progressive disease , toxic 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
27 | P a g e  
 
death; family decision to stop due to toxicity; patient found to have leukemic involvement and physician elected to 
change treatment .  
 
Dubois et al54 conducted a phase I multicenter clinical trial conducted through the New Approaches to Neuroblastoma 
Therapy (NANT) consortium with the primary objective to determine the MTD of vorinostat and MIBG when used in 
combination. Five dosage levels were assessed: 8 mCi/kg 131I-MIBG + 180 mg/m2 VOR; 12 mCi/kg 131I-MIBG + 180 
mg/m2 VOR; 12 mCi/kg 131I-MIBG + 230 mg/m2 VOR; 15 mCi/kg 131I-MIBG + 230 mg/m2 VOR; 18 mCi/kg 131I-MIBG + 
230 mg/m2 VOR. There was no DLT at dose levels 1-3; at dose level 4, there was 1 DLT; and at dose level 5 – 2 
patients had DLT. Due to 2/2 patients with DLT at Dose 5, the dose was de-escalated to 18 mCi/kg 131I-MIBG + 180 
mg/m2 VOR because there were no DLT at that dose level. Therefore the MTD is 18 mCi/kg 131I-MIBG + 180 
mg/m2VOR; this is because MIBG is the main active agent in this combination and VOR acts a radiation sensitizer; the 
usual maximum feasible dose is 18 mCi/kg  
 
 
3.1.2 PHASES OF STUDY 
 
There are three phases to the study. 
 
Phase 1: Screening period 
 
During this phase, participants will be screened for study eligibility, which will last a total of 4 weeks. This will include 
several baseline investigations including full review of medical history and current medications, seizure frequency, 
physical examination, vital signs, laboratory safety testing, pregnancy testing for eligible patients, and 
electrocardiogram (ECG) (see Section 5 Schedule of Assessments and Procedures for complete list of screening 
procedures). In addition, baseline seizure frequency will be determined during this period. Clinically stable participants, 
fulfilling all eligibility criteria (see sections 4.2 and 4.3) will be enrolled in the treatment period of the study.  
 
 
Phase 2: Treatment period 
 
The duration of the treatment period will be 6 weeks. VOR will be given as fixed doses of 230 mg/m2/day. Following 
the enrollment visit, participants will visit the clinic for 2 more visits every 2 weeks, plus an end of treatment (EOT) visit 
(see Section 5.1 for detailed schedule). Participants may be seen more frequently for unscheduled visits for follow up 
of AEs, etc. as per the investigator’s discretion. Study visits will include a physical examination, height and weight 
measurement, vital signs, pregnancy testing (required patients only). Safety monitoring during the treatment period will 
include laboratory safety testing and ECG. Investigators will review current medications, AEs, seizure diary/frequency 
at each visit. Investigators will assess study medication adherence at all visits; unused study medication will be returned 
to site at each visit and new study medication will be dispensed by local pharmacy, as recommended by the 
investigator. Unused study medication will be destroyed as per local standard operating procedures. All assessments 
and visit procedures will occur as stipulated in Section 5: Schedule of Assessments and Procedures.  
 
 
Phase 3: Follow-up period 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
28 | P a g e  
 
A safety follow-visit (SFU) will take place 6 weeks after the EOT Visit. The SFU visit will include a physical examination, 
height and weight measurement, vital signs. Safety monitoring for this visit will include laboratory safety testing and 
ECG. Investigators will review AEs since last visit and seizure diary/frequency. Any ongoing AEs will be followed by 
the investigator until resolution or stability. 
 
 
3.1.2 END OF STUDY 
 
The end of the study is defined as the date of the last patient’s last visit, or the date at which the last data point, required 
for analysis, is completed, whichever date is later. 
 
 
3.2 RATIONALE FOR STUDY DESIGN 
 
The pre-clinical data for VOR is highly suggestive of a potential novel therapy for the treatment of medically intractable 
epilepsy. However, VOR is currently approved only for the treatment of cutaneous manifestations in patients with 
advanced CTCL who have progressive, persistent or recurrent disease subsequent to prior systemic therapies. A 
safety/efficacy trial of VOR in a population with medically intractable epilepsy is largely warranted, given the existing 
need for additional therapeutic strategies. The target population will consist of pediatric patients with medically 
intractable epilepsy, recruited from the Alberta Children’s Hospital (ACH) Neurology Outpatient Clinic, with medically 
intractable epilepsy despite exhaustive treatment with current standard therapies, who would be anticipated to benefit 
from a novel intervention strategy.  
 
The primary endpoints of this study are the safety & tolerability of VOR in pediatric patients with medically intractable 
epilepsy. The secondary endpoints of this study is the efficacy of VOR in reducing seizure frequency in this population 
pool. Participants will receive 230 mg/m2/day of VOR in addition to standard of care anti-seizure medication for a 
duration of 6 weeks, to evaluate the risk/benefit of VOR at this dosage on top of standard of care anti-seizure treatment.  
 
The proposed study design will allow for the study objectives to be met within the context of a typical Canadian clinical 
epilepsy treatment centre. Completion of this pilot study in this population will begin to indicate the safety & efficacy 
profile of VOR at a dosage of 230 mg/m2/day as a potential therapy for the treatment of seizures, and based on findings 
may justify a larger randomized study to further investigate this potential avenue in children with medically intractable 
epilepsy in a rapidly translational manner.  
 
 
3.3 NUMBER OF SUBJECTS 
 
12 pediatric patients meeting the criteria of medically intractable epilepsy in addition to the other eligibility criteria, 
recruited from the ACH Neurology Outpatient Clinic will be enrolled in study.  
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
29 | P a g e  
 
SECTION 4: STUDY POPULATION 
 
4.1 OVERVIEW 
 
The target population will consist of pediatric patients with medically intractable epilepsy, recruited from the ACH 
Neurology Outpatient Clinic, who continue to experience seizures despite exhaustive treatment with current standard 
therapies, and anticipated to possibly benefit from a novel intervention strategy. 
 
 
4.2 INCLUSION CRITERIA 
 
Patients must meet ALL of the following criteria in order to be eligible for this study: 
1. Males or females aged 2 – 17 years (inclusive)  
2. Medically intractable epilepsy, defined as having failed at least 2 standard anti-seizures therapies and 
experiencing at least 3 motor seizures per week, separated by at least 24 hours that are quantifiable by 
observation (e.g. discrete episodes of motor activity). Participants experiencing other seizure types in addition 
to motor seizures may also be enrolled but must meet the minimal requirement for motor seizures. 
3. Ability and willingness of family and/or caregiver (when appropriate) to give written informed consent and to 
comply with requirement of the study  
4. Adequate bone marrow function (defined as an absolute neutrophil count (ANC) of > 2 x 109/L; platelet count 
of > 150 x 109/L; hemoglobin of > 110 g/L [3-11 years], > 120 g/L [females 12 years or over], > 125 g/L [males 
12-14 years], > 137 g/L [males 15 years or older])  
5. Adequate renal function (defined as serum creatinine < 1.5X age-adjusted upper limit of normal [ULN], or 
glomerular filtration rate ≥ 70 mL/min/1.73 m2) 
6. Adequate hepatic function (defined as total bilirubin <1.5 times ULN, and alanine aminotransferase [ALT] and 
aspartate transaminase [AST] < 3 times ULN, and albumin >33 g/L) 
7. Corrected QT (QTc) interval of < 450 msec  
8. Prothrombin time (PTT) < 1.5 ULN/International Normalized Ratio (INR) < 1.5 ULN 
9. Participants on corticosteroids must be taking a stable or decreasing dose for at least 7 days prior to 
enrollment  
 
4.3 EXCLUSION CRITERIA 
 
Patients meeting any of the following criteria by the day of enrollment are NOT eligible for this study  
1. Treatment with valproic acid or other HDACi class drugs within at least the last 3 months at time of screening 
2. Enzyme-inducing AEDs (including oxcarbazepine (Trileptal), phenobarbital, phenytoin (Dilantin), topiramate 
(Topamax) 
3. Coumarin-derivative anti-coagulants 
4. Participants being considered for surgery for management of seizures during screening or who will be 
receiving surgery during for management of seizures during study period (includes all neurosurgery for the 
management of seizures or device implantation for the management of seizures) 
5. Neurosurgery within the past 12 months 
6. Use of Vagus Nerve Stimulator (VNS) where settings have not been stable for at least 6 months 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
30 | P a g e  
 
7. Planned surgery or other invasive medical treatment during screening of during treatment period  
8. Hypokalemia or hypomagnesemia  
9. Participants starting or currently on any neurometabolic diet (including but not limited to ketogenic diet; 
medium-chain triglyceride diet; modified Atkins diet; low glycemic index diet) during study 
10. History of non-catheter related deep venous thrombosis  
11. Pleural effusion  
12. Malignancy within the past 5 years. 
13. Any serious medical condition that according to the investigator could interfere with the conduct of the study 
14. Serious comorbid disease in which the life expectancy of the patient is shorter than the duration of the trial  
15. Unwillingness or inability to comply with study requirements 
16. Positive pregnancy test, lactating females or heterosexually active participants not willing to use highly 
effective methods of contraception (See Section 4.6)  
17. Participation in any clinical trial with an investigational drug, or therapy not approved by Health Canada, within 
one month prior to screening 
 
 
4.4 DIAGNOSTIC CRITERIA FOR MEDICALLY INTRACTABLE EPILEPSY  
 
Medically intractable epilepsy as defined by the ILAE 2010 task force as experiencing at least 3 motor seizures per 
week, separated by at least 24 hours that are quantifiable by observation (e.g. discrete episodes of motor activity), 
despite treatment with standard clinical therapies. Participants experiencing other seizure types in addition to motor 
seizures may also be enrolled but must meet the minimal requirement for motor seizures. 
 
 
4.5 CONCOMITANT MEDICATIONS AND TREATMENTS 
 
4.5.1 
PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS 
 
Participants may not be initiated on the following treatments or therapies during the study: 
• 
neurometabolic diets including but not limited to ketogenic diet; medium-chain triglyceride diet; modified Atkins 
diet; low glycemic index diet 
• 
surgery for the management of seizures; patients who have previously had surgery for the treatment of 
seizures may participate as long as surgery was completed a minimum of 12 months at time of enrolment  
• 
device implantation or use of other devices for the management of seizures; patients may be entered if device 
was implanted a minimum of 12 months prior to enrolment and settings have remained stable for a minimum 
of 6 months at time of enrollment 
• 
Valproic acid/valproate/divalproex sodium or other Histone Deacetylase (HDAC) Inhibitors 
• 
Enzyme inducing AEDs, including oxcarbazepine (Trileptal), phenobarbital, phenytoin (Dilantin), topiramate 
(Topamax) 
• 
Coumarin-derivative Anticoagulants 
• 
Any other therapy that is experimental or not approved by Health Canada (e.g. cannabidiol oil) 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
31 | P a g e  
 
4.5.2 PERMITTED CONCOMITTANT MEDICATIONS 
 
The use of any concomitant medication will be recorded in the study record.  
 
Treatment for Epilepsy  
 
Patients will continue on their evidence-based medical care for epilepsy as described in regional guidelines and 
institutional care pathways. All contemporary evidence-based medical care for ACH should be initiated as early as 
possible during the screening period to allow time for stabilization of the treatment effects before enrollment.  
 
Investigators will monitor patients/treat patients as per normal clinical practice with regard to these medications for the 
duration of the study. Therapy dose adjustments for the treatment of epilepsy will be left to the investigators’ discretion, 
however it is highly recommended that adjustments be minimized throughout the period of the study.  
 
Patients who have a VNS device implanted for the management of seizures, and whose device treatment parameters 
are optimized and stable for the last 6 months may participate in study. Changes to the device treatment parameters 
should be avoided during the study. 
 
 
Permitted medications with special precautions 
 
Other QT/QTc Prolonging Drugs:  
 
As per the product insert, concomitant use of VOR with another QTc prolonging drug may have an additive effect on 
QTc interval, and the concomitant use of VOR with another QT/QTc-prolonging drug should be avoided. This includes: 
Class IA antiarrhythmics; Class III antiarrhythmics; Class IC antiarrhythmics; anthracyclines; tyrosine kinase inhibitors 
antipsychotics; antidepressants; opioids; macrolide antibiotics and analogues; quinolone antibiotics; pentamidine; 
antimalarials; azole antifungals; domperidone; 5-HT3 receptor antagonists; tacrolimus; beta-2 adrenoceptor agonists. 
In the case where a participant is taking a QT/QTc prolonging drug during treatment phase, it is recommended that an 
ECG be conducted within one week or starting VOR and the QT/QTc prolonging drug if the next protocol ECG is longer 
than one week. Additional ECGs should be conducted as per the investigator’s discretion if the participant is exhibiting 
signs of QT/QTc prolongation. 
 
 
Drugs that Disrupt Electrolyte Levels:  
 
Electrolyte imbalance such as hypokalemia increases the risk of QTc interval prolongation, therefore the use of VOR 
with drugs disrupting electrolyte level is discouraged. Drugs that can disrupt electrolyte levels include, but is not limited 
to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; and high dose 
corticosteroids. Additional laboratory testing may be conducted as per the investigator’s discretion if the participant is 
exhibiting signs of disruption of electrolyte levels. 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
32 | P a g e  
 
4.6 CONTRACEPTION PROTECTION  
 
Heterosexually active females and males (partners of male participants, as appropriate) must use an acceptable 
method of contraception to prevent pregnancy. Acceptable methods of contraception include the following: 
 
• 
Abstinence  
• 
Barrier type devices (e.g. female condom, diaphragm and contraceptive sponge) used ONLY in combination 
with a spermicide 
• 
Intra-uterine devices 
• 
Oral contraceptive agents started at least 90 days before start of study 
• 
Depo-Provera (medroxyprogesterone acetate) 
• 
Levonorgestrel implants 
• 
Naturally or surgically sterile females (amenorrheic for at least 1 year and no record of conception for naturally 
sterile persons) 
• 
Male partner is sterile and is the only sexual partner. 
 
 
4.7 CRITERIA FOR PREMATURE WITHDRAWAL 
 
Participants have the right to refuse treatment or completely withdraw from the study at any time for any reason. The 
investigator also has the right to discontinue treatment and withdraw participants from the study treatment in the event 
of intercurrent illness, AE, treatment failure, protocol violations, administrative reasons, or other reasons deemed 
necessary by the investigator. 
 
Participants with significant drug compliance issues or safety monitoring compliance issues, not related to AEs will be 
withdrawn from the treatment phase of the study by the investigator and an EOT visit as well as an SFU visit will be 
attempted to be performed in all cases.  
 
If the participant withdraws from study treatment only, they will undergo an EOT visit and SFU visit. If the reason for 
removal of a participant from the study is an AE or an abnormal laboratory test result, the principal specific event or 
test will be recorded in the study record. If the participant explicitly withdraws consent for additional follow-up, the 
participant will be asked to undergo a phone SFU visit at the absolute minimum. In addition, all efforts will be made to 
complete and report the observations prior to withdrawal as thoroughly as possible. A complete final evaluation at the 
time of the participant’s withdrawal should be made with an explanation of why the participant is withdrawing from the 
study. In the event that a participant is lost to follow up, the last assumed day of medication will be the last day for 
which number of doses was provided. An attempt will be made to contact participants, via provided phone, email, and 
registered letter to the address provided. All attempts to contact will be recorded in the study record. In the event that 
all attempts for contact fail, a chart review and review of NetCare will done at 6 weeks following the last assumed day 
of medication. 
 
 
4.8 REPLACEMENT POLICY  
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
33 | P a g e  
 
Participants who withdraw/are withdrawn or discontinue study medication will not be replaced. Participants who 
discontinue medication/withdraw from study for non-safety issues within 14 days of commencing study medication will 
not be included in the final analysis.   
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
34 | P a g e  
 
SECTION 5: SCHEDULE OF ASSESSMENTS AND PROCEDURES 
 
5.1 PROCEDURES 
 
A detailed schedule of assessments by visit is shown in Table 5 below.  
Table 5: Schedule of events 
 
Study Period 
Screening 
Enrollment 
Treatment Period 
Follow Up 
Visit 
V1 
V2 
V3 
V4 
EOT6 
SFU7 
Total duration 
(weeks) 
- 4 weeks 
0 
2 
4 
6 
12 
Visit windows 
(weeks)  
 
 
+ 2  
days 
+ 2  
days 
+ 2  
days 
+ 5  
days 
Written informed 
consent 
X 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
Medical history1  
X 
X 
 
 
 
 
Physical 
examination 
X 
 
X 
X2 
X 
X 
Complete 
Neurological 
examination 
X 
X 
X 
X 
X 
X 
Anthropometrics 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
Laboratory 
testing 
X 
 
X 
X 
X 
X 
Serum 
Pregnancy test4 
X 
 
 
X 
 
X 
Urine pregnancy 
test 
 
X 
 
 
 
 
Study 
medication 
dispense 
 
X 
X 
X 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
35 | P a g e  
 
Medication 
compliance audit 
 
 
X 
X 
X 
 
Concomitant 
medication 
review 
X 
X 
X 
X 
X 
X 
Seizure 
Frequency 
review 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
ECG 
X5 
 
X 
 
 
X 
1. Medical history and Epilepsy history, including other relevant baseline disease characteristics. All available 
epilepsy history will be collected. Other Medical history will be collected for the past 12 months. 
2. Abbreviated physical exam 
3. Blood pressure, heart rate, breathing rate, and temperature. 
4. Only for female patients of childbearing potential. 
5. For screening, the results of a clinically indicated ECG, found to be non-clinically significant within the last 4 
weeks can be utilized. 
6. EOT may occur prior to 6 weeks if participant is discontinued or withdrawn before completing entire study as 
per protocol. In the case of withdrawal, the EOT visit should be completed within 2 weeks of the date of 
withdrawal. 
7. SFU visit may occur prior to 12 weeks if participant is discontinued or withdrawn before completing entire study 
as per protocol. In the case of withdrawal, an SFU visit (or at minimum telephone contact) should be completed 
within 6 weeks of the EOT visit. 
 
 
 
5.1.1 SCREENING EXAMINATION AND ELIGIBILITY SCREENING FORM – VISIT 1 
 
All participants must sign and date the most current Institutional Review Board (IRB)-approved written informed consent 
before any study-specific assessments or procedures are performed. A screening number will be allocated to each 
participant. An Eligibility Screening Form (ESF) documenting the investigator’s assessment of each screened 
participant with regard to the protocol’s inclusion and exclusion criteria will be completed by the investigator. A screen 
failure log will be maintained by the investigator. 
 
The following study-specific activities will be completed at the screening examination: 
• 
Medical history: Medical history for the past 12 months and all Epilepsy history will be abstracted from 
participant’s hospital medical record and patient interview.  
• 
Physical examination: the investigator will conduct a complete physical and neurological examination 
• 
Anthropometrics: height and weight will be taken  
• 
Vital signs: blood pressure and heart rate, breathing rate, and temperature will be taken 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
36 | P a g e  
 
• 
Baseline laboratory testing (see Section 5.3.2.4 for description of laboratory testing): This will be done through 
a service contract via Calgary Lab Services. The Calgary Lab Services reference range will be utilized to 
assess the clinical relevance of results.  
• 
Pregnancy test: a serum pregnancy test will be administered to all sexually active females of post-menarche 
status. All heterosexually active males and females will be counseled on the use of appropriate contraceptives 
during study participation. 
• 
Concomitant medications: will be collected to ensure that the patient is not on any prohibited medications 
• 
Seizure frequency: current seizure types and frequency will be reviewed. Proper seizure tracking will be 
reviewed with the participant/patient and family; participants will be encouraged to download and use the 
Seizure Tracker app on their smart phone. Participants will be asked to track their seizures for the duration of 
the screening period. 
• 
ECG: An ECG will be collected through a service contract via the Cardiology department at the ACH. 
Participants who have had a clinically indicated ECG, found to be non-clinically significant, within 1 month 
prior to screening will not require another ECG, provided the investigator deems the participant stable. The 
ECG may be collected at any point following the screening visit until enrollment visit (Visit 2), as long as results 
are available and may be reviewed by the investigator prior to enrollment 
 
 
5.1.2 ENROLLMENT VISIT – VISIT 2  
 
Participants meeting all inclusion and no exclusion criteria will be enrolled. Participants will receive study medication 
at this visit.  
 
The following study specific activities will be completed at the enrolment visit (Visit 2): 
• 
Medical history: Medical history and Epilepsy history will be reviewed once again to ensure that any new 
history since screening is captured.  
• 
Anthropometrics: height and weight will be captured to establish baseline growth and to calculate body surface 
area (BSA) for proper medication dosing 
• 
Vital signs: blood pressure and heart rate 
• 
Pregnancy test: a urine pregnancy test will be done for all applicable participants 
• 
Study medication dispensed: Study medication will be prepared and dispensed by the ACH research 
pharmacy, with dosage based on participant BSA (see Section 6.1). Participants will be counseled by the 
investigator on: how to take the medication, including to consume enough fluids to maintain adequate daily 
hydration, as adjusted for age; to contact the investigator promptly if excessive vomiting/diarrhea; or dizziness, 
palpitations, syncope, or increased seizures develop; or to contact the investigator immediately or present to 
the emergency room if leg swelling, chest pain, or shortness of breath develop. Participants will take VOR, 
230 mg/m2 once daily, preferably at the same time of the day throughout the treatment portion of the study, 
in addition to their prescribed evidence-based medical care for seizure management. 
• 
Participants will be given enough study medication to last until the next study visit plus 2 days in the event 
that the participant cannot make this visit. In this case, the study coordinator will ensure, via phone 
communication, that participant is not missing a visit due to AEs. In the event of an AE, the investigator will 
speak to participants/caregivers to give further instruction. If patient is hospitalized, appropriate SAE 
measures will be undertaken. If participants need to reschedule beyond the 2-day window, additional study 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
37 | P a g e  
 
medication may be prescribed by the investigator and dispensed by the ACH research pharmacy on a case 
by case basis. Participants will not be given medication if the following visit is also missed, without explicit 
permission by the investigator.  
• 
Concomitant medications: will be reviewed again to ensure that information has not changed since screening 
visit 
• 
Seizure frequency: current seizure types and frequency will be reviewed. Proper seizure tracking will be 
reviewed again with the participant/patient and family. 
 
 
5.1.3 ASSESSMENTS AND PROCEDURES DURING THE TREATMENT PERIOD 
 
Participants will be required to undergo regular visits during the treatment period for the assessments of 
safety/tolerability and efficacy as outlined in Table 5: Schedule of events 
. They will visit the study center at 2-, and 4 weeks, at 6 weeks for the EOT visit, and 6-weeks after the EOT for the 
SFU visit. If a participant is discontinued from study medication and/or withdrawn prior to completing the study as per 
protocol, the EOT visit may occur prior to 6 weeks following enrollment. The SFU visit should be completed within 6 
weeks of medication discontinuation.  
 
In addition, the following evaluations will be performed at each visit at the clinic throughout the treatment period: 
• 
Physical examination: standardized physical examinations will be performed at all study visits; an abbreviated 
physical exam will be conducted at Visit 4 (week 4 visit) 
• 
Complete neurological examination: a complete neurological examination will be completed at all study visits. 
• 
Anthropometrics: height and weight will be captured at all study visits to assess for appropriate growth and 
for proper medication dosing  
• 
Vital signs: will be captured at all study visits 
• 
Laboratory monitoring: participants will visit the lab for testing at all study visits during this period. Investigators 
will contact participants if results warrant intervention prior to the next scheduled visit.   
• 
Pregnancy test: Serum pregnancy test will be taken at Visit 4.  
• 
Study medication dispensing and medication compliance: Following investigator recommendation, 
participants will receive new drug supply at each defined visit. Participants will be required to bring in old 
unused drug for assessment of compliance. The importance of compliance will be emphasized at each visit. 
Participants will also be reminded to strive to consume enough fluids to maintain adequate daily hydration, as 
adjusted for age. Medication will not be dispensed at the EOT visit. 
• 
Concomitant medications: will be reviewed at each study visit. 
• 
Review of AE: Participant’s AEs will be reviewed at each study visit. However participants are encouraged to 
inform investigators about occurrence of AEs as soon as possible; i.e. not wait until their next scheduled visit.  
• 
Seizure Frequency: Participants will be asked to provide their seizure tracker information since the last study 
visit. Participants’ seizure types and how to accurately record seizure frequency will be reviewed by the 
investigator at each study visit. If participants commence to exhibit new seizure types, they will be asked to 
collect the seizure frequency of the new seizure type. 
• 
ECG: an ECG will be conducted on Visit 3. The ECG may be collected within 1 week prior to study visit 
depending on appointment availability at the ECG lab. 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
38 | P a g e  
 
 
5.1.4 SAFETY FOLLOWUP 
 
An SFU for all participants, including patients prematurely withdrawn from treatment, will be conducted 6 weeks after 
the EOT visit. This visit will include:  
 
• 
Physical examination 
• 
Complete neurological examination 
• 
Anthropometrics 
• 
Vital signs 
• 
Laboratory monitoring. Participants will be contacted with results requiring intervention  
• 
Pregnancy test: a serum pregnancy test will be taken for applicable participants. 
• 
Concomitant medications 
• 
Seizure Frequency 
• 
Review of Adverse Events  
• 
Review of seizure frequency 
• 
ECG: may be collected within 1 week prior to study visit. 
 
 
5.2 OUTCOMES ASSESSMENTS 
 
5.2.1 SAFETY AND TOLERABILITY ASSESSMENT  
 
The safety and tolerability of VOR at a dose of 230 mg/m2/day in a pediatric population with medically intractable 
epilepsy will be assessed via incidence of AEs and SAEs, as well as discontinuations due to intolerable AEs, identified 
through Safety Monitoring Activities (See Section 5.3).  
 
It is anticipated that the tolerability of VOR in a medically resistant population of pediatric patients with epilepsy will be 
similar to that seen with currently prescribed AED therapies. Namely, the incidence rate for overall AEs is anticipated 
to be up to 55%; incidence of SAEs to be no more than 10%; no deaths are expected in the course of the trial; and 
discontinuation rate due to intolerable AEs is expected to be up to 30%.  
 
5.2.2 EFFICACY ASSESSMENTS 
 
5.2.2.1 PRIMARY EFFICACY ASSESSMENTS 
 
Treatment response will be determined by the proportion of participants who have at least at 50% reduction rate of 
seizures. 
 
 
5.3 SAFETY MONITORING 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
39 | P a g e  
 
5.3.1 ADVERSE EVENTS 
 
AEs (serious and non-serious) reported by the participant or observed by the investigator will be collected throughout 
the study. At each visit, the investigator will ask the participant if any untoward medical event occurred since the last 
visit. For each event, the date of onset and date of resolution, intensity, relationship to study medication, outcome and 
treatments administered for the event will be recorded in the study record. 
 
AEs will include any symptom, sign, illness or experience, or clinically relevant lab abnormality, regardless of causality, 
which develops or worsens in severity during the course of the study. An SAE will comprise of any AE, occurring at 
any dose, regardless of causality that was either life-threatening, requires inpatient hospitalization or prolonging an 
existing hospitalization, or is determined as an important medical event by the treating physician, or results in death.  
 
All AEs will be reported as stipulated in Section 7.1. SAEs will be reported to the research ethics board (REB) and to 
Health Canada.  
 
 
5.3.2 SAFETY MONITORING 
 
All safety monitoring will be performed as summarized in Table 5: Schedule of events. 
.  
5.3.2.1 VITAL SIGNS 
 
Seated blood pressure and pulse will be recorded after at least a 5-minute rest. Two measurements should be made 
for each blood pressure measurement and the average derived.  
 
 
5.3.2.2 ANTHROPOMETRICS 
 
Body weight and height will be measured at each study visit.  
 
 
5.3.2.3 DIRECTED PHYSICAL EXAM 
 
The directed physical examination will include a general physical examination and neurological examination. Special 
attention will be paid to the signs and symptoms reported with VOR. Any clinically significant abnormalities persisting 
at the end of the study will be followed by the investigator until resolution or until achievement of a clinically stable 
endpoint. 
 
 
5.3.2.4 LABORATORY BLOOD SAMPLES 
 
All blood samples will be taken and processed by the Calgary Lab Services.  
 
Hematology  

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
40 | P a g e  
 
Blood samples will be obtained to conduct a complete blood count, according to the schedule summarized in Table 5: 
Schedule of events. 
 
 
Coagulation 
Blood samples will be obtained to assess coagulation (PTT/INR) 
 
Serum Chemistry 
Blood samples will be obtained to assess the following, according to the schedule summarized in Table 5: Schedule of 
events: 
• 
renal function (serum creatinine and blood urea nitrogen) 
• 
hepatic function (bilirubin, ALT, AST, and albumin) 
• 
electrolyte monitoring, including: sodium, potassium, chloride, magnesium, and calcium 
• 
blood glucose 
• 
lactate dehydrogenase 
 
 
5.3.2.5 PREGNANCY TEST  
 
Serum β-HCG levels test will be obtained for heterosexually active women of childbearing potential, according to the 
schedule summarized in Table 5: Schedule of events. 
. 
 
A urine pregnancy test will be done in office at the enrollment visit for applicable participants. 
 
 
5.3.2.6 ECG 
 
ECG will be recorded a total of 3 times, according to the schedule summarized in Table 5: Schedule of events. 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
41 | P a g e  
 
SECTION 6: INVESTIGATIONAL MEDICINAL PRODUCT 
 
6.1 FORMULATION, PACKAGING AND LABELING 
 
6.1.1 FORMULATION 
 
The oral formulation of VOR is available as a 100-mg capsule.  
 
 
6.1.2 PACKAGING & LABELING 
 
VOR will be packaged by the ACH research pharmacy in an open-label fashion in high-density polyethylene bottles. 
Labeling will be labeled as per Health Canada requirements, which includes the drug name, pill count, dosing 
instructions and storage instructions. 
 
 
6.1.3 STORAGE 
 
The study medication must be stored in a secure place at room temperature (not above 25°C). 
 
 
6.2 DOSE AND SCHEDULE OF STUDY MEDICATION  
 
6.2.1 DOSAGE RATIONALE 
 
Several studies have investigated the MTD, and DLT, when administered as a single agent and in combination of other 
cancer treatment in pediatric populations with various malignancies50-54. VOR administered orally to these populations 
at a dosage of 230 mg/m2/day was found to be efficacious, and was overall considered to be well-tolerated in these 
populations.  
 
6.2.2 DOSAGE 
 
Participants will take 100 mg VOR capsules orally to meet dose of 230 mg/m2 once per day as closely as possible. The 
following dose rounding table will be used as a reference for drug dosing dispensed based on BSA, where  
 
BSA(m2) = SQRT([height(cm) x weight (kg)]/3600) 
 
VOR 
dosage 
(mg/m2) 
BSA 
0.5 –  
0.74 
0.75 
– 
0.99 
1 –  
1.24 
1.25 
– 
1.49 
1.5 –  
1.74 
1.75 
– 
1.99 
2 –  
2.24 
2.25 
– 
2.49 
230 
100 
200 
200 
300 
300 
400 
400 
500 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
42 | P a g e  
 
 
6.2.3 DOSE INTERRUPTIONS 
 
If a dose is missed, it should be taken as soon as possible. If the participant does not remember until it is nearly time 
for the next dose, the participant should skip the missed dose and go back to the regular schedule. A double dose of 
should not be taken. 
 
There will be no temporary interruptions of study medication due to safety reasons. If study medication is stopped due 
to safety reason, there will be no re-challenge. 
 
 
6.3 ASSESSMENT OF COMPLIANCE 
 
Assessment Accountability and subject compliance will be assessed by maintaining adequate drug dispensing and 
return records. Participants will be asked to return all used and unused drug supply containers at each visit as a 
measure of compliance. An investigator may decide to withdraw a participant within the first 14 days, if the participant 
is found to be non-compliant. Compliance will be defined as having taking study medication as directed 80% of the 
time. Participants will be encouraged to discuss issues affecting compliance with the investigator. 
 
A Drug Dispensing Log will be kept current with the following information: 
• 
Identification of the participant to whom the study medication was dispensed 
• 
Date[s], quantity of the study medication dispensed to the participant 
• 
Date[s] and quantity of the study medication returned by the participant 
 
 
6.4 DESTRUCTION OF STUDY MEDICATION  
 
Following reconciliation against the documentation of quantity dispensed and returned, destruction of drug will be done 
as per the ACH Research pharmacy’s standard operating procedures.  
 
This includes:  
• 
Identity [batch numbers or subject numbers] of study medication destroyed 
• 
Quantity of study medication destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of responsible person looking after study medication destruction 
 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
43 | P a g e  
 
SECTION 7: SAFETY INSTRUCTION AND GUIDANCE 
 
7.1 ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
 
 
7.1.1 CLINICAL ADVERSE EVENTS 
 
An AE is any untoward medical occurrence in a patient or clinical investigation participant, administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign including an abnormal laboratory finding, symptom, or disease temporally 
associated with the use of a medicinal investigational product, whether or not considered related to the medicinal 
investigational product. Pre-existing conditions which worsen during a study are also to be reported as AEs. 
 
 
7.1.1.1 INTENSITY 
 
All clinical AEs encountered during the clinical study will be reported in the study record. The intensity of AEs will be 
graded by the investigator on a three-point scale (mild, moderate, severe) and reported in detail on the CRF. 
 
Mild 
discomfort noticed but no disruption of normal daily activity 
Moderate  
discomfort sufficient to reduce or affect daily activity 
Severe 
inability to work or perform normal daily activity 
 
 
7.1.1.2. DRUG – ADVERSE EVENT RELATIONSHIP 
 
Relationship of the AE to the treatment will be assessed by the investigator as either: Yes or No 
 
If there is a reasonable suspected causal relationship to the study medication, i.e., there are facts (evidence) or 
arguments to suggest a causal relationship, drug-event relationship should be assessed as Yes. The following criteria 
should be considered in order to assess the relationship as Yes: 
 
• 
Reasonable temporal association with drug administration. 
• 
May or may not have been produced by the patient’s clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient 
• 
Known response pattern to suspected drug 
• 
Disappears or decreases on cessation 
 
The following criteria should be considered in order to assess the relationship as No: 
 
• 
It does not follow a reasonable temporal sequence from the administration of the drug. 
• 
It may readily have been produced by the patient’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the patient. 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
44 | P a g e  
 
• 
It does not follow a known pattern of response to the suspected drug. 
 
 
7.1.1.3 SERIOUS ADVERSE EVENTS 
 
An SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution. It is any AE 
that at any dose fulfills at least one of the seriousness criteria following criteria: 
 
• 
is fatal/results in death (NOTE: death is an outcome, not an event) 
• 
is life-threatening (i.e. refers to an event in which the patient was at immediate risk of death at the time of the 
event; it does not refer to an event which could hypothetically have caused a death had it been more severe).  
• 
requires in-patient hospitalization or prolongation of existing hospitalization; 
• 
results in persistent or significant disability/incapacity; 
• 
is a congenital anomaly/birth defect; 
• 
is medically significant or requires intervention to prevent one or other of the outcomes listed above. 
 
SAE reporting procedures are described in Section 7.2. Death is the outcome of an event and will not be reported as 
the SAE term, rather the event causing the death will be reported as the SAE. The only exception is when the cause 
of death is not known; these cases will be reported as “Death Unknown”. 
 
 
7.1.2 LABORATORY TEST ABNORMALITIES 
 
Any laboratory result abnormality fulfilling the criteria for a SAE will be reported as such, in addition to being recorded 
as an AE in the study record. 
 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting one or more of the 
following conditions, will be recorded as a single diagnosis in the study record: 
 
• 
Accompanied by clinical symptoms 
• 
Leading to a change in study medication (e.g., interruption or permanent discontinuation) 
• 
Requiring a change in concomitant therapy (e.g., addition of, interruption of, discontinuation of, or any other 
change in a concomitant medication, therapy or treatment). 
 
This will apply to any protocol and non-protocol specified safety and efficacy laboratory result from tests performed 
after the first dose of study medication, which falls outside the laboratory reference range and meets the clinical 
significance criteria. 
 
This will not apply to any abnormal laboratory result which falls outside the laboratory reference range but which does 
not meet the clinical significance criteria, or those which are a result of an AE which has already been reported. 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
45 | P a g e  
 
7.1.3 TREATMENT AND FOLLOW UP OF AEs  
 
AEs will be followed up until they have returned to baseline status or stabilized. Details of follow up will be recorded in 
the study record including if return to baseline status or stabilization cannot be achieved. 
 
In the event of medically significant unexplained abnormal laboratory test values, the tests will be repeated and followed 
up until they have returned to the normal range or the baseline value and/or an adequate explanation of the abnormality 
is found. All details will be included in the study record. 
 
If the study drug is discontinued due to an AE or a laboratory abnormality, the study medication will not be reinstated. 
If the investigator decides to discontinue study drug treatment, the rationale for their decision will be provided in the AE 
comment/SAE narrative field of the study record.  
 
Study drug will be discontinued in the presence of an SAE that is deemed to be related or possibly related. 
Thromboembolic events or any event which a participant finds intolerable, which cannot be mitigated with therapy, will 
be cause for VOR discontinuation. Participants experiencing a > 50% increase in seizure frequency, as 
compared to baseline at any time during the treatment period will be discontinued from study medication. 
Additionally, participants presenting with status epilepticus at any time during the treatment period will be 
discontinued from study medication. 
 
 
7.1.3.1 Project Specific Adverse Events 
 
The following AEs are noted in the VOR product monograph as warning and precautions, based on CTCL clinical trials 
in adults. 
 
 
Thromboembolism 
 
Pulmonary embolism and DVT have been reported as drug-related AEs in clinical trials with VOR. In greater than 1000 
patients with hematologic malignancies and solid tumors who have been treated with VOR as monotherapy, or in 
combination with other chemotherapy agents, in completed and ongoing clinical studies, the proportion of patients that 
experienced a venous thromboembolic event was approximately 5.0%40. An increase in the incidence of venous 
thromboembolic events was also found in patients with advanced non-small cell lung cancer who received VOR (400 
mg once daily) in combination with chemotherapy (carboplatin and paclitaxel) as compared to patients who received 
chemotherapy alone. In this study, deep venous thrombosis and/or pulmonary embolism was reported in 6.5% (8/124) 
of patients in the VOR chemotherapy treatment arm compared to 2.4% (3/124) of patients in the placebo/chemotherapy 
treatment arm40.  
 
Investigators will closely monitor patients for signs and symptoms of these events, particularly in patients with a prior 
history of thromboembolic events. In the instance of a thromboembolic event, study drug will be discontinued.  
 
 
Hyperglycemia 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
46 | P a g e  
 
 
Hyperglycemia has been observed in patients receiving VOR40. Serum glucose will be monitored as part of the 
biochemistry laboratory safety panel as summarized in Table 5: Schedule of events. 
. In the event of hyperglycemia, adjustment of diet or anti-hyperglycemic therapy may be trialed in the event of 
intolerable hyperglycemia.  
 
 
Gastrointestinal Disturbances 
 
Gastrointestinal disturbances, including nausea, vomiting and diarrhea have been reported very commonly in patients 
treated with VOR40. Antiemetic and/or antidiarrheal medications may be trialed in the event of moderate to severe 
nausea, vomiting, diarrhea. Additional potassium and magnesium monitoring should be considered in symptomatic 
patients.  
 
 
Dehydration 
 
Dehydration has been reported as a common serious drug-related adverse experience in clinical trials40. Participants 
will be instructed to consume enough fluids to maintain adequate daily hydration, as adjusted for age.  
 
 
Hematologic Disturbances 
 
Treatment with VOR is associated with dose-related hematologic adverse effects40. Participants will be monitored as 
per laboratory testing schedule to identify such disturbances. Additionally participants will be advised to contact the 
investigator if presenting with frequent bruising, nose bleeds or gum bleeding, blood in urine or stools, or petechiae. 
 
 
QT/QTc Prolongation 
 
Treatment with VOR is associated with QT/QTc interval prolongation40, which is suspected to increase the risk of 
Torsade de pointes. Torsade de pointes may be asymptomatic or may be experienced as dizziness, palpitations, 
syncope, or increased seizures. Participants will be instructed to contact the investigator if presenting with these 
symptoms. Additional ECG monitoring may be conducted. 
 
 
7.2 HANDLING OF SAFETY PARAMETERS 
 
7.2.1 REPORTING OF SERIOUS ADVERSE EVENTS 
 
All new AEs occurring during the study should be recorded in the study record. AEs that occur intermittently will be 
recorded as a single AE. AEs will be collected and reported for up to 6 weeks after the last dose of study medication. 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
47 | P a g e  
 
 
7.2.2 EXEMPTION OF PROJECT SPECIFIC SERIOUS AEs FROM IMMEDIATE REPORTING TO HEALTH 
AUTHORITIES AND IRBs 
 
For any clinical AE or abnormal laboratory test value that is serious [as defined in Section 7.1.1.3], the investigator will 
complete SAE reporting in the study record within 24 hours of the study team becoming aware of the event. The REB 
and Health Canada will be notified as per reporting requirements.  
 
SAEs monitoring and reporting will commence at the time following administration of the first dose of study medication 
until 6 weeks following administration of the last dose of study medication. At any time after the 6-week period following 
the last dose of study drug, only SAEs considered by the investigator to be related to study drug or protocol procedures 
will continue to be reported as stipulated.  
 
 
7.2.3. PREGNANCY 
 
Pregnancies occurring in female participants exposed to the study medication, or partners of male participants exposed 
to the study medication, will be reported to the REB. Female participants, or partners of male participants will be 
instructed to notify the investigator as soon as possible. Female participants will be instructed to discontinue taking the 
study medication immediately. Study medication will be permanently discontinued in female participants and an EOT 
and SFU visit will be conducted as per protocol. Participants or partners of male participants will be followed until the 
conclusion of pregnancy. Pregnancies occurring up to 90 days after the completion of the study medication will be 
followed in the same manner. 
   
The investigator will counsel and discuss with the participant/partner of participant the risks of continuing with the 
pregnancy and the possible effects of early exposure to study medication on the fetus. 
 
Where a SAE occurs in the pregnant female participant, the SAE must be collected separately, regardless of whether 
it is pregnancy related or not. 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
48 | P a g e  
 
 
SECTION 8: STATISTICAL CONSIDERATION AND ANALYTICAL 
PLAN 
 
8.1 PRIMARY AND SECONDARY STUDY ENDPOINTS 
 
8.1.1 PRIMARY ENDPOINTS 
 
The primary endpoint for this study will be the incidence of related AEs and SAEs, and discontinuation of therapy due 
to intolerable AEs. 
 
8.1.2 SECONDARY ENDPOINT 
 
The secondary endpoint for this study will be efficacy. Treatment response will be evaluated by:  
• 
Proportion of patients who have at least a 50% reduction in seizures 
• 
Change in seizure remission status 
 
 
8.2 STATISTICAL AND ANALYTICAL METHODS 
 
8.2.1 SAMPLE SIZE 
 
The rationale for selection of sample size to investigate safety in a pilot study in this population was based on feasibility 
in regards to recruitment potential, according to prior knowledge of our referred/existing clinical base, and cost of 
conducting this study. Further, as this medication has not been tested in this population and rate of AEs in this 
population is not known, a power based/effect size calculation of sample size cannot be determined. 
 
 
8.2.2 ANALYSIS 
. 
8.2.2.1. SAFETY & TOLERABILITY ANALYSIS 
 
Safety and tolerability will be assessed by calculating the incidence rate of AEs per number of drug days from the time 
medication is started through to the completion of the SFU (or 42 days following the last dose of study medication). 
This will be done for the following time points: 14 days following drug initiation; 30 days following drug initiation; 42 
days following drug initiation; and 42 days following drug discontinuation. AEs will be further stratified by mild/moderate 
AEs, severe AEs, and SAEs, as well as project specific AEs (thromboembolism, hyperglycemia, gastrointestinal 
disturbances, dehydration, hematologic disturbances, QT/QTc prolongation).  
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
49 | P a g e  
 
 
8.2.2.2 EFFICACY ANALYSIS 
 
Primary efficacy assessment: 
• 
Treatment response will be evaluated by calculating the proportion of response of participants who demonstrate 
a 50% reduction rate or greater at 6 weeks as compared to baseline.  
 
Secondary efficacy assessments: 
• 
Seizure status will be tabulated 14 days following drug initiation; 30 days following drug initiation; 42 days following 
drug initiation; and 42 days following drug discontinuation. Seizure status will be defined as: significant response 
(at least 50% reduction in seizure frequency as compared to baseline, or no seizures while on medication; partial 
response (25% - 49% reduction in seizure frequency as compared to baseline); no change, (0 – 24% reduction 
in seizure frequency as compared to baseline); and worsening (increase in seizure frequency as compared to 
baseline). 
 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
50 | P a g e  
 
SECTION 9: DATA COLLECTION & MANAGEMENT 
 
Source visit data will be captured via the electronic clinic note during clinic visits. This will then be transcribed on the 
electronic data collection form which will be developed, maintained and managed via RedCap software. RedCap is a 
browser-based electronic data capture (EDC) software, in which electronic data collection form (eDCFs) can be 
custom-built by the user. RedCap is managed and supported by the Clinical Research Unit at the University of Calgary, 
in collaboration with Cumming School of Medicine. RedCap also maintains an audit trail which tracks a record of initial 
entries and changes made; time and date of entry; and username of person who made the change. 
 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
51 | P a g e  
 
SECTION 10: ETHICAL ASPECTS 
 
INFORMED CONSENT 
 
The investigator, or designate will obtain signed informed consent/assent from each participant/legal guardian prior to 
participating in this study as per our departmental SOPs (SOP002: Obtaining Informed Consent V1_2017-08-04; and 
SOP003: Obtaining Assent, Consent & Decision making Capacity in Minors V1_2017-08-14). Briefly, the investigator 
or designate will explain the aims, methods, anticipated benefits, and potential hazards of the study. The 
investigator/designee will also explain that the participant is completely free to refuse to enter the study or to withdraw 
at any time without any consequence to their future care, for any reason. If new safety information results in significant 
changes in the risk/benefit assessment, the consent form will be reviewed and updated if necessary. All participants 
(including those already being treated) will be notified of the new information, and the revised consent form will be 
given for review for participants to give consent to continue in the study for the revised study.  
 
INSTITUTIONAL REVIEW BOARD 
 
This protocol (and future modifications) along with all other study conduct procedures, and study documentation, will 
be submitted for review by the Conjoint Health Research Ethics Board (CHREB) at the University of Calgary. The study 
will not commence until it is approved by the CHREB.  
 
 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
52 | P a g e  
 
SECTION 11: STUDY DOCUMENTATION, RECORDKEEPING, AND 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PARTICIPANT 
RECORDS 
 
11.1 INVESTIGATOR’S FILES/RETENTION OF DOCUMENTS 
 
Adequate and accurate records will be maintained to enable the conduct of the study to be fully documented and the 
study data to be subsequently verified. These documents will be kept via the Investigator's Study File and participant 
clinical source documents. 
 
As per Good Clinical Practice Guidelines, the Investigator's Study File will contain the protocol/amendments, 
Institutional Review Board documentation, governmental approvals with correspondence, sample informed consent, 
drug records, staff curriculum vitae, authorization forms and other appropriate documents/correspondence related to 
study conduct, etc.  
 
Participant clinical source documents include completed data collection forms, participant hospital/clinic records, 
physicians’ and nurses’ notes, appointment book, original laboratory reports, ECG reports, and signed informed 
consent forms. Data collection forms will also include all changes to data and reasons for changes. 
 
All study documents will be kept on site for 2 years following study publication. Following the on-site archiving period, 
study records will be moved to a secure storage facility to be stored for a total of 25 years, as per Health Canada 
requirements. Following the required archiving period, study documents will be securely destroyed as per the facility’s 
standard operating procedure for secure document destruction.   
 
 
11.2 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PARTICIPANT RECORDS 
 
Participants’ anonymity will be maintained and their identities protected from unauthorized parties. Master identification 
lists will be updated and maintained by research personnel. The master list will be managed and stored via an Excel 
sheet, will be kept separate from the main data set and stored on a research drive on a firewall-protected AHS server, 
which is password protected and available only to the Investigators and research personnel.     
 
Investigators and/or research personnel will review the medical records of patients meeting eligibility criteria. Study 
data collected will be anonymized, entered, stored and managed using RedCap. The RedCap database will be 
maintained by a member of the research team assigned as the database manager for this data set. The data base 
manager will oversee programming the collections form; issuing/removing access for participating research team 
members; data locks and pulling data for analysis. All research team members will have access to view and enter data.   
 
At the time of data disposal, the data set will be purged as per the University of Calgary Clinical Research Unit standard 
protocols. The master list will be purged from the AHS server at the same time point. All data analysis will take place 
on anonymized data.     
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
53 | P a g e  
 
All staff involved in research activities are aware of and adhere to, the privacy standards set out by AHS and the 
requirements set forth by the Alberta Health Information Act.  All study activities occurring at the ACH will be conducted 
as per the terms of agreement set forth by the Alberta Health Services Provincial Research Administration, Innovation 
& Research Management. 
 
 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
54 | P a g e  
 
SECTION 12: REFERENCES 
 
1. 
Major P, Thiele EA. Seizures in children: Determining the variation. Pediatrics in review. 2007;28:363-371 
2. 
Theodore WH, Spencer SS, Wiebe S, Langfitt JT, Ali A, Shafer PO, Berg AT, Vickrey BG. Epilepsy in north 
america: A report prepared under the auspices of the global campaign against epilepsy, the international 
bureau for epilepsy, the international league against epilepsy, and the world health organization. Epilepsia. 
2006;47:1700-1722 
3. 
Arya R, Glauser TA. Pharmacotherapy of focal epilepsy in children: A systematic review of approved agents. 
CNS drugs. 2013;27:273-286 
4. 
Glauser TA, Loddenkemper T. Management of childhood epilepsy. Continuum (Minneapolis, Minn.). 
2013;19:656-681 
5. 
Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365:919-926 
6. 
Chaves J, Sander JW. Seizure aggravation in idiopathic generalized epilepsies. Epilepsia. 2005;46 Suppl 
9:133-139 
7. 
Perucca E, Meador KJ. Adverse effects of antiepileptic drugs. Acta neurologica Scandinavica. Supplementum. 
2005;181:30-35 
8. 
Sillanpaa M, Schmidt D. Natural history of treated childhood-onset epilepsy: Prospective, long-term 
population-based study. Brain : a journal of neurology. 2006;129:617-624 
9. 
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshe SL, Perucca E, Wiebe S, 
French J. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc task force of the ilae 
commission on therapeutic strategies. Epilepsia. 2010;51:1069-1077 
10. 
Bell B, Lin JJ, Seidenberg M, Hermann B. The neurobiology of cognitive disorders in temporal lobe epilepsy. 
Nat Rev Neurol. 2011;7:154-164 
11. 
Bernhardt BC, Bernasconi N, Concha L, Bernasconi A. Cortical thickness analysis in temporal lobe epilepsy: 
Reproducibility and relation to outcome. Neurology. 2010;74:1776-1784 
12. 
Pavlou E, Gkampeta A. Learning disorders in children with epilepsy. Child's nervous system : ChNS : official 
journal of the International Society for Pediatric Neurosurgery. 2011;27:373-379 
13. 
Thompson PJ, Duncan JS. Cognitive decline in severe intractable epilepsy. Epilepsia. 2005;46:1780-1787 
14. 
Souza-Oliveira C, Escosi-Rosset S, Funayama SS, Terra VC, Machado HR, Sakamoto AC. Intellectual 
functioning in pediatric patients with epilepsy: A comparison of medically controlled, medically uncontrolled 
and surgically controlled children. Jornal de pediatria. 2010;86:377-383 
15. 
Moreira H, Carona C, Silva N, Frontini R, Bullinger M, Canavarro MC. Psychological and quality of life 
outcomes in pediatric populations: A parent-child perspective. The Journal of pediatrics. 2013;163:1471-1478 
16. 
Austin JK, Caplan R. Behavioral and psychiatric comorbidities in pediatric epilepsy: Toward an integrative 
model. Epilepsia. 2007;48:1639-1651 
17. 
Camfield P, Camfield C, Arts WF, Brouwer OF, Arzimanoglou A. The outcome of childhood epilepsy: What 
improvements are needed? Epileptic disorders : international epilepsy journal with videotape. 2013;15:101-
104 
18. 
Sperling MR. The consequences of uncontrolled epilepsy. CNS spectrums. 2004;9:98-101, 106-109 
19. 
England MJ, Liverman CT, Schultz AM, Strawbridge LM. Epilepsy across the spectrum: Promoting health and 
understanding. A summary of the institute of medicine report. Epilepsy & behavior : E&B. 2012;25:266-276 
20. 
Yoon D, Frick KD, Carr DA, Austin JK. Economic impact of epilepsy in the united states. Epilepsia. 
2009;50:2186-2191 
21. 
Begley CE, Famulari M, Annegers JF, Lairson DR, Reynolds TF, Coan S, Dubinsky S, Newmark ME, Leibson 
C, So EL, Rocca WA. The cost of epilepsy in the united states: An estimate from population-based clinical 
and survey data. Epilepsia. 2000;41:342-351 
22. 
Cramer JA, Wang ZJ, Chang E, Powers A, Copher R, Cherepanov D, Broder MS. Healthcare utilization and 
costs in adults with stable and uncontrolled epilepsy. Epilepsy & behavior : E&B. 2014;31:356-362 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
55 | P a g e  
 
23. 
Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. The 
ketogenic diet for the treatment of childhood epilepsy: A randomised controlled trial. The Lancet. Neurology. 
2008;7:500-506 
24. 
Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. A 
randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood 
epilepsy. Epilepsia. 2009;50:1109-1117 
25. 
Kossoff EH, Rho JM. Ketogenic diets: Evidence for short- and long-term efficacy. Neurotherapeutics : the 
journal of the American Society for Experimental NeuroTherapeutics. 2009;6:406-414 
26. 
Rogawski MA, Loscher W, Rho JM. Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold 
Spring Harbor perspectives in medicine. 2016;6 
27. 
Kang HC, Lee YM, Kim HD, Lee JS, Slama A. Safe and effective use of the ketogenic diet in children with 
epilepsy and mitochondrial respiratory chain complex defects. Epilepsia. 2007;48:82-88 
28. 
Greco T, Glenn TC, Hovda DA, Prins ML. Ketogenic diet decreases oxidative stress and improves 
mitochondrial respiratory complex activity. Journal of cerebral blood flow and metabolism : official journal of 
the International Society of Cerebral Blood Flow and Metabolism. 2016;36:1603-1613 
29. 
Pathak D, Berthet A, Nakamura K. Energy failure: Does it contribute to neurodegeneration? Annals of 
neurology. 2013;74:506-516 
30. 
Ibhazehiebo K, Gavrilovici C, de la Hoz CL, Ma SC, Rehak R, Kaushik G, Meza Santoscoy PL, Scott L, Nath 
N, Kim DY, Rho JM, Kurrasch DM. A novel metabolism-based phenotypic drug discovery platform in zebrafish 
uncovers hdacs 1 and 3 as a potential combined anti-seizure drug target. Brain : a journal of neurology. 2018 
31. 
Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, 
Matthews L, McLaren S, Sealy I, Caccamo M, Churcher C, Scott C, Barrett JC, Koch R, Rauch GJ, White S, 
Chow W, Kilian B, Quintais LT, Guerra-Assuncao JA, Zhou Y, Gu Y, Yen J, Vogel JH, Eyre T, Redmond S, 
Banerjee R, Chi J, Fu B, Langley E, Maguire SF, Laird GK, Lloyd D, Kenyon E, Donaldson S, Sehra H, 
Almeida-King J, Loveland J, Trevanion S, Jones M, Quail M, Willey D, Hunt A, Burton J, Sims S, McLay K, 
Plumb B, Davis J, Clee C, Oliver K, Clark R, Riddle C, Elliot D, Threadgold G, Harden G, Ware D, Begum S, 
Mortimore B, Kerry G, Heath P, Phillimore B, Tracey A, Corby N, Dunn M, Johnson C, Wood J, Clark S, Pelan 
S, Griffiths G, Smith M, Glithero R, Howden P, Barker N, Lloyd C, Stevens C, Harley J, Holt K, Panagiotidis 
G, Lovell J, Beasley H, Henderson C, Gordon D, Auger K, Wright D, Collins J, Raisen C, Dyer L, Leung K, 
Robertson L, Ambridge K, Leongamornlert D, McGuire S, Gilderthorp R, Griffiths C, Manthravadi D, Nichol S, 
Barker G, Whitehead S, Kay M, Brown J, Murnane C, Gray E, Humphries M, Sycamore N, Barker D, Saunders 
D, Wallis J, Babbage A, Hammond S, Mashreghi-Mohammadi M, Barr L, Martin S, Wray P, Ellington A, 
Matthews N, Ellwood M, Woodmansey R, Clark G, Cooper J, Tromans A, Grafham D, Skuce C, Pandian R, 
Andrews R, Harrison E, Kimberley A, Garnett J, Fosker N, Hall R, Garner P, Kelly D, Bird C, Palmer S, Gehring 
I, Berger A, Dooley CM, Ersan-Urun Z, Eser C, Geiger H, Geisler M, Karotki L, Kirn A, Konantz J, Konantz M, 
Oberlander M, Rudolph-Geiger S, Teucke M, Lanz C, Raddatz G, Osoegawa K, Zhu B, Rapp A, Widaa S, 
Langford C, Yang F, Schuster SC, Carter NP, Harrow J, Ning Z, Herrero J, Searle SM, Enright A, Geisler R, 
Plasterk RH, Lee C, Westerfield M, de Jong PJ, Zon LI, Postlethwait JH, Nusslein-Volhard C, Hubbard TJ, 
Roest Crollius H, Rogers J, Stemple DL. The zebrafish reference genome sequence and its relationship to 
the human genome. Nature. 2013;496:498-503 
32. 
Schier AF. Genomics: Zebrafish earns its stripes. Nature. 2013;496:443-444 
33. 
Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E, van Eeden F, Sealy I, White 
RJ, Herd C, Nijman IJ, Fenyes F, Mehroke S, Scahill C, Gibbons R, Wali N, Carruthers S, Hall A, Yen J, 
Cuppen E, Stemple DL. A systematic genome-wide analysis of zebrafish protein-coding gene function. 
Nature. 2013;496:494-497 
34. 
Baraban SC, Taylor MR, Castro PA, Baier H. Pentylenetetrazole induced changes in zebrafish behavior, 
neural activity and c-fos expression. Neuroscience. 2005;131:759-768 
35. 
Baraban SC, Dinday MT, Castro PA, Chege S, Guyenet S, Taylor MR. A large-scale mutagenesis screen to 
identify seizure-resistant zebrafish. Epilepsia. 2007;48:1151-1157 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
56 | P a g e  
 
36. 
Baxendale S, Holdsworth CJ, Meza Santoscoy PL, Harrison MR, Fox J, Parkin CA, Ingham PW, Cunliffe VT. 
Identification of compounds with anti-convulsant properties in a zebrafish model of epileptic seizures. Disease 
models & mechanisms. 2012;5:773-784 
37. 
Zdebik AA, Mahmood F, Stanescu HC, Kleta R, Bockenhauer D, Russell C. Epilepsy in kcnj10 morphant 
zebrafish assessed with a novel method for long-term eeg recordings. PloS one. 2013;8:e79765 
38. 
White HS, Johnson M, Wolf HH, Kupferberg HJ. The early identification of anticonvulsant activity: Role of the 
maximal electroshock and subcutaneous pentylenetetrazol seizure models. Italian journal of neurological 
sciences. 1995;16:73-77 
39. 
Barton ME, Peters SC, Shannon HE. Comparison of the effect of glutamate receptor modulators in the 6 hz 
and maximal electroshock seizure models. Epilepsy research. 2003;56:17-26 
40. 
MerckCanadaInc. Product monograph zolinza® vorinostat capsules 100mg histone deacetylase inhibitor, 
anti-neoplastic agent. 2013 
41. 
Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci 
PG, Heinzel T. Valproic acid defines a novel class of hdac inhibitors inducing differentiation of transformed 
cells. The EMBO journal. 2001;20:6969-6978 
42. 
Marks PA, Richon VM, Breslow R, Rifkind RA. Histone deacetylase inhibitors as new cancer drugs. Current 
opinion in oncology. 2001;13:477-483 
43. 
Marks PA, Dokmanovic M. Histone deacetylase inhibitors: Discovery and development as anticancer agents. 
Expert opinion on investigational drugs. 2005;14:1497-1511 
44. 
Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist 
JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, Richon VM. Phase i study of an oral 
histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23:3923-3931 
45. 
Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, 
Rosner G, Loboda A, Fantin VR, Randolph SS, Hardwick JS, Reilly JF, Chen C, Ricker JL, Secrist JP, Richon 
VM, Frankel SR, Kantarjian HM. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide 
hydroxamic acid [saha]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 
2008;111:1060-1066 
46. 
Kelly WK, Richon VM, O'Connor O, Curley T, MacGregor-Curtelli B, Tong W, Klang M, Schwartz L, 
Richardson S, Rosa E, Drobnjak M, Cordon-Cordo C, Chiao JH, Rifkind R, Marks PA, Scher H. Phase i clinical 
trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 2003;9:3578-3588 
47. 
O'Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, Curly T, Moskowitz C, 
Portlock C, Horwitz S, Zelenetz AD, Frankel S, Richon V, Marks P, Kelly WK. Clinical experience with 
intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid 
in patients with advanced hematologic malignancies. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2006;24:166-173 
48. 
Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. Fda approval summary: Vorinostat for treatment of 
advanced primary cutaneous t-cell lymphoma. The oncologist. 2007;12:1247-1252 
49. 
Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, Ricker JL, Arduino JM, 
Duvic M. Phase iib multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory 
cutaneous t-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2007;25:3109-3115 
50. 
Fouladi M, Park JR, Stewart CF, Gilbertson RJ, Schaiquevich P, Sun J, Reid JM, Ames MM, Speights R, Ingle 
AM, Zwiebel J, Blaney SM, Adamson PC. Pediatric phase i trial and pharmacokinetic study of vorinostat: A 
children's oncology group phase i consortium report. J Clin Oncol. 2010;28:3623-3629 
51. 
Hummel TR, Wagner L, Ahern C, Fouladi M, Reid JM, McGovern RM, Ames MM, Gilbertson RJ, Horton T, 
Ingle AM, Weigel B, Blaney SM. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or 
refractory primary brain or spinal cord tumors: A children's oncology group phase 1 consortium study. Pediatr 
Blood Cancer. 2013;60:1452-1457 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
57 | P a g e  
 
52. 
Muscal JA, Thompson PA, Horton TM, Ingle AM, Ahern CH, McGovern RM, Reid JM, Ames MM, Espinoza-
Delgado I, Weigel BJ, Blaney SM. A phase i trial of vorinostat and bortezomib in children with refractory or 
recurrent solid tumors: A children's oncology group phase i consortium study (advl0916). Pediatr Blood 
Cancer. 2013;60:390-395 
53. 
Burke MJ, Lamba JK, Pounds S, Cao X, Ghodke-Puranik Y, Lindgren BR, Weigel BJ, Verneris MR, Miller JS. 
A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute 
lymphoblastic leukemia. Am J Hematol. 2014;89:889-895 
54. 
DuBois SG, Groshen S, Park JR, Haas-Kogan DA, Yang X, Geier E, Chen E, Giacomini K, Weiss B, Cohn 
SL, Granger MM, Yanik GA, Hawkins R, Courtier J, Jackson H, Goodarzian F, Shimada H, Czarnecki S, Tsao-
Wei D, Villablanca JG, Marachelian A, Matthay KK. Phase i study of vorinostat as a radiation sensitizer with 
131i-metaiodobenzylguanidine (131i-mibg) for patients with relapsed or refractory neuroblastoma. Clin 
Cancer Res. 2015;21:2715-2721 
55. 
Colletti RB, Trainer TD, Krawisz BR. Reversible valproate fulminant hepatic failure. Journal of pediatric 
gastroenterology and nutrition. 1986;5:990-994 
56. 
Hsia Y, Neubert A, Sturkenboom MC, Murray ML, Verhamme KM, Sen F, Giaquinto C, Ceci A, Wong IC. 
Comparison of antiepileptic drug prescribing in children in three european countries. Epilepsia. 2010;51:789-
796 
57. 
Cvitanovic-Sojat L, Bielen I, Sruk A, Kosicek M, Planjar-Prvan M, Baraba R, Bergman-Markovic B, Butkovic-
Soldo S. Social and medical care of preschool children with epilepsy in croatia: Population-based survey. 
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology 
Society. 2010;14:73-77 
58. 
Berg AT, Levy SR, Testa FM, Shinnar S. Treatment of newly diagnosed pediatric epilepsy: A community-
based study. Archives of pediatrics & adolescent medicine. 1999;153:1267-1271 
59. 
Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clinical biochemistry. 
2013;46:1323-1338 
60. 
Brodie MJ. Established anticonvulsants and treatment of refractory epilepsy. Lancet (London, England). 
1990;336:350-354 
61. 
Verrotti A, Scaparrotta A, Grosso S, Chiarelli F, Coppola G. Anticonvulsant drugs and hematological disease. 
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical 
Neurophysiology. 2014;35:983-993 
62. 
Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. British medical 
journal (Clinical research ed.). 1981;283:577-581 
63. 
Easter D, O'Bryan-Tear CG, Verity C. Weight gain with valproate or carbamazepine--a reappraisal. Seizure. 
1997;6:121-125 
64. 
Novak GP, Maytal J, Alshansky A, Eviatar L, Sy-Kho R, Siddique Q. Risk of excessive weight gain in epileptic 
children treated with valproate. Journal of child neurology. 1999;14:490-495 
65. 
Jallon P, Picard F. Bodyweight gain and anticonvulsants: A comparative review. Drug safety. 2001;24:969-
978 
66. 
Privitera MD, Brodie MJ, Mattson RH, Chadwick DW, Neto W, Wang S. Topiramate, carbamazepine and 
valproate monotherapy: Double-blind comparison in newly diagnosed epilepsy. Acta neurologica 
Scandinavica. 2003;107:165-175 
67. 
Cnaan A, Shinnar S, Arya R, Adamson PC, Clark PO, Dlugos D, Hirtz DG, Masur D, Glauser TA. Second 
monotherapy in childhood absence epilepsy. Neurology. 2017;88:182-190 
68. 
Jedrzejczak J, Kuncikova M, Magureanu S. An observational study of first-line valproate monotherapy in focal 
epilepsy. European journal of neurology. 2008;15:66-72 
69. 
Beydoun A, Sackellares JC, Shu V. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: 
A double-blind, concentration-response design clinical trial. Depakote monotherapy for partial seizures study 
group. Neurology. 1997;48:182-188 
70. 
Richens A, Davidson DL, Cartlidge NE, Easter DJ. A multicentre comparative trial of sodium valproate and 
carbamazepine in adult onset epilepsy. Adult epiteg collaborative group. Journal of neurology, neurosurgery, 
and psychiatry. 1994;57:682-687 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
58 | P a g e  
 
71. 
Verity CM, Hosking G, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in 
paediatric epilepsy. The paediatric epiteg collaborative group. Developmental medicine and child neurology. 
1995;37:97-108 
72. 
Christe W, Kramer G, Vigonius U, Pohlmann H, Steinhoff BJ, Brodie MJ, Moore A. A double-blind controlled 
clinical trial: Oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy 
research. 1997;26:451-460 
73. 
Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, 
Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett 
M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, 
Vanoli A, Williamson PR. The sanad study of effectiveness of valproate, lamotrigine, or topiramate for 
generalised and unclassifiable epilepsy: An unblinded randomised controlled trial. Lancet (London, England). 
2007;369:1016-1026 
74. 
Lenz RA, Elterman RD, Robieson WZ, Vigna NV, Saltarelli MD. Divalproex sodium in children with partial 
seizures: 12-month safety study. Pediatric neurology. 2009;41:101-110 
75. 
Hu Y, Huang X, Shen D, Ding M, Sun H, Peng B, Hu X, Li H, Zeng K, Xi Z, Zhang Y, Cao Q, Liu J, Zhou Y, 
Wu M, Lu Y, Chen G, Wang X. Outcomes of sustained-release formulation of valproate and topiramate 
monotherapy in patients with epilepsy: A multi-centre, cohort study. PloS one. 2012;7:e47982 
76. 
Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of 
complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The department of 
veterans affairs epilepsy cooperative study no. 264 group. The New England journal of medicine. 
1992;327:765-771 
77. 
Wheless JW, Neto W, Wang S. Topiramate, carbamazepine, and valproate monotherapy: Double-blind 
comparison in children with newly diagnosed epilepsy. Journal of child neurology. 2004;19:135-141 
78. 
Mohanraj R, Brodie MJ. Pharmacological outcomes in newly diagnosed epilepsy. Epilepsy & behavior : E&B. 
2005;6:382-387 
79. 
Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: A prospective monotherapy study. 
Epilepsia. 2008;49:438-445 
80. 
Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC. 
Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. The New England journal of 
medicine. 2010;362:790-799 
81. 
Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Adamson PC. Ethosuximide, 
valproic acid, and lamotrigine in childhood absence epilepsy: Initial monotherapy outcomes at 12 months. 
Epilepsia. 2013;54:141-155 
82. 
Verrotti A, Nanni G, Agostinelli S, Alleva ET, Aloisi P, Franzoni E, Spalice A, Chiarelli F, Coppola G. Effects 
of the abrupt switch from solution to modified-release granule formulation of valproate. Acta neurologica 
Scandinavica. 2012;125:e14-18 
83. 
Rosati A, De Masi S, Guerrini R. Antiepileptic drug treatment in children with epilepsy. CNS drugs. 
2015;29:847-863 
84. 
Schmidt D. Drug treatment of epilepsy: Options and limitations. Epilepsy & behavior : E&B. 2009;15:56-65 
85. 
Brodie MJ, Ben-Menachem E, Chouette I, Giorgi L. Zonisamide: Its pharmacology, efficacy and safety in 
clinical trials. Acta neurologica Scandinavica. Supplementum. 2012:19-28 
86. 
Cilio MR, Kartashov AI, Vigevano F. The long-term use of felbamate in children with severe refractory 
epilepsy. Epilepsy research. 2001;47:1-7 
87. 
Lyseng-Williamson KA. Levetiracetam: A review of its use in epilepsy. Drugs. 2011;71:489-514 
88. 
Kennedy GM, Lhatoo SD. Cns adverse events associated with antiepileptic drugs. CNS drugs. 2008;22:739-
760 
89. 
Chung AM, Eiland LS. Use of second-generation antiepileptic drugs in the pediatric population. Paediatric 
drugs. 2008;10:217-254 
90. 
McGinnis E, Kessler SK. Lacosamide use in children with epilepsy: Retention rate and effect of concomitant 
sodium channel blockers in a large cohort. Epilepsia. 2016;57:1416-1425 

PROTOCOL: VOR-17-2471 
Version 2: 2018-07-18 
59 | P a g e  
 
91. 
Steinhoff BJ, Bacher M, Bucurenciu I, Hillenbrand B, Intravooth T, Kornmeier R, Kurth C, Stockinger J, Staack 
AM. Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy-a monocenter survey. 
Seizure. 2017;48:11-14 
92. 
Frampton JE. Perampanel: A review in drug-resistant epilepsy. Drugs. 2015;75:1657-1668 
93. 
Bottcher S, Lutz MT, Mayer T. Lacosamide in the treatment of patients with epilepsy and intellectual 
disabilities: A long-term study of 136 patients. Epilepsia. 2017;58:1749-1754