Clinical trial NCT02994732
Conditions: Healthy
Sponsor: BioMed Valley Discoveries, Inc
Start date: 2017-01-01; Completion date: 2017-05-15
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to characterize the metabolic disposition, pharmacokinetics (PK), and routes of elimination of \[14C\]-labeled BVD-523 after administration of a single, oral dose to healthy male subjects.

The secondary objective of this study is to evaluate the safety and tolerability of a single oral dose of \[14C\]-labeled BVD-523 in healthy male subjects.

Detailed description:
This study will be an open-label, absorption, metabolism, and excretion study of \[14C\]-BVD-523 administered as a 600-mg (approximately 200 µCi) oral dose to 6 healthy male subjects following a 2-hour fast from food (not including water) that follows breakfast.

Arms: arm 1: Open-label, nonrandomized, absorption, metabolism, and excretion study of \[14C\]-BVD-523 administered as a 600 mg (approximately 200 µCi) oral dose to 6 healthy male subjects following at least an 8-hour fast from food (not including water).
Interventions: intervention 1: [14C]-BVD-523
Intervention descriptions: intervention 1: \[14C\]-BVD-523 administered as a 600-mg (approximately 200 µCi) oral dose to 6 healthy male subjects following a 2-hour fast from food (not including water) that follows breakfast.

Protocol documents:
Prot_000.pdf: 
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A PHASE 1 STUDY TO INVESTIGATE THE ABSORPTION, METABOLISM, 
AND EXCRETION OF [14C]-BVD-523 FOLLOWING SINGLE ORAL DOSE 
ADMINISTRATION IN HEALTHY MALE SUBJECTS 
 
 
 
 
Protocol 523HV001 
 
Covance Study 8353316 
 
IND 115,451 
 
 
 
for 
 
BioMed Valley Discoveries Inc. 
4520 Main Street, Suite 1650 
Kansas City, Missouri 64111 
 
 
 
 
by 
 
Covance Early Clinical Services 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 


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STUDY IDENTIFICATION 
 
Sponsor 
BioMed Valley Discoveries Inc. 
 
4520 Main Street, Suite 1650 
 
Kansas City, Missouri 64111 
 
(816) 960-6600 (Main Telephone No.) 
 
(816) 960-6976 (Main Facsimile No.) 
 
Sponsor’s Study Contact 
Deborah L. Knoerzer, MS 
 
Associate Director, Translational Sciences 
 
BioMed Valley Discoveries Inc. 
 
4520 Main Street, Suite 1650 
 
Kansas City, Missouri 64111 
 
(636) 887-6429 (Office Telephone No.) 
 
(816) 960-6976 (Office Facsimile No.) 
 
(636) 887-6429 (After Hours Telephone No.) 
 
Medical Monitor 
Jane Royalty, MD 
 
Covance Clinical Research Unit, Inc. 
 
617 Oakley Street 
 
Evansville, Indiana 47710 
 
(812) 474-5015 (Office Telephone No.) 
 
(608) 260-7779 (Office Facsimile No.) 
 
jane.royalty@covance.com 
 
Clinical Site 
Covance Clinical Research Unit, Inc. 
 
3402 Kinsman Boulevard 
 
Madison, Wisconsin 53704 
 
(608) 442-8200 (Main Telephone No.) 
 
(608) 661-8169 (Main Facsimile No.) 
 
Principal Investigator 
Irene Mirkin, MD 
 
Covance Clinical Research Unit, Inc. 
 
(608) 443-1477 (Office Telephone No.) 
 
irene.mirkin@covance.com 


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Main Clinical Laboratory 
Meriter Laboratories 
 
36 South Brooks Street 
 
Madison, Wisconsin 53715 
 
(608) 417-6529 (Main Telephone No.) 
 
Bioanalytical Laboratory 
Covance Bioanalytical Laboratory Services, Inc. 
 
3301 Kinsman Boulevard 
 
Madison, Wisconsin 53704 
 
Radiation Safety Officer 
Robert G. Kochan, PhD 
 
Covance Inc. 
 
(608) 210-7668 (Office Telephone No.) 
 
robert.kochan@covance.com 
 
Clinical Nuclear Pharmacist Brett Pick, PharmD, RPh, BCNP 
 
Covance Inc. 
 
(608) 443-1549 (Office Telephone No.) 
 
brett.pick@covance.com 
 
Protocol Biostatistician 
Xin Chen, MS 
 
Covance Early Clinical Biometrics 
 
(608) 310-2943 (Office Telephone No.) 
 
xin.chen@covance.com 
 
Protocol Pharmacokineticist Stuart Hossack, BS 
 
Covance Early Clinical Biometrics 
 
44 (0) 113 301 3637 (Office Telephone No.) 
 
stuart.hossack@covance.com 
 
Protocol Medical Writer 
Stephanie Linn, MS 
 
Covance Global Medical and Regulatory Writing 
 
(608) 395-3729 (Office Telephone No.) 
 
stephanie.linn@covance.com 
 


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TABLE OF CONTENTS 
 
TITLE PAGE .......................................................................................................................1 
STUDY IDENTIFICATION ...............................................................................................2 
TABLE OF CONTENTS .....................................................................................................4 
ABBREVIATIONS .............................................................................................................8 
1 
SYNOPSIS .............................................................................................................10 
2 
INTRODUCTION .................................................................................................12 
2.1 
Background ................................................................................................12 
2.1.1 Nonclinical Data ............................................................................12 
2.1.2 Clinical Data ..................................................................................14 
2.2 
Study Rationale ..........................................................................................16 
2.3 
Dose Rationale ...........................................................................................16 
3 
STUDY OBJECTIVE AND ENDPOINTS ...........................................................17 
3.1 
Objectives ..................................................................................................17 
3.2 
Endpoints ...................................................................................................17 
3.2.1 Pharmacokinetic Endpoints ...........................................................17 
3.2.2 Safety Endpoints ............................................................................18 
4 
INVESTIGATIONAL PLAN ................................................................................18 
4.1 
Study Design ..............................................................................................18 
4.2 
Discussion of Study Design .......................................................................19 
5 
SUBJECT SELECTION ........................................................................................20 
5.1 
Inclusion Criteria .......................................................................................20 
5.2 
Exclusion Criteria ......................................................................................21 
5.3 
Removal of Subjects from Study Participation ..........................................22 
6 
STUDY PROCEDURES .......................................................................................23 
6.1 
Schedule of Study Procedures ...................................................................23 
6.2 
Study Treatment .........................................................................................25 


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6.2.1 Drug Supplies and Accountability .................................................25 
6.2.2 Subject Number and Identification ................................................26 
6.2.3 Dose Preparation and Administration ............................................26 
6.2.4 Blinding..........................................................................................27 
6.3 
Study Restrictions ......................................................................................27 
6.3.1 Diet, Fluid, and Activity Control ...................................................27 
6.3.2 Concomitant Medications ..............................................................27 
6.3.3 Contraception .................................................................................28 
6.4 
Pharmacokinetic, [14C] Radioactivity, and Metabolism Procedures .........28 
6.4.1 Blood Sample Collection for Pharmacokinetic, [14C] Radioactivity, 
and Metabolism Analysis ...................................................28 
6.4.2 Urine Sample Collection for Pharmacokinetic, [14C] Radioactivity, 
and Metabolism Analysis ...................................................28 
6.4.3 Fecal Sample Collection for [14C] Radioactivity and Metabolism 
Analysis..............................................................................29 
6.4.4 Emesis Sample Collection .............................................................29 
6.4.5 Bioanalytical Methodology ............................................................29 
6.5 
Safety Procedures.......................................................................................29 
6.5.1 Adverse Events ..............................................................................30 
6.5.2 Clinical Laboratory Evaluations ....................................................30 
6.5.3 Vital Signs ......................................................................................30 
6.5.4 Twelve-lead Electrocardiograms ...................................................30 
6.5.5 Physical Examinations ...................................................................31 
7 
DATA ANALYSES AND SAMPLE SIZE ...........................................................31 
7.1 
Sample Size ................................................................................................31 
7.2 
Study Populations ......................................................................................31 
7.3 
Pharmacokinetic Analysis ..........................................................................31 
7.4 
Statistical Analysis of Pharmacokinetic Data ............................................34 
7.5 
Statistical Analyses of Safety Data ............................................................34 


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7.6 
Data Handling and Record Keeping ..........................................................34 
7.7 
Quality Control and Quality Assurance .....................................................35 
8 
ADMINISTRATIVE ASPECTS ...........................................................................35 
8.1 
Change in Protocol .....................................................................................35 
8.2 
Site Initiation Visit/Investigator Meeting ..................................................36 
8.3 
Disclosure ..................................................................................................36 
8.4 
Monitoring .................................................................................................36 
8.5 
Institutional Review Board ........................................................................36 
8.6 
Informed Consent.......................................................................................37 
8.7 
Records ......................................................................................................37 
8.8 
Reference to Declaration of Helsinki/Basic Principles ..............................38 
8.9 
Financing and Insurance ............................................................................38 
INVESTIGATOR AGREEMENT.....................................................................................39 
SPONSOR AGREEMENT ................................................................................................40 
REFERENCES ..................................................................................................................41 
APPENDIX A - CLINICAL LABORATORY EVALUATIONS ....................................42 
APPENDIX B - BLOOD SAMPLING SUMMARY ........................................................43 
APPENDIX C - ADVERSE EVENTS ..............................................................................44 
 
 
 


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LIST OF TABLES AND FIGURES 
 
Table 6-1 Study Flow Chart .............................................................................................. 24 
Table 6-2 Study Drugs ...................................................................................................... 25 
 
Figure 4-1 Study Design Schematic ................................................................................. 18 
 


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ABBREVIATIONS 
% AUCextrap 
percentage extrapolation 
% Fef 
percent of dose excreted in feces over sampling interval 
% Feu 
percent of dose excreted in urine over sampling interval 
Aeu 
amount excreted in urine over sampling interval 
Aef 
amount excreted in feces over sampling interval 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
AUC0-12 
area under the concentration-time curve from Hour 0 to Hour 12 
AUC0-24 
area under the concentration-time curve from Hour 0 to Hour 24 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last 
measurable concentration 
BID 
twice daily 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL/F 
apparent oral clearance 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
Ct 
last measurable concentration 
CRU 
Clinical Research Unit 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ERK 
extracellular signal-regulated kinase 
FDA 
Food and Drug Administration 
HCl 
hydrochloride 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
λZ 
apparent terminal elimination rate constant 
MAPK 
mitogen-activated protein kinase 


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MDS 
myelodysplastic syndromes 
MTD 
maximum tolerated dose 
PE 
physical examination 
PK 
pharmacokinetic(s) 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
t1/2 
terminal phase half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
UA 
urinalysis 
US 
United States 
Vz/F 
apparent volume of distribution 


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1 SYNOPSIS 
Title of Study: 
A Phase 1 Study to Investigate the Absorption, Metabolism, and Excretion of 
[14C]-BVD-523 Following Single Oral Dose Administration in Healthy Male 
Subjects  
Objectives: 
The primary objective of this study is to characterize the metabolic disposition, 
pharmacokinetics (PK), and routes of elimination of [14C] labeled BVD-523 after 
administration of a single, oral dose to healthy male subjects. 
The secondary objective of this study is to evaluate the safety and tolerability of a 
single oral dose of [14C] labeled BVD-523 in healthy male subjects. 
Methodology/Study 
Design: 
This is an open-label, absorption, metabolism, and excretion study. Blood/plasma, 
urine, and fecal samples for bioanalytical, radioanalytical, and metabolism 
analysis, as applicable, will be obtained through 168 hours postdose. If Discharge 
occurs after Day 8, additional samples (blood/plasma, urine, and fecal) for 
radioanalysis will be collected every 24 hours until Discharge. 
Number of Subjects: 
Six healthy male subjects will be enrolled and dosed on Day 1 to complete at least 
4 subjects. 
Diagnosis and Main 
Criteria for Inclusion: 
Healthy male subjects between 18 and 65 years of age, inclusive, with a body 
mass index of 18.5 to 32.0 kg/m2, inclusive. 
Test Product(s), Dose, 
and Mode of 
Administration: 
Subjects will receive a single oral 600-mg (4 ×150-mg capsules) dose of 
BVD-523 containing approximately 200 µCi of [14C] labeled BVD-523 following 
a 2-hour fast that follows breakfast. 
Duration of 
Treatment: 
Planned Enrollment/Screening Duration: up to 27 days (Days -28 to -2) 
Length of Confinement: up to 16 days (Day -1 to Day 15) 
Planned Study Conduct Duration (Screening to Discharge): up to 43 days 
Criteria for 
Evaluation: Safety 
Safety endpoints for this study include: incidence, nature, and severity of adverse 
events (AEs), clinically significant changes in results of clinical laboratory 
evaluations, vital signs measurements, 12-lead electrocardiograms (ECGs), and 
physical examination (PE) findings. 
Criteria for 
Evaluation: 
Pharmacokinetics 
The following PK parameters will be calculated, whenever possible, based on the 
plasma concentrations of BVD-523, metabolites, and total radioactivity in whole 
blood and plasma: maximum observed concentration (Cmax), time to maximum 
concentration (Tmax), area under the concentration-time curve (AUC) from Hour 0 
to the last measurable concentration (AUC0-t), AUC from Hour 0 to Hour 12 
(AUC0-12), AUC from Hour 0 to Hour 24 (AUC0-24), AUC extrapolated to infinity 
(AUC0-∞), percentage extrapolation (% AUCextrap), apparent terminal elimination 
rate constant (λZ), terminal phase half-life (t1/2), apparent oral clearance (CL/F; for 
BVD-523 only), apparent volume of distribution (Vz/F; for BVD-523 only), the 
ratio of AUC0-12 of nonradiolabeled BVD-523 in plasma to AUC0-12 of total 
radioactivity in plasma (AUC0-12 plasma BVD-523/Total Radioactivity Ratio), the 
ratio of AUC0-24 of nonradiolabeled BVD-523 in plasma to AUC0-24 of total 
radioactivity in plasma (AUC0-24 plasma BVD-523/Total Radioactivity Ratio), the 
ratio of AUC0-∞ of nonradiolabeled BVD-523 in plasma to AUC0-∞ of total 
radioactivity in plasma (AUC0-∞ plasma BVD-523/Total Radioactivity Ratio), the 
ratio of AUC0-12 of nonradiolabeled metabolites in plasma/AUC0-12 of total 
radioactivity in plasma (AUC0-12 Plasma Metabolites/Total Radioactivity Ratio), 
the ratio of AUC0-24 of nonradiolabeled metabolites in plasma/AUC0-24 of total 
radioactivity in plasma (AUC0-24 Plasma Metabolites/Total Radioactivity Ratio), 
the ratio of AUC0-∞ of nonradiolabeled metabolites in plasma/AUC0-∞ of total 
radioactivity in plasma (AUC0-∞ Plasma Metabolites/Total Radioactivity Ratio), 
the ratio of AUC0-∞ of total radioactivity in whole blood to AUC0-∞ of total 
radioactivity in plasma (AUC0-∞ Blood/Plasma Ratio), the ratio of AUC0-12 of total 


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radioactivity in whole blood to AUC0-12 of total radioactivity in plasma (AUC0-12 
Blood/Plasma Ratio), and the ratio of AUC0-24 of total radioactivity in whole 
blood to AUC0-24 of total radioactivity in plasma (AUC0-24 Blood/Plasma Ratio). 
The following PK parameters will be calculated, whenever possible, based on the 
urine concentrations of BVD-523 and total radioactivity: amount excreted in urine 
over sampling interval (Aeu), cumulative Aeu, renal clearance (CLR; for BVD-523 
only), percent of dose excreted in urine over sampling interval (% Feu), and 
cumulative % Feu. 
The following PK parameters will be calculated, whenever possible, based on the 
fecal concentrations of total radioactivity: amount excreted in feces over sampling 
interval (Aef), cumulative Aef, percent of dose excreted in feces over sampling 
interval (% Fef), and cumulative % Fef. 
Metabolites of [14C]-BVD-523 will be identified and characterized in plasma, 
urine, and feces. Pharmacokinetic parameters for the metabolites of 
[14C]-BVD-523 will be calculated, as deemed appropriate, based on plasma, urine, 
and fecal concentration levels. 
Statistical Methods: 
Descriptive statistics (arithmetic mean, standard deviation, geometric mean, 
geometric coefficient of variation, median, minimum, maximum, and number of 
observations) will be calculated for the PK parameters. No formal statistical 
analyses are planned. 
Safety data (AEs, clinical laboratory data, vital signs measurements, ECG data, 
and PE findings) will be listed and summarized by parameters and timepoints, as 
appropriate. 


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2 INTRODUCTION 
2.1 Background 
BVD-523 is a small molecule inhibitor of extracellular signal-regulated kinase (ERK) 
family kinases (ERK1 and ERK2) that is being developed as a novel anti-cancer drug. 
Extracellular signal-regulated kinase family kinases are downstream components of the 
mitogen-activated protein kinase (MAPK) signaling cascade (RAS-RAF-MEK-ERK). 
Drugs that inhibit MAPK pathway components, BRAF or MEK kinases, are effective 
cancer therapies, but tumors often display primary and acquired resistance to these 
agents. The ERK kinase inhibitor BVD-523 may effectively treat both naïve and drug-
resistant cancers. 
BVD-523 is a potent (Ki approximately 0.04 nM for ERK2, < 0.3 nM for ERK1), 
selective, ATP competitive, reversible kinase inhibitor. BVD-523 demonstrates potent 
anti-cancer activity in in vitro cell studies, especially in cells with activating mutations in 
the MAPK pathway. Consistent with its mechanism, BVD-523 inhibits phosphorylation 
of ERK substrates and inhibited cell proliferation and survival. Importantly, BVD-523 is 
effective in cells that show acquired resistance to MEK kinase inhibitors; BVD-523 alone 
and in combination may effectively treat non-overlapping tumor drug resistance. 
2.1.1 Nonclinical Data 
BVD-523 shows in vivo anti-cancer activity when dosed orally in mouse xenografts 
dependent on ERK signaling, including models of melanoma, colon, and pancreatic 
cancers. Tumor biomarker effects, including protein phosphorylation and gene expression 
changes, occur in an exposure-dependent fashion following BVD-523 administration; 
biochemical and anti-tumor effects are typically observed when BVD-523 tissue 
concentrations exceed low micromolar concentrations, consistent with in vitro 
observations. These data demonstrate that BVD-523 as a single agent has anti-tumor 
activity in multiple cancer cell lines; doses required for efficacy are consistent with 
exposures required for BVD-523 to inhibit its molecular target in cell assays. 
BVD-523 is highly cell permeable, a putative P-glycoprotein transporter substrate, and is 
highly protein bound in multiple species (96% to 100%). In vivo, the compound exhibits 
oral bioavailability ranging from 23% in dogs to approximately 100% in monkeys and 
exhibits predominantly linear dose-exposure characteristics at pharmacologically active 
doses. In vivo, the compound effectively distributes to multiple tissues, with initial peak 
concentrations highest in liver, kidney, and lung; BVD-523 was poorly distributed into 


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brain tissue. Radiolabeled studies in the dog with [14C]-BVD-523 demonstrated 
metabolism in the gastrointestinal tract and/or by first-pass metabolism after absorption 
was the primary mechanism of clearance after an oral dose. [14C]-BVD-523 underwent 
substantive metabolism in dogs after a single oral dose of [14C]-BVD-523 to produce 5 
identified/characterized radiolabeled metabolites. 
BVD-523 exhibits suitable safety properties in vitro and in vivo. BVD-523 shows no 
significant interaction in in vitro screens against 65 receptors, transporters, and ion 
channels. In functional tissue assays of adenosine A1 receptor activity at concentrations 
up to 30 μM BVD-523 no significant response was observed, despite affinity for the 
human adenosine A1 receptor half maximal inhibitory concentration (IC50; IC50 = 77 nM) 
in a screening assay. BVD-523 exhibits no significant genetic toxicology risks in reverse 
mutation and micronucleus assays. BVD-523 absorbs ultraviolet light at 320 nM; patients 
are being advised to limit skin exposure to light. 
While BVD-523 inhibits the human ether-a-go-go related gene current (IC50 = 3.4 μM), 
dog Purkinje fiber assays revealed no significant effects up to 10 μg/mL. Additionally, no 
cardiovascular findings were observed in telemetered dogs receiving a single dose of 
BVD-523 maximum observed concentration (Cmax; Cmax = 17.3 μM) or in dogs after 
28 days of dosing at a dose level above its 28-day maximum tolerated dose (MTD). 
Patients dosed with BVD-523 are being monitored for potential corrected QT interval 
prolongation and related cardiotoxicities. 
BVD-523 does not significantly inhibit cytochrome P450 (CYP) enzymes in vitro, nor 
does it significantly induce CYP enzymes, either in vitro or ex vivo. The compound is 
metabolized via oxidation and de-alkylation, predominantly by CYP3A4, and to a lesser 
extent by CYP2D6 and CYP1A2. The metabolite profile of BVD-523 is very similar in 
mouse, rat, dog, and human assays; a disproportionate amount of a +30 amu metabolite is 
produced in the monkey. In preclinical studies, the disposition of BVD-523 administered 
orally in vivo is not significantly affected by food or gender differences. BVD-523 
exhibits rapid absorption and is eliminated predominantly through hepatic mechanisms. 
The compound is cleared completely following dose discontinuation, and exhibits modest 
accumulation after repeated dosing. The compound half-life ranges from 1.1 hours in 
mice to 3.2 hours in dogs. 
A variety of BVD-523-related toxicologic findings occurred following 28 days of dosing 
in Good Laboratory Practice studies conducted in rats and dogs. 
In rats, BVD-523-related tissue mineralization occurs in multiple tissues in a 
dose-dependent fashion. Animals demonstrating mineralization following treatment with 


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BVD-523 exhibit significantly increased serum phosphorus and modestly decreased 
serum calcium. Calcium and phosphorus are being monitored during the clinical studies. 
Skin lesions characterized by inflammation, dermatitis, ulceration, and acanthosis occur 
in rats chronically dosed with BVD-523. The incidence and severity of skin lesions are 
dose- and exposure-dependent, and skin toxicities are partially reversible following dose 
discontinuation. Additional BVD-523-related adverse findings that are partially 
reversible in rats include swelling in the neck; decreased forelimb strength; enlarged 
lymph node, spleen, and mammary gland tissues. Microscopic findings were also 
observed in various tissues. The tolerated dose in rats was 12.5 mg/kg twice daily (BID), 
with a Cmax of 25 and 32 μg/mL, and an area under the concentration-time curve (AUC) 
from Hour 0 to Hour 12 (AUC0-12) of 156 and 227 μg*h/mL at steady state in males and 
females, respectively. 
BVD-523 can be dosed in dogs without severe toxicity for 28 days at 5 mg/kg BID, while 
doses starting at 15 mg/kg BID are toxic. Toxicity in dogs treated at 5 mg/kg BID and 
lower is mainly limited to the digestive tract, although additional clinical pathology 
(increased fibrinogen and decreased albumin) and microscopic findings (inflammation in 
ileum and cecum and lymphoid depletion in gut-associated lymphoid tissue) are also 
observed. Signs of poor health resolve following dose cessation, and additional findings 
are fully reversible 1 month after dose discontinuation. The tolerated dose in dogs was 
5 mg/kg BID, with a Cmax of 0.54 and 0.55 μg/mL, and an AUC0-12 of 3.1 and 
2.9 μg*h/mL at steady state in males and females, respectively. Importantly, biomarker 
studies suggest significant ERK kinase inhibition occurs in peripheral blood cells of dogs 
treated with doses of BVD-523 that are tolerated. 
2.1.2 Clinical Data 
BVD-523 has been administered to 128 patients with a wide variety of solid tumors 
(104 patients) and myelodysplastic syndromes (MDS)/acute myelogenous leukemia 
(AML) (24 patients). BVD-523 is administered orally, on an empty stomach, and on a 
chronic basis with dosing interruptions only when necessary to manage adverse events 
(AEs) or to manage events related to underlying malignancy. In some, but not all 
instances, reinitiation of study drug after a dosing interruption for AE management has 
been at a reduced dose; the need for dose reduction has been at the discretion of the 
treating physician in consultation with the Medical Monitor. Patients were allowed to 
remain on study until unacceptable toxicity or until disease progression, with the majority 
of discontinuations thus far related to progression of the underlying malignancy. 


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The emerging safety profile has been largely anticipated based on the preclinical, 
Investigational New Drug-enabling, animal studies and on the clinical experience of other 
anti-cancer agents targeting components of the MAPK pathway. An MTD of 600 mg 
(4 x 150-mg capsules) BID was determined in patients with solid tumors and also in 
patients with MDS/AML, and this dose subsequently became the starting dose for all 
patients initiating therapy with BVD-523. Dose limiting toxicities at doses higher than 
the MTD included rash, vomiting, diarrhea, elevated alanine aminotransferase (ALT), 
elevated creatinine, hypotension, and anemia in the solid tumor study, and rash and 
elevated liver function tests in the MDS/AML study. 
The emerging AE profile is revealing that events related to the skin and gastrointestinal 
tract are particularly common, as are the general disorders of fatigue, edema, and fever. 
Adverse events related to skin, pruritus and rash, have been common, although other less 
common but significant skin events have also been reported, including erythema 
multiforme, light sensitivity, and keratoacanthoma. Rash has been managed with topical 
and/or oral concomitant medications and dose interruptions and/or reductions as 
necessary. The gastrointestinal events of nausea, vomiting, and diarrhea have been 
observed commonly, in some cases occurring in association with dehydration and 
elevated creatinine and renal insufficiency. Nausea, vomiting, and diarrhea have been 
managed with study drug dosing interruptions (and/or dose reductions) and supportive 
medications as needed. The general events of fatigue, edema, and fever have also been 
managed variably with supportive medications and/or interruption of study drug 
administration until improvement or resolution. 
Study drug-related events of elevated aspartate aminotransferase and/or ALT and 
elevated creatinine, while not common, have been reported and have been managed with 
study drug interruption and, in some instances, dose reduction or discontinuation. Other 
possibly related or related AEs of particular interest include ocular effects, cardiac 
failure, thrombotic thrombocytopenia purpura, effects on peripheral blood counts, and 
photosensitivity. 
BVD-523 has, to date, been administered to adult patients and has not been administered 
in conjunction with other anti-neoplastic agents with the exception of hydroxyurea 
(allowed short-term in the MDS/AML study) and hormonal therapy. 
Orally administered BVD-523 at doses ranging from 10 to 900 mg BID was generally 
slowly absorbed in patients with advanced malignancies, with individual time to 
maximum concentration (Tmax) values of 2 to 8 hours at dose levels of 10 to 150 mg BID, 
and median Tmax values of 3 to 4 hours at dose levels of 300 to 900 mg BID. After 
reaching Cmax, plasma BVD-523 concentrations remained somewhat sustained for 


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approximately 2 to 4 hours. The compound half-life ranges from 9 to 11 hours. Exposure 
(Cmax and AUC0-12) to BVD-523, as well as selected metabolites, generally increased in a 
dose-related fashion from dose levels of 10 to 600 mg BVD-523 BID. At Day 1, a further 
increase in exposure was seen at 750 mg BVD-523 BID, but exposure was similar 
between 750 and 900 mg BID. At Day 15, no further increase in exposure was observed 
as the dose increased from 600 to 900 mg BVD-523 BID. 
A single-dose, 2-way crossover study to evaluate the effects of food on the 
pharmacokinetics (PK), safety, and tolerability of an orally administered 600-mg dose of 
BVD-523 has been completed in healthy volunteers. Fourteen healthy volunteers were 
dosed in this study. Following single-dose oral administration of 600 mg BVD-523, the 
median Tmax occurred at 3.1 hours in fasted subjects and at 6.1 hours in fed subjects 
(high-fat breakfast). Overall, a total of 6 treatment-emergent AEs (TEAEs) were reported 
in 5 subjects (35.7%). There were no deaths or serious AEs (SAEs) reported during the 
study and no TEAEs that led to discontinuation of subjects. All TEAEs were transient 
and had resolved by the end of the study. 
2.2 Study Rationale 
The purpose of this study is to evaluate the absorption and excretion characteristics as 
well as relevant PK properties of BVD-523; and to characterize and, where possible, 
identify the metabolites present in plasma, urine, and feces in healthy male subjects 
following a single dose of 600 mg (approximately 200 µCi) of [14C]-BVD-523 
administered as an oral dose of 4 × 150-mg capsules. 
Female subjects will be excluded to align with regulatory guidance. The “as low as (is) 
reasonably achievable” principle prescribed by both the Food and Drug Administration 
(FDA) and Nuclear Regulatory Commission (2007) recommends that radiation exposure 
to subjects should be kept as low as is reasonably achievable; therefore, if no specific 
reason exists to include females (ie, no available data suggest metabolism of the study 
drug is different in females versus males), then the radiation exposure to female subjects 
should be kept at zero potential by not including females in radioactivity studies and only 
enrolling and dosing male subjects. 
2.3 Dose Rationale 
The total administered dose will be 600 mg (4 × 150-mg capsules) to ensure sufficient 
quantifiable concentrations of BVD-523 for determination of systemic PK. As of 
16 January 2016, 27 patients have been administered BVD-523, dosed between 10 mg 
BID to 900 mg BID; 18 out of 27 patients received at least 600 mg BID. From this, the 


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MTD and recommended Phase 2 dose were determined to be 600 mg BID, which is the 
starting dose for all patients initiating therapy with BVD-523. 
The radioactive dose will be approximately 200 μCi. This is an acceptable dose for 
[14C]-labeled human drug metabolism studies of this type. Based on data in male 
Long-Evans (pigmented) rats, the overall whole-body radiation dose in a human male 
subject following administration of the equivalent of a single 200-μCi (7.4 MBq) dose of 
[14C]-BVD-523 was mathematically derived from the 100-μCi dose used in the dosimetry 
report to be 17.1 mrem (0.1708 mSv).1 This value is well below the FDA exposure limit 
of 3000 mrem after a single dose for human isotope studies. The highest calculated 
radiation absorbed doses following oral administration of [14C]-BVD-523 were in uveal 
tract, epididymis, eyes, skin (pigmented), and liver in males, with values of 140.8, 29.2, 
27.6, 19.0, and 14.6 mRad, respectively (1.408, 0.292, 0.276, 0.190, and 0.146 mGy, 
respectively). It is expected that this dose will provide a sufficient radioactive signal for 
total radioactivity counting and quantitative radioprofiling of [14C]-BVD-523 in blood, 
plasma, and/or excreta with minimal radiation risk to subjects. 
Please refer to the Investigator’s Brochure2 for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and AE profile of 
the investigational product. 
3 STUDY OBJECTIVE AND ENDPOINTS 
3.1 Objectives 
• The primary objective of this study is to characterize the metabolic disposition, 
PK, and routes of elimination of [14C] labeled BVD-523 after administration of a 
single, oral dose to healthy male subjects. 
• The secondary objective of this study is to evaluate the safety and tolerability of a 
single oral dose of [14C] labeled BVD-523 in healthy male subjects. 
3.2 Endpoints 
3.2.1 Pharmacokinetic Endpoints 
The PK endpoints are derived from the following biological samples and analytes: 
• 
Plasma and urine concentrations of BVD-523; 
• 
Plasma and whole blood concentrations of total radioactivity; 
• 
Pharmacokinetic parameters of BVD-523 and its metabolites; 


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• 
Total radioactivity recovery in excreta (feces + urine); 
• 
Identification and characterization of [14C] labeled BVD-523 metabolites 
in plasma, urine, and feces. 
3.2.2 Safety Endpoints 
The safety endpoints for this study are: 
• 
Incidence, nature, and severity of AEs; 
• 
Clinically significant changes in results of clinical laboratory evaluations, 
vital signs measurements, 12-lead electrocardiograms (ECGs), and 
physical examination (PE) findings. 
4 INVESTIGATIONAL PLAN 
4.1 Study Design 
This study will be an open-label, absorption, metabolism, and excretion study of 
[14C]-BVD-523 administered as a 600-mg (approximately 200 µCi) oral dose to 6 healthy 
male subjects following a 2-hour fast from food (not including water) that follows 
breakfast. 
A schematic of the study design is presented in Figure 4-1. The start of the study is 
defined as the date the first subject signs an Informed Consent Form (ICF). This is 
specifically for a subject enrolled (assigned a dose) in the study and does not include 
screen failure subjects for clinical pharmacology studies. A subject who completes all 
PK, radioactivity, and metabolism sampling prior to Discharge is considered to have 
completed the study. This is the last planned contact with the subject, and does not 
include any unplanned follow-up (eg, return to the clinic for repeat clinical laboratory). 
The end of the study is defined as the date the last subject completes the study. The 
planned duration of study conduct is up to 43 days (Screening through Discharge). 
Figure 4-1 Study Design Schematic 
Screening 
Check-in 
Dosing 
PK/Radioactivity Sampling 
Study Completiona 
Days -28 to -2 
Day -1 
Day 1 
Day 1 to Study Completion 
Day 8 to Day 15 
 
Confined to CRU 
CRU = Clinical Research Unit; PK = pharmacokinetic. 
a Subjects will be discharged from the CRU starting on Day 8 if plasma radioactivity levels are below the 
limit of quantitation, ≥90% of the radioactive dose is recovered, and if ≤1% of the radioactive dose is 
recovered in urine and feces for 2 consecutive 24-hour collection intervals. If these criteria are not satisfied 


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by the morning of Day 8, subjects will continue to be confined in the CRU until these criteria are met, up to 
a maximum of Day 15. 
 
Subjects will be confined at the clinical site from the time of Check-in until Discharge 
(between Days 8 and 15). After completing discharge procedures, subjects will be 
discharged from the clinical site on Day 15 or as early as Day 8, provided radioactivity 
has reached the following threshold values: 
• 
Plasma radioactivity levels below the limit of quantitation; and 
• 
≥90% of the dose is recovered; and 
• 
Urine and fecal total radioactivity combined ≤1% of the 
administered dose for 2 consecutive 24-hour intervals. 
Sample collection and confinement will continue until discharge criteria are met or the 
maximum stay is reached. Subjects experiencing emesis during the first 4 hours postdose 
may be discharged on the same day from the clinical site, provided there are no safety 
concerns, and after follow-up study procedures are performed. 
In this study design, safety will be monitored with AE inquiries, clinical laboratory 
evaluations (Appendix A), vital signs measurements, 12-lead ECGs, and PE findings 
during the study. 
Blood/plasma, urine, and fecal samples will be collected for bioanalytical, 
radioanalytical, and metabolism analysis through 168 hours postdose. If Discharge occurs 
after Day 8, additional samples (blood/plasma, urine, and fecal) for radioanalysis will be 
collected every 24 hours until Discharge. A study flow chart is presented in Table 6-1. 
4.2 Discussion of Study Design 
This study is designed to characterize the absorption, metabolism, and excretion of 
BVD-523 using radiolabeled drug in healthy adult male subjects to support its further 
development and registration. 
The study will be conducted as an open-label trial as the study measures are objective 
outcomes (eg, total radioactivity in select biological matrices, metabolite 
profiling/characterization). Conducting the study in healthy subjects will allow the 
evaluation of BVD-523 metabolism in the absence of concomitant medications. The 
dose, subject population, study duration, and sample collection timing are considered 
adequate to achieve the study objectives. 


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5 SUBJECT SELECTION 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria 
apply will be eligible to be enrolled into the study. Safety evaluations may be repeated at 
the Investigator’s (or designee’s) discretion. 
Six subjects will be enrolled to have at least 4 subjects complete the study. 
5.1 Inclusion Criteria 
Subjects who meet the following criteria may be included in the study: 
1. 
Males, between 18 and 65 years of age, inclusive, at Screening; 
2. 
Have a body mass index range of 18.5 to 32.0 kg/m2, inclusive, at 
Screening; 
3. 
In good health, determined by no clinically significant findings from 
medical history, 12-lead ECG, and vital signs measurements at Screening 
or Check-in and PE findings at Check-in as determined by the Investigator 
(or designee); 
4. 
Clinical laboratory evaluations (including clinical chemistry panel [fasted 
at least 8 hours], hematology/complete blood count [CBC], and urinalysis 
[UA]; Appendix A) within the reference range for the test laboratory at 
Screening and Check-in, unless deemed not clinically significant by the 
Investigator (or designee); 
5. 
Negative test for selected drugs of abuse and cotinine at Screening (does 
not include alcohol) and at Check-in (does include alcohol; Appendix A); 
6. 
Negative hepatitis panel (including hepatitis B surface antigen and 
hepatitis C virus antibody) and negative human immunodeficiency virus 
(HIV) antibody screens (Appendix A) at Screening; 
7. 
Males will be surgically sterile for at least 90 days (confirmed by 
documented azoospermia) or, when sexually active with female partners 
of childbearing potential, will agree to use contraception as detailed in 
Section 6.3.3 from Check-in until 90 days following dosing; 
8. 
Males must be willing to refrain from sperm donation from Check-in to 
90 days from the day of dosing; 
9. 
Able to comprehend and willing to sign an ICF; 
10. 
A minimum of 1 bowel movement per day. 


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5.2 Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. 
Significant history or clinical manifestation of any metabolic, allergic, 
infectious, dermatological, hepatic, renal, hematological, pulmonary, 
cardiovascular, gastrointestinal, neurological, or psychiatric disorder (as 
determined by the Investigator [or designee]) prior to Check-in; 
2. 
History of significant hypersensitivity, intolerance, or allergy to any drug 
compound, food, or other substance, unless approved by the Investigator 
(or designee) prior to Check-in; 
3. 
History of stomach or intestinal surgery or resection that could alter 
absorption or excretion of orally administered drugs prior to Check-in, 
except appendectomy and hernia repair will be allowed if it was not 
associated with complications; 
4. 
History of Gilbert’s Syndrome; 
5. 
History or presence of an abnormal ECG that, in the Investigator’s (or 
designee’s) opinion, is clinically significant; 
6. 
History of alcoholism or drug addiction within 1 year prior to Check-in; 
7. 
History of nicotine use within 6 months prior to Check-in or positive 
cotinine at Screening or Check-in; 
8. 
Participation in more than 1 other radiolabeled investigational study drug 
trial within 12 months prior to Check-in. The previous radiolabeled study 
drug must have been received more than 6 months prior to Check-in for 
this study and the total exposure from this study and the previous study 
will be within the recommended levels considered safe, per United States 
(US) Title 21 Code of Federal Regulations (CFR) 361.1 (eg, less than 
3,000 mrem whole body annual exposure); 
9. 
Exposure to significant radiation (eg, serial x-ray or computed tomography 
scans, barium meal, current employment in a job requiring radiation 
exposure monitoring) within 12 months prior to Check-in; 
10. 
Use of any drugs or substances known to be strong inhibitors or strong 
inducers of CYP3A enzyme within 30 days prior to study drug 
administration, unless otherwise stated, and throughout the study; 


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11. 
Participation in any other investigational study drug trial in which receipt 
of an investigational study drug occurred within 5 half-lives (if known) or 
30 days prior to Check-in, whichever is longer; 
12. 
Use of any prescription medications/products within 14 days prior to 
Check-in, unless deemed acceptable by the Investigator (or designee); 
13. 
Use of any over-the-counter, nonprescription preparations (including 
vitamins, minerals, and phytotherapeutic/herbal/plant-derived 
preparations) within 7 days prior to Check-in, unless deemed acceptable 
by the Investigator (or designee); 
14. 
Poor peripheral venous access prior to Check-in; 
15. 
Donation of whole blood from 56 days prior to Screening through 
Discharge, inclusive, or of plasma from 30 days prior to Screening 
through Discharge, inclusive; 
16. 
Receipt of blood products within 2 months prior to Check-in; 
17. 
Any acute or chronic condition that, in the opinion of the Investigator (or 
designee), would limit the subject’s ability to complete or participate in 
this clinical study; 
18. 
Any other unspecified reason that, in the opinion of the Investigator (or 
designee) or Sponsor, makes the subject unsuitable for enrollment. 
5.3 Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and 
for any reason. The Investigator (or designee) may remove a subject from the study if, in 
the Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to 
continue the study. Subjects may be withdrawn due to the following: change in 
compliance with inclusion/exclusion criterion that is clinically relevant and affects 
subject safety, occurrence of AEs, intake of nonpermitted concomitant medication that 
might affect subject safety or study assessments/objectives, etc. Notification of 
withdrawal will immediately be made to the Sponsor’s Study Monitor. In case of 
withdrawal of study participation, efforts will be made to perform all final study day 
assessments (Table 6-1). The date the subject is withdrawn from the study and the reason 
for withdrawal will be recorded on the subject’s electronic Case Report Form (eCRF). All 
withdrawn subjects will be followed until resolution of all their AEs or until the 
unresolved AEs are judged by the Investigator (or designee) to have stabilized. 


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The entire study may be discontinued at the discretion of the Investigator (or designee), 
Sponsor, or Sponsor’s Medical Monitor based on the occurrence of the following: 
• 
AEs unknown to date with respect to their nature, severity, and/or 
duration; 
• 
Increased frequency and/or severity and/or duration of known AEs; 
• 
Medical or ethical reasons affecting the continued performance of 
the study; 
• 
Difficulties in the recruitment of subjects; 
• 
Cancellation of drug development. 
6 STUDY PROCEDURES 
6.1 Schedule of Study Procedures 
A study flow chart is presented in Table 6-1. The total blood volume that will be taken 
during the study is outlined in Appendix B. 


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Table 6-1 Study Flow Chart 
Study Procedures 
Screening 
(-28 to –2) 
Check-in 
(Day –1) 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Days 
5 to 7 
Discharge/Early 
Termination 
(Days 8 to 15)a 
Informed Consent 
X 
 
 
 
 
 
 
 
Confined to the 
CRU 
 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
Hepatitis and HIV 
Screen 
X 
 
 
 
 
 
 
 
Drug Screenc 
X 
X 
 
 
 
 
 
 
Height, Weight, and 
BMI 
X 
Xd 
 
 
 
 
 
 
12-lead ECGe 
X 
X 
 
 
 
 
 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Evaluationsg 
X 
X 
 
 
 
 
 
X 
Physical 
Examination 
 
X 
 
 
 
 
 
X 
Doseh 
 
 
X 
 
 
 
 
 
Blood Samples for 
PK/Radioactivity 
Analysisi 
 
 
X 
X 
X 
X 
X 
X 
Blood Samples for 
Metabolism 
Analysisj 
 
 
X 
X 
X 
X 
X 
X 
Urine Samples for 
PK, Radioactivity, 
and Metabolism 
Analysisk 
 
X 
X 
X 
X 
X 
X 
X 
Fecal Samples for 
Total Radioactivity 
and Metabolism 
Analysisl 
 
X 
X 
X 
X 
X 
X 
X 
SAE Monitoringm 
X 
X 
X 
X 
X 
X 
X 
X 
AE Inquiryn 
 
X 
X 
X 
X 
X 
X 
X 
Previous Medication 
X 
X 
 
 
 
 
 
 
Concomitant 
Medication 
Monitoring 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; BMI = body mass index; CRU = Clinical Research Unit; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; PK = pharmacokinetic; SAE = serious adverse 
event. 
a Early termination procedures are to be performed in close proximity to discontinuation of subject from the study. 
Other procedures may be performed at Investigator (or designee) or Sponsor discretion. 
b Interim medical history only. 
c Drug screen does not include breath alcohol testing at Screening and does include breath alcohol testing at Check-in. 
d Height and BMI measured at Screening only. 
e Twelve-lead ECG will be collected after the subject has rested in the supine position for at least 5 minutes. 


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f Vital sign measurements (oral body temperature, respiratory rate, and seated blood pressure and pulse) obtained at 
Screening, Check-in, 0 Hour (predose); 2, 4, and 24 (Day 2) hours postdose; and daily (24-hour intervals) up to and 
including day of discharge. Vital signs measurements should be carried out prior to having blood drawn, except at 
Screening and Day -1. Vital signs will be measured after the subject has been seated for at least 5 minutes. 
g Clinical chemistry panel (fasted at least 8 hours), complete blood count, and urinalysis. 
h Single oral dose of [14C]-BVD-523 at 600 mg (approximately 200 µCi) administered orally after a 2-hour fast that 
follows breakfast. 
i Blood samples for PK and radioanalysis collected at 0 Hour (predose); 30 minutes postdose; and 1, 2, 3, 4, 5, 6, 8, 12, 
24, 48, 72, 96, 120, 144, and 168 hours postdose (Day 8). If subject is not discharged on Day 8, additional blood 
samples will be collected for radioanalysis every 24 hours until Discharge. 
j Blood samples for metabolite profiling and identification collected at 0 Hour (predose); 30 minutes postdose; and 1, 2, 
3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose (Day 8). 
k Urine samples collected at -12 to 0 (predose, the last void within 1 hour prior to dosing), 0 to 6, 6 to 12, and 12 to 
24 hours postdose; and 24-hour intervals until Discharge. 
l Fecal samples collected predose (within 24 hours of dosing, if possible), from 0 to 24 hours postdose, and 24-hour 
intervals until Discharge. 
m Any SAEs occurring after the subject signs the Informed Consent Form will be collected. 
n Subjects will be monitored for AEs beginning at initiation of study drug. An AE inquiry will be performed at 
Check-in and at each postdose vital sign measurement. 
6.2 Study Treatment 
6.2.1 Drug Supplies and Accountability 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the study drug (Table 6-2). 
 
Table 6-2 Study Drugs 
Study Drug 
[14C]-BVD-523 
Forma 
Blended crystalline solid 
Specific Activityb 
approximately 0.31 µCi/mg (HCl salt) 
Supplier 
EAG Laboratories 
Manufacturer 
EAG Laboratories 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the 
study drug(s). 
bSpecific Activity is calculated based on the mass of the hydrochloride (HCl) salt. The oral dose of 600 mg will be 
based on the free base content of the drug. 
 
The lot numbers for the study drugs will be provided to the clinical site by the 
supplier/manufacturer as soon as available. 
Radiolabeled study drug will be stored in a freezer set to maintain a temperature 
of -20°C. 
The Investigator (or designee) will maintain an accurate record of the receipt of the 
clinical trial materials as shipped by the Sponsor (or designee), including the date 


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received. One copy of this receipt will be returned to the Sponsor when the contents of 
the shipment have been verified. In addition, an accurate drug disposition record will be 
kept, specifying the amount dispensed to each subject and the date of dispensation. This 
drug accountability record will be available for inspection at any time. At the completion 
of the study, the original drug accountability record will be available for review by the 
Sponsor on request. 
At the completion of the study, all unused drug supplies will be returned to the Sponsor 
(or designee) or disposed of by the clinical site, per the Sponsor’s (or designee’s) written 
instructions. 
6.2.2 Subject Number and Identification 
Subjects will be assigned a number by clinical site staff. Assignment of numbers will be 
in ascending order and no numbers will be omitted. Subject numbers will be used on all 
study documentation. For subjects who are withdrawn by the Investigator (or designee) 
or who voluntarily withdraw prematurely from the study, replacement subjects will be 
enrolled only if deemed necessary by the Sponsor. Replacement subjects will be assigned 
a subject number by adding 100 to the number of the subject they are replacing (eg, 
Subject No. 105 replaces Subject No. 005). 
6.2.3 Dose Preparation and Administration 
Each unit dose will be prepared by qualified clinical staff. Each unit dose container will 
be appropriately labeled. 
Appropriate unit doses, as described above, will be administered to 
consecutively-numbered subjects. Although the timing of events requires that each 
subject will be consistently administered the appropriate dose at specific times, the exact 
dose time of consecutive subjects may be staggered to obviate the need to have all 
subjects on precisely the same study schedule. For each dose, the subject’s actual dose 
time will be recorded in the source documents and transcribed into the eCRFs. 
Each dose will be administered orally with approximately 240 mL room temperature 
water. A hand and mouth check will be performed to verify that the dose administered 
was swallowed. After a 2-hour fast from food (not including water) that follows a 
standard high-fiber breakfast, doses will be administered. After a 1-hour fast from food 
(not including water) that follows dosing, a snack will be served. During the study, 
subjects may consume water ad libitum. 


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Except when they are using the toilet, study subjects will be observed for approximately 
4 hours postdose. Note: Amount of time corresponds to the time postdose in which 
subjects with emesis could be replaced and is to ensure that they are not having AEs or 
becoming nauseated. Subjects will not lay supine for 1 hour following dose 
administration, except as necessitated by the occurrence of an AE(s) and/or study 
procedures. 
6.2.4 Blinding 
This is an open-label study. 
6.3 Study Restrictions 
6.3.1 Diet, Fluid, and Activity Control 
Subjects are required to refrain from use of tobacco- or nicotine-containing products 
within 6 months prior to Check-in until Discharge. 
Subjects are required to abstain from consuming alcohol-, grapefruit-, or 
caffeine-containing foods and beverages for 48 hours prior to Check-in until Discharge, 
unless deemed acceptable by the Investigator (or designee). 
Subjects will refrain from strenuous exercise from 72 hours prior to Check-in and during 
the period of confinement at the clinical site and will otherwise maintain their normal 
level of physical activity throughout the entire study (ie, will not begin a new exercise 
program or participate in any unusually strenuous physical exertion). 
While confined at the clinical site, subjects will receive a standardized high-fiber diet at 
scheduled times that do not conflict with other study-related activities. Prune juice may 
be administered on an as-needed basis to aid in normal bowel function. 
6.3.2 Concomitant Medications 
Subjects will refrain from participation in any other investigational study drug trial in 
which receipt of any investigational drug occurred within 5 half-lives (if known) or 
30 days, whichever is longer, prior to Check-in through Discharge. 
Subjects will also refrain from the use of any prescription medications/products during 
the interval from 14 days prior to Check-in through Discharge, unless deemed acceptable 
by the Investigator (or designee). In addition, subjects will refrain from the use of any 
over-the-counter, nonprescription medications (including vitamins, minerals, and 


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phytotherapeutic/herbal/plant-derived preparations) from 7 days prior to Check-in 
through Discharge, unless deemed acceptable by the Investigator (or designee). 
Subjects will not be allowed to consume any drugs or substances known to be strong 
inhibitors or strong inducers of CYP3A enzyme within 30 days prior to study drug 
administration and, unless otherwise stated, throughout the study. 
A mild laxative (eg, Milk of Magnesia®, Colace®) may be used to help with bowel 
movements if necessary. Up to 2 grams per day of acetaminophen may be administered if 
approved by the Investigator (or designee). The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary in a medical emergency. Any medication 
taken by a subject during the study and the reason for its use will be documented in the 
source documents and the eCRF. 
6.3.3 Contraception 
Males will be surgically sterile for at least 90 days (confirmed by documented 
azoospermia) or, when sexually active with female partners of childbearing potential, will 
be required to use the following form of contraception from Check-in until 90 days 
following dosing: male condom with spermicide. 
Males will refrain from sperm donation from Check-in until 90 days following the day of 
dosing. 
6.4 Pharmacokinetic, [14C] Radioactivity, and Metabolism Procedures 
6.4.1 Blood Sample Collection for Pharmacokinetic, [14C] Radioactivity, and 
Metabolism Analysis 
Blood samples for analysis of BVD-523, total radioactivity, and metabolite profiling and 
identification will be collected via direct venipuncture. Blood samples will be collected at 
the timepoints specified in Table 6-1. 
6.4.2 Urine Sample Collection for Pharmacokinetic, [14C] Radioactivity, and 
Metabolism Analysis 
Urine samples for analysis of BVD-523, total radioactivity, and metabolite profiling and 
identification will be collected during the time intervals specified in Table 6-1. Subjects 
will be encouraged to completely void urine immediately prior to the end of each 
respective collection interval. 


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6.4.3 Fecal Sample Collection for [14C] Radioactivity and Metabolism Analysis 
Fecal samples for total radioactivity and metabolite profiling and identification will be 
collected during the time intervals specified in Table 6-1. 
6.4.4 Emesis Sample Collection 
For subjects experiencing emesis within 4 hours following dosing, vomitus will be 
collected. Attempts will be made to collect vomitus from subjects experiencing emesis 
after 4 hours postdose. All vomitus collected will be stored for possible analysis. The 
time and date of collection will be recorded on the subject’s source documents and eCRF. 
Vomitus will be analyzed as deemed appropriate. 
6.4.5 Bioanalytical Methodology 
BVD-523 and metabolite(s) concentrations in plasma, BVD-523 concerntrations in urine, 
and total radioactivity concentrations in whole blood, plasma, urine, and feces will be 
determined via established analytical procedures. Profiling and characterization of 
metabolites in plasma, urine, and feces will be conducted using standard laboratory 
procedures. Specifics of the analytical methods will be provided in a separate document 
(ie, the laboratory manual[s]). 
6.5 Safety Procedures 
Safety evaluations may be repeated at the Investigator’s (or designee’s) discretion. 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical 
restrictions, and the other procedures to be performed at the same timepoint. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
• 
Dosing 
• 
PK blood sampling 
• 
Start and end of urine and feces collections (for drug assay) 
• 
Vital signs measurements 
• 
ECGs 
• 
Blood and urine samples for clinical laboratories 
• 
PEs 


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6.5.1 Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; 
and procedures for reporting SAEs are detailed in Appendix C. 
Subjects will be asked a nonleading question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified 
in Table 6-1 to assess for the occurrence of AEs. Subjects will also be encouraged to 
voluntarily report AEs occurring at any other time during the study. 
All nonserious AEs, whether volunteered, elicited, or noted on PE, will be recorded from 
initiation of study drug until study completion. Nonserious AE information observed 
before dosing will not be listed as an AE in the eCRF but will be listed as medical history 
instead, unless the AE becomes more severe postdose, in which case it will be recorded 
as an AE in the eCRF. Serious AEs will be recorded from the time the subject signs the 
ICF until study completion. 
All AEs (nonserious and serious) should be followed until the event has resolved, 
returned to baseline, or is assessed as stable by the Investigator (or designee). 
6.5.2 Clinical Laboratory Evaluations 
Clinical laboratory evaluations (including clinical chemistry panel [fasted at least 
8 hours], CBC, and UA; Appendix A) will be collected at the timepoints specified in 
Table 6-1. 
Screens for a hepatitis panel and HIV antibody will be performed at Screening. A drug 
screen for selected drugs of abuse (not including alcohol) will be performed at Screening 
and repeated (including alcohol) at Check-in. 
6.5.3 Vital Signs 
Vital signs measurements (including oral body temperature, respiratory rate, and seated, 
blood pressure and pulse) will be obtained at the timepoints specified in Table 6-1. Vital 
signs will be measured after the subject has been seated for at least 5 minutes. 
6.5.4 Twelve-lead Electrocardiograms 
A 12-lead ECG will be obtained at the timepoints specified in Table 6-1. Subjects will be 
supine for at least 5 minutes prior to obtaining an ECG measurement. 


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Electrocardiogram parameters (including heart rate; PR, QRS, and QT intervals; and QT 
interval corrected for heart rate using Fridericia’s formula) and the Investigator’s overall 
interpretation of the ECG will be recorded in the eCRF. 
6.5.5 Physical Examinations 
A routine PE will be performed at the timepoints specified in Table 6-1. 
The time and date of the PE will be recorded in the eCRF and any clinically significant 
findings will be recorded as AEs. 
7 DATA ANALYSES AND SAMPLE SIZE 
7.1 Sample Size 
The sample size chosen for this study was based on precedent set by other PK studies of 
similar nature and was not based on power calculations. No formal statistical hypotheses 
are planned to be tested in this study. 
7.2 Study Populations 
The PK population will consist of all subjects who receive study drug and have evaluable 
PK data. 
The safety population will consist of all subjects who receive study drug and have at least 
1 postdose safety assessment. 
The all subjects population will consist of all subjects who are enrolled in the study 
(signed the ICF) and have study assessments recorded in the eCRF. The all subjects 
population will be consistent with the safety population. 
7.3 Pharmacokinetic Analysis 
For each subject, the following PK parameters will be calculated, whenever possible, 
based on the plasma concentrations of BVD-523, metabolites, and total radioactivity in 
whole blood and plasma, according to the model independent approach3: 
Cmax 
maximum observed concentration 
Tmax 
time to maximum concentration 
AUC0-t 
area under the concentration-time curve calculated using 
the linear trapezoidal rule from Hour 0 to the last 
measurable concentration 


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AUC0-12 
area under the concentration-time curve calculated using 
the linear trapezoidal rule from Hour 0 to Hour 12 
AUC0-24 
area under the concentration-time curve calculated using 
the linear trapezoidal rule from Hour 0 to Hour 24 
AUC0-∞ 
area under the concentration-time curve extrapolated to 
infinity, calculated using the formula: 
 
 
AUC0-∞ = AUC0-t + 
z
t
λ
C  
 
 
where Ct is the last measurable concentration and λZ is the 
apparent terminal elimination rate constant 
% AUCextrap 
percentage extrapolation 
λZ 
apparent terminal elimination rate constant, where λZ is the 
magnitude of the slope of the linear regression of the log 
concentration versus time profile during the terminal phase 
t1/2 
terminal phase half-life, where t1/2 = natural log (2)/λ Z 
CL/F 
apparent oral clearance (for BVD-523 only) 
Vz/F 
apparent volume of distribution (for BVD-523 only) 
AUC0-∞ Blood/Plasma Ratio 
 
AUC0-∞ of total radioactivity in whole blood/AUC0-∞ of 
total radioactivity in plasma 
AUC0-∞ Plasma BVD-523/Total Radioactivity Ratio 
 
AUC0-∞ of nonradiolabeled BVD-523 in plasma/AUC0-∞ of 
total radioactivity in plasma 
AUC0-12 Blood/Plasma Ratio 
 
AUC0-12 of total radioactivity in whole blood/AUC0-12 of 
total radioactivity in plasma 
AUC0-12 Plasma BVD-523/Total Radioactivity Ratio 
 
AUC0-12 of nonradiolabeled BVD-523 in plasma/AUC0-12 
of total radioactivity in plasma 
AUC0-24 Blood/Plasma Ratio 
 
AUC0-24 of total radioactivity in whole blood/AUC0-24 of 
total radioactivity in plasma 
AUC0-24 Plasma BVD-523/Total Radioactivity Ratio 
 
AUC0-24 of nonradiolabeled BVD-523 in plasma/AUC0-24 
of total radioactivity in plasma 
AUC0-∞ Plasma Metabolites/Total Radioactivity Ratio 


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AUC0-∞ of nonradiolabeled metabolites in plasma/AUC0-∞ 
of total radioactivity in plasma 
AUC0-12 Plasma Metabolites/Total Radioactivity Ratio 
 
AUC0-12 of nonradiolabeled metabolites in plasma/AUC0-12 
of total radioactivity in plasma 
AUC0-24 Plasma Metabolites/Total Radioactivity Ratio 
 
AUC0-24 of nonradiolabeled metabolites in plasma/AUC0-24 
of total radioactivity in plasma 
 
In addition, the following PK parameters will be calculated, whenever possible, for each 
subject based on the urine concentrations of BVD-523 and total radioactivity: 
Aeu 
amount excreted in urine over sampling interval 
Cumulative Aeu 
 
cumulative amount excreted in urine, calculated as the sum 
of the amount excreted in urine for each collection period 
CLR 
renal clearance, where CLR = Ae/AUC0-∞ (for BVD-523 
only) 
% Feu 
percent of dose excreted in urine over sampling interval, 
where % Excreted = 100 (Aeu/dose) 
Cumulative % Feu 
 
cumulative percent of dose excreted in urine, calculated as 
the sum of the percent of dose excreted in urine for each 
collection period 
 
The following PK parameters will be calculated, whenever possible, for each subject 
based on the fecal concentrations of total radioactivity: 
 
Aef 
amount excreted in the feces over sampling interval 
Cumulative Aef 
 
cumulative amount excreted in feces, calculated as the sum 
of the amount excreted in feces for each collection period 
 
% Fef 
percent of dose excreted in feces over sampling interval, 
where % Excreted = 100 (Aef/dose) 
Cumulative % Fef 


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cumulative percent of dose excreted in feces, calculated as 
the sum of the percent of dose excreted in feces for each 
collection period 
 
Pharmacokinetic calculations will be performed, if appropriate, using commercial 
software such as Phoenix™ WinNonlin® (Certara USA, Inc., Version 6.4 or higher). 
Pharmacokinetic parameters for the metabolites of [14C]-BVD-523 may be calculated, as 
deemed appropriate, based on plasma, urine, and fecal concentration levels. 
Appropriate analyte ratios will be based on relevant AUC values. Other parameters may 
be added as appropriate. Final PK parameters reported will be detailed in the Statistical 
Analysis Plan (SAP). 
Pharmacokinetic analysis will use actual times as recorded in the eCRF. Other data 
handling procedures will be detailed in the SAP. 
7.4 Statistical Analysis of Pharmacokinetic Data 
Descriptive statistics (arithmetic mean, standard deviation, geometric mean, geometric 
coefficient of variation, median, minimum, maximum, and number of observations) will 
be calculated for the PK parameters. No formal statistical analyses are planned. 
Specification of PK parameters for analysis; procedures for accounting for missing, 
unused, or spurious data; procedures for reporting deviations from the original statistical 
plan; and selection of subjects to be included in the analyses population(s), as applicable, 
will be presented in the Clinical Study Report and/or SAP as appropriate. 
7.5 Statistical Analyses of Safety Data 
Descriptive statistics will be calculated on the safety parameters. No formal statistical 
analyses are planned. Baseline will be defined as the last result prior to the dose of study 
drug, including any unscheduled predose measurements. Clinical laboratory data, vital 
signs, PE results, and ECG data will be listed and summarized by parameters and 
timepoints, as appropriate. 
7.6 Data Handling and Record Keeping 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a clinical site staff member 
authorized to make the change. Changes will be made by striking a single line through 
erroneous data and clearly entering the correct data (eg, wrong data right data). If the 


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reason for the change is not apparent, a brief explanation for the change will be written 
adjacent to the change by the clinician. 
The Data Management Plan will be approved by the Sponsor. 
Data will be validated during data entry by the clinical site and verified by the Study 
Monitor. Data will then be reviewed by the data management group to resolve any 
outstanding issues. Listings will be generated after the database is cleaned by Data 
Management and will be reviewed by the Covance scientific team. The eCRF and 
ancillary data will be converted into final SAS datasets following Study Data Tabulation 
Model or client-provided specifications. The final datasets structure will be verified using 
Web Submission Data Manager®, while the dataset content will be peer-reviewed by an 
independent programmer. 
The tables, figures, and listings will be programmed per the final SAP. All tables, figures, 
and listings will be peer-reviewed by an independent programmer. In addition, draft 
tables, figures, and listings will be reviewed by the Covance scientific team during the 
dry run and data review meetings. 
The peer-review will be performed by independent programmers following the quality 
control process and programming checklists. 
7.7 Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures or per client request and as applicable according to the contract 
between Covance and the Sponsor. 
8 ADMINISTRATIVE ASPECTS 
8.1 Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and 
the Investigator. 
There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, Investigator, and the Institutional Review Board (IRB; 
see Form FDA 1572). 


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8.2 Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with 
the Investigator and appropriate clinical staff to familiarize the Investigator and clinical 
staff with the materials necessary for conducting the clinical study. 
8.3 Disclosure 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Any publication of the results, in part or in total (eg, articles in journals or newspapers, 
oral presentations, abstracts) by the Investigator or their representative(s), shall require 
prior notification and review, within a reasonable timeframe, by the Sponsor, and cannot 
be made in violation of the Sponsor’s confidentiality restrictions or to the detriment of the 
Sponsor’s intellectual property rights. 
8.4 Monitoring 
The Sponsor will designate a Sponsor’s Study Monitor who will be responsible for 
monitoring this clinical trial. The Sponsor’s Study Monitor will monitor the study 
conduct, proper eCRF and source documentation completion and retention, and accurate 
study drug accountability. To this end, the Sponsor’s Study Monitor will visit the clinical 
site at suitable intervals and be in frequent contact through verbal and written 
communication. It is essential that the Sponsor’s Study Monitor has access to all 
documents (related to the study and the individual participants) at any time these are 
requested. In turn, the Sponsor’s Study Monitor will adhere to all requirements for 
subject confidentiality as outlined in the ICF. The Investigator and Investigator’s staff 
will be expected to cooperate with the Sponsor’s Study Monitor, to be available during a 
portion of the monitoring visit to answer questions, and to provide any missing 
information. 
8.5 Institutional Review Board 
In accordance with US Title 21 CFR 56, the protocol, advertisement, ICF, and other 
information provided to subjects will be reviewed and approved by the IRB. The Sponsor 
will supply relevant material for the Investigator (or designee) to submit to the IRB for 
the protocol’s review and approval. Verification of the IRB unconditional approval of the 


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protocol and the written ICF statement will be transmitted to the Investigator (or 
designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will 
be transmitted in writing to the Investigator (or designee). If requested, the Investigator 
(or designee) will permit audits by the IRB and regulatory inspections by providing direct 
access to source data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate 
intervals (not to exceed 1 year) and a Study Progress Report following the completion, 
termination, or discontinuation of the Investigator’s participation in the study. 
8.6 Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the 
test product. The subjects will be informed that participation is voluntary and that they 
can withdraw from the study at any time. In accordance with 21 CFR 50, the informed 
consent process shall be documented by the use of a written ICF approved by the IRB 
and signed by the subject prior to protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the 
other will be maintained with the subject’s records. 
8.7 Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s eCRF. To maintain confidentiality, the subjects will be identified only by 
numbers. 
The completed eCRFs will be transferred to the Sponsor (or designee). Copies of each 
eCRF will be retained by the Investigator (or designee). All source documents, records, 
and reports will be retained by the clinical site in accordance with 21 CFR 312.62(c). 
All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the clinical site archives. 


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8.8 Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the 
US CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by 
Clinical Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug 
Application (21 CFR 312), Applications for FDA Approval to Market a New Drug 
(21 CFR 314), and Radioactive Drugs For Certain Research Uses (21 CFR 361.1), as 
appropriate. As such, these sections of US Title 21 CFR, along with the applicable 
International Conference on Harmonisation Guidelines, are commonly known as Good 
Clinical Practices, which are consistent with the Declaration of Helsinki. 
8.9 Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 


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INVESTIGATOR AGREEMENT 
I have read the foregoing protocol and agree to conduct the study as described herein. 
IJ<(\ne Mirkin, MD 
Principal Investigator 
Covance Clinical Research Unit, Inc. 
Final2.0: 07 December 2016 
Date 
· 
Page 39 of48 


Clinical Protocol Amendment l 
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SPONSOR AGREEMENT 
CONFIDENTIAL 
Protocol 523HV001 
I have read the foregoing protocol and agree to the conduct of the study as described 
herein: 
Associate Director, Translational Sciences 
BioMed Valley Discoveries Inc. 
Final2.0: 07 December 2016 
Date 
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REFERENCES 
1. Fitzsimmons ME and Oswald J. Covance 8336350. Tissue Distribution of 
Radioactivity After a Single Oral Dose of [14C]BVD-523 to Pigmented Rats. 
Covance, Inc.; Madison, Wisconsin (2016). 
2. Investigator’s Brochure, BVD-523. Version 3.0, 17 June 2016. 
3. Gibaldi M, Perrier D. Pharmacokinetics. 2nd edition. New York, NY: Marcel 
Dekker Inc.; 1982. 


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APPENDIX A - CLINICAL LABORATORY EVALUATIONS 
Clinical Chemistry Panel (Fasted): Complete Blood Count: 
Urinalysis: 
Alanine aminotransferase 
Hematocrit 
Bilirubin 
Albumin 
Hemoglobin 
Color and appearance 
Alkaline phosphatase 
Mean corpuscular hemoglobin 
Glucose 
Aspartate aminotransferase 
Bilirubin (direct, indirect and total)  
Mean corpuscular hemoglobin 
concentration 
Ketones 
Leukocyte esterase 
Blood urea nitrogen 
Mean corpuscular volume 
Nitrite 
Calcium 
Platelet count 
Occult blood 
Chloride 
Red blood cell (RBC) count 
pH and specific gravity 
Cholesterol 
RBC distribution width 
Protein 
Creatinine 
White blood cell (WBC) count 
Urobilinogen 
Glucose 
WBC differential (absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Microscopic exam including 
bacteria, casts, crystals, 
epithelial cells, RBCs, and 
WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Iron 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
 
 
Uric acid 
 
 
 
 
 
 
 
 
Drug Screen: 
Other Tests: 
 
Including but not limited to the 
following: 
Hepatitis B surface antigen 
Hepatitis C virus antibody 
 
Alcohol (ethanol, via breathalyzer, 
at Check-in only) 
Amphetamines 
HIV antibody 
 
Barbiturates 
Benzodiazepines 
 
 
Cannabinoids 
 
 
Cocaine (metabolite) 
 
 
Methadone 
 
 
Opiates 
 
 
Phencyclidine 
 
 
Cotinine 
 
 


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APPENDIX B - BLOOD SAMPLING SUMMARY 
Purpose 
Maximum Blood Volume 
per Sample (mL) 
Maximum Number of 
Blood Samples 
Maximum Total 
Volume (mL) 
Serology 
4 
1 
4 
Clinical Laboratory Tests 
8 
3 
24 
Sampling for 
Pharmacokinetic Analysis 
3 
17 
51 
Sampling for Total 
Radioactivity Analysis 
4 
24 
96 
Sampling for Metabolism 
Analysis 
10 
17 
170 
Total 
 
 
345 mL 


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APPENDIX C - ADVERSE EVENTS 
1  
ADVERSE EVENTS 
1.1  Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical 
occurrence experienced by a patient or healthy subject, whether or not considered 
drug-related by the Investigator (or designee). A treatment-emergent AE is an AE that is 
reported after a dose of study drug. 
The following are all AEs: 
• 
Unfavorable changes in general condition; 
• 
Subjective or objective signs/symptoms; 
• 
Concomitant diseases or accidents; 
• 
Clinically relevant adverse changes in laboratory parameters 
observed in a subject during a clinical study. 
Adverse events comprise all disturbances of general health status, subjective and 
objective disease symptoms (including clinically significant laboratory abnormalities), 
and accidents observed in the context of a clinical trial, irrespective of a possible causal 
relationship with the administration of the trial substance. Events occurring in the 
framework of a clinical trial during drug-free and post-treatment periods, under placebo, 
or in a reference group receiving drug or nondrug therapy are also to be designated as 
AEs. 
1.2  Categorization of Adverse Events 
The severity of AEs will be categorized as follows: 
• 
MILD = of little concern to the subject and/or of no clinical 
significance, is not expected to affect the subject’s health or 
well-being; 
• 
MODERATE = discomforting enough to cause interference with 
or change in usual activities, is likely to require medical 
intervention or close follow-up; 
• 
SEVERE = incapacitating or causing inability to work or 
participate in many or all usual activities, is of concern to the 
subject or poses substantial risk to the subject’s health or 


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well-being, is likely to require medical intervention or close 
follow-up. 
The Investigator (or designee) will make a determination of the relationship of the AE to 
the study drug using a 4-category system according to the following guidelines: 
• 
NOT RELATED = an AE that does not follow a reasonable 
temporal sequence from administration of the drug and can be 
reasonably explained by other factors, including underlying 
disease, complications, concomitant drugs, or concurrent 
treatment; 
• 
UNLIKELY RELATED = an AE that follows a reasonable 
temporal sequence from the administration of the drug (including 
after withdrawal of the drug) and cannot be excluded as being 
possibly caused by the drug (eg, existence of similar reports 
attributed to the suspected drug and/or its analogues, reactions 
attributable to the pharmacological effect of the drug), although 
other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatment are presumable; 
• 
POSSIBLY RELATED = an AE that follows a reasonable 
temporal sequence from administration of the drug (including after 
withdrawal of the drug) and can be excluded as being possibly 
caused by other factors, such as underlying disease, complications, 
concomitant drugs, or concurrent treatment; 
• 
RELATED = an AE that follows a reasonable temporal sequence 
from administration of the drug (including after withdrawal of the 
drug), follows a known or hypothesized cause-effect relationship, 
and (if appropriate) satisfies the following: 
• 
Positive results obtained in drug sensitivity tests; 
• 
Toxic level of the drug present in blood or other body 
fluids. 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
The following categories will be used for the action taken with the study drug for the AE: 
drug withdrawn, dose not changed, drug interrupted, unknown, and not applicable. 


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The following categories will be used for the outcome of the AE: resolved, resolved with 
sequelae, ongoing, fatal, and unknown. 
1.3  Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported 
immediately to the Investigator (or designee) and the Sponsor, including pregnancy in 
female partners of male subjects. Pregnancy should be reported to the Sponsor’s safety 
representative using the Pregnancy Form provided within 24 hours of knowledge of the 
diagnosis. 
The pregnancy may be followed to term or outcome and this outcome may be reported to 
the Sponsor. Pregnancy, in and of itself, is not regarded as an AE or serious AE (SAE) 
unless the birth results in a congenital anomaly/birth defect or there is suspicion that the 
study medication may have interfered with the effectiveness of a contraceptive 
medication or method. 
1.4  Definition of Serious Adverse Events 
An SAE (by Food and Drug Administration [FDA] definition) is any adverse drug 
experience occurring at any dose that results in any of the following outcomes: 
• 
Death; 
• 
A life-threatening adverse drug experience (ie, places the subject, 
in the view of the Investigator [or designee], at immediate risk of 
death); 
• 
Inpatient hospitalization or prolongation of existing 
hospitalization; 
• 
A persistent or significant disability/incapacity; 
• 
A congenital anomaly/birth defect; 
• 
Important medical event that may require medical or surgical 
intervention to prevent one of the above outcomes. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. All SAEs must be 
collected that occur after the subject signs the ICF. 
All SAEs must be reported to the Sponsor and the Sponsor’s safety representative within 
24 hours of first knowledge of the event by study personnel. Serious AEs must be 


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reported on the SAE Form provided by the Sponsor and submitted to the Sponsor’s safety 
representative via email to: safety@clinipace.com 
A representative from the Sponsor’s safety team may contact the site for clarification of 
data entered onto the SAE Form, or to obtain missing information. In the event of 
questions regarding SAE reporting, the site may contact the Sponsor’s safety 
representative at: safety@clinipace.com 
1.5  Unexpected Adverse Drug Experience 
An unexpected adverse drug experience is any adverse drug experience, the specificity or 
severity of which is not consistent with the current Investigator’s Brochure (IB) or, if an 
IB is not required or available, the specificity or severity of which is not consistent with 
the risk information described in the general investigational plan or elsewhere in the 
current application, as amended. 
1.6  Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of 
the drug and are serious and unexpected. Food and Drug Administration-reportable AEs 
will be reported by the clinical site to the Sponsor, Medical Monitor assigned by the 
Sponsor, and the responsible Institutional Review Board (IRB). 
The Sponsor and Sponsor’s Representatives and Medical Monitor will be notified in 
writing within 24 hours of when an SAE that is potentially FDA-reportable is first 
recognized or reported using the SAE Form provided by the Sponsor. 
Contact Information for Safety Reporting 
Safety Associate 
Clinipace Worldwide, Inc. 
safety@clinipace.com 
 
Subsequently, a written confirmation or summary of the SAE (using FDA Form 3500A, 
or equivalent) will be sent to the Sponsor within 3 working days of the original 
notification. (Instructions for completion of FDA Form 3500A may be obtained from the 
FDA website at www.fda.gov/medwatch/how.htm.) 
The IRB will be notified of any FDA-reportable AE within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the 
AE. 


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The Sponsor or the Sponsor’s safety representative is responsible for submitting reports 
of AEs associated with the use of the drug that are serious, unexpected, and thought to 
have at least a reasonable possibility of having been caused by the drug, to the FDA 
according to 21 CFR 312.32 and current guidance. 

SAP_001.pdf: 
Final: 29 MARCH 2017 
 
 
Page 1 of 19
STATISTICAL ANALYSIS PLAN 
A PHASE 1 STUDY TO INVESTIGATE THE ABSORPTION, METABOLISM,  
AND EXCRETION OF [14C]-BVD-523 FOLLOWING SINGLE ORAL DOSE 
ADMINISTRATION IN HEALTHY MALE SUBJECTS 
Statistical Analysis Plan Status: Final  
Statistical Analysis Plan Date: 29 MARCH 2017 
Study Drug: [14C]-BVD-523 
Sponsor Reference Number: 523HV001 
Covance Study Number: 8353316 
Clinical Phase 1 
 
 
Sponsor: 
 
BioMed Valley Discoveries 
4520 Main Street, Suite 1650 
Kansas City, Missouri 64111 
USA 
Study Site: 
Covance Clinical Research Unit 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
 
 
Sponsor Signatory: 
Deborah Knoerzer, MS 
Associate Director, Translational Sciences 
BioMed Valley Discoveries 
Telephone: (636) 887-6429 
Principal Investigator: 
Irene Mirkin,MD  
Telephone: (608) 443-1477  
 
 
 
 
 




Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8353316 
 
Sponsor Reference: 523HV001 
 
Final: 29 MARCH 2017 
 
 
Page 3 of 19
2. TABLE OF CONTENTS 
1. 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................................................... 2 
2. 
TABLE OF CONTENTS ....................................................................................................................... 3 
3. 
ABBREVIATIONS .............................................................................................................................. 5 
4. 
INTRODUCTION ............................................................................................................................... 7 
5. 
STUDY OBJECTIVES .......................................................................................................................... 7 
6. 
STUDY DESIGN ................................................................................................................................. 8 
7. 
TREATMENT .................................................................................................................................... 8 
8. 
SAMPLE SIZE JUSTIFICATION ........................................................................................................... 8 
9. 
DEFINITION OF ANALYSIS POPULATIONS ........................................................................................ 9 
10.  STATISTICAL METHODOLOGY .......................................................................................................... 9 
10.1 GENERAL ......................................................................................................................................... 9 
10.1.1 
DEFINITION OF BASELINE AND CHANGE FROM BASELINE .................................................... 10 
10.1.2 
REPEAT AND UNSCHEDULED READINGS ............................................................................... 10 
10.2 DEMOGRAPHICS AND SUBJECT DISPOSITION ............................................................................... 10 
10.3 PHARMACOKINETIC ASSESSMENT ................................................................................................ 10 
10.3.1 
PHARMACOKINETIC ANALYSIS ............................................................................................... 10 
10.3.1.1 
CRITERIA FOR HANDLING CONCENTRATIONS BELOW THE LIMIT OF QUANTIFICATION IN 
PHARMACOKINETIC ANALYSIS ...................................................................................................... 14 
10.3.1.2 
CRITERIA FOR THE CALCULATION OF AN APPARENT TERMINAL PHASE  HALF‐LIFE ... 15 
10.3.2 
PRESENTATION OF PHARMACOKINETIC DATA ...................................................................... 16 


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10.3.2.1 
PRESENTATION OF PHARMACOKINETIC PLASMA DRUG CONCENTRATION DATA ..... 16 
10.3.2.2 
PRESENTATION OF PHARMACOKINETIC PARAMETERS............................................... 17 
10.3.3 
PHARMACOKINETIC STATISTICAL METHODOLOGY ............................................................... 17 
10.4 SAFETY AND TOLERABILITY ASSESSMENTS ................................................................................... 17 
10.4.1 
ADVERSE EVENTS ................................................................................................................... 17 
10.4.2 
CLINICAL LABORATORY PARAMETERS ................................................................................... 18 
10.4.3 
VITAL SIGNS ........................................................................................................................... 18 
10.4.4 
ELECTROCARDIOGRAM .......................................................................................................... 18 
10.4.5 
OTHER ASSESSMENTS ............................................................................................................ 18 
10.4.6 
SAFETY AND TOLERABILITY STATISTICAL METHODOLOGY .................................................... 18 
11.  INTERIM ANALYSES ....................................................................................................................... 18 
12.  CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ........................................... 19 
13.  DATA PRESENTATION .................................................................................................................... 19 
13.1  
 INSUFFICIENT DATA FOR PRESENTATION ............................................................................. 19 
14.  REFERENCES .................................................................................................................................. 19 
 


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3. ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ADaM 
analysis data model 
AE 
adverse event 
Aef 
amount excreted in feces over sampling interval 
Aeu 
amount excreted in urine over sampling interval 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last 
measurable concentration 
AUC0-12 
area under the concentration-time curve from Hour 0 to Hour 12 
AUC0-24 
area under the concentration-time curve from Hour 0 to Hour 24 
AUC0- 
area under the concentration-time curve from hour 0 extrapolated to 
infinity 
BLOQ 
below the lower level of quantification 
BMI 
body mass index 
CBC 
complete blood count 
CDISC 
Clinical Data Interchange Standards Consortium 
CL/F 
apparent oral clearance 
CLR 
renal clearance 
Cmax 
maximum observed plasma concentration 
CSR 
Clinical Study Report 
Ct 
the last measurable plasma concentration 
CV% 
coefficient of variation 
EC 
Early Clinical 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
LLOQ 
lower limit of quantification 
max 
maximum (Max) 


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MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
N, n 
number 
NC 
not calculated 
NR 
no result 
PK 
pharmacokinetic 
QTc 
QT correction; QT interval corrected for heart rate 
QTcF 
QTc calculated using the Fridericia correction  
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
t1/2 
terminal phase half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
Tmax  
time to maximum plasma concentration 
UA 
urinalysis 
Vz/F 
apparent volume of distribution  
Z 
the apparent terminal elimination rate constant 
% Fef 
percent of dose excreted in feces over sampling interval 
% Feu 
percent of dose excreted in urine over sampling interval 
% AUCextrap 
percentage of AUC0- determined by extrapolation 


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4. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final 2.0 dated 
07 December 2016). 
This SAP describes the planned analysis of the safety, tolerability, metabolism and PK data from 
this study. A detailed description of the planned TFLs to be presented in the Clinical Study 
Report (CSR) is provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for planned analysis of the safety, 
metabolism, and PK data. In general, the analyses are based on information from the protocol, 
unless they have been modified by agreement between BioMed Valley Discoveries Inc. and 
Covance Early Clinical (EC) Biometrics. A limited amount of information concerning this study 
(eg, objectives, study design) is given to help the reader’s interpretation. This SAP must be 
finalized prior to the lock of the clinical database for this study. When the SAP and TFL shells 
are agreed upon and finalized, they will serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between BioMed Valley Discoveries Inc. and Covance EC Biometrics and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports.”1,2 
5. STUDY OBJECTIVES 
 The primary objective of this study is to characterize the metabolic disposition, 
pharmacokinetics,  and routes of elimination of [14C] labeled BVD-523 after administration 
of a single, oral dose to healthy male subjects. 
 The secondary objective of this study is to evaluate the safety and tolerability of a single 
oral dose of [14C] labeled BVD-523 in healthy male subjects. 


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6. STUDY DESIGN 
This study will be an open-label, absorption, metabolism, and excretion study of [14C]-BVD-523 
administered as a 600-mg (approximately 200 μCi) oral dose to 6 healthy male subjects 
following a 2-hour fast from food (not including water) that follows breakfast. 
A schematic of the study design is presented in Figure 1. The start of the study is defined as the 
date the first subject signs an Informed Consent Form (ICF). This is specifically for a subject 
enrolled (assigned a dose) in the study and does not include screen failure subjects. A subject 
who completes all PK, radioactivity, and metabolism sampling prior to Discharge is considered 
to have completed the study. This is the last planned contact with the subject, and does not 
include any unplanned follow-up (eg, return to the clinic for repeat clinical laboratory test). 
The end of the study is defined as the date the last subject completes the study. The planned 
duration of study conduct for each subject is up to 43 days (Screening through Discharge). 
Figure 1 Study Design Schematic 
Screening 
Check-in 
Dosing 
PK/Radioactivity Sampling 
Study Completiona
Days -28 to -2 
Day -1 
Day 1 
Day 1 to Study Completion 
Day 8 to Day 15 
 
Confined to CRU 
CRU = Clinical Research Unit; PK = pharmacokinetic. 
a Subjects will be discharged from the CRU starting on Day 8 if plasma radioactivity levels are below the limit of quantification, ≥90% of the 
radioactive dose is recovered, and if ≤1% of the radioactive dose is recovered in urine and feces for 2 consecutive 24-hour collection intervals. If 
these criteria are not satisfied by the morning of Day 8, subjects will continue to be confined in the CRU until these criteria are met, up to a 
maximum of Day 15. 
7. TREATMENT 
Subjects in this study will be administered [14C]-BVD-523 as a 600-mg (approximately 200 µCi) 
oral dose) which will be abbreviated as [14C]-BVD-523 in the TFLs. 
8. SAMPLE SIZE JUSTIFICATION 
The sample size chosen for this study was based on precedent set by other PK studies of similar 
nature and was not based on power calculations. No formal statistical hypotheses are planned to 
be tested in this study. 


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9. DEFINITION OF ANALYSIS POPULATIONS 
The All Subjects Population will consist of all subjects who are enrolled in the study (signed 
the ICF) and have study assessments recorded in the electronic Case Report Form (eCRF).  
The Safety Population will consist of all subjects who receive study drug and have at least 1 
postdose safety assessment. 
The PK Population will consist of all subjects who receive study drug and have evaluable PK 
data. Subjects may be excluded from the PK summary statistics and statistical analysis if a 
subject has an adverse event (AE) of vomiting that occurs within approximately 2 times median 
time to maximum concentration (Tmax). 
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
10. STATISTICAL METHODOLOGY 
10.1 
GENERAL 
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations 
(Safety/PK).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation (SD), median, minimum (min), maximum (max), and number of observations (n). Data 
listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
Missing values will not be imputed. 
Data analysis will be performed using SAS® Version 9.3 or higher. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilized to ensure 
compliance with CDISC standards. 


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10.1.1 DEFINITION OF BASELINE AND CHANGE FROM BASELINE 
Baseline for each parameter is defined as the last value measured prior to dosing, including 
repeat (vital signs) and unscheduled predose readings (see Section 10.1.2 for definitions of repeat 
and unscheduled readings). 
For safety data, mean change from baseline is the mean of all individual subjects’ change from 
baseline values. Each individual change from baseline will be calculated by subtracting the 
individual subject’s baseline value from the value at the time point. The individual subject’s 
change from baseline values will be used to calculate the mean change from baseline using a 
SAS procedure such as Proc Univariate. 
10.1.2 REPEAT AND UNSCHEDULED READINGS 
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as ‘Repeat’ in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading.  
With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
All results not taken at a scheduled time point for other data types (eg, clinical laboratory 
parameters) are unscheduled. Unscheduled readings are labeled as ‘Unscheduled’ in the listings. 
Because unscheduled postdose readings are not associated with any scheduled time point, they 
are excluded from all summaries. 
10.2 
Demographics and Subject Disposition 
The demographic variables age, sex, race, ethnicity, body weight, height, and body mass index 
(BMI) will be summarized and listed. Subject disposition will be summarized and listed. 
10.3 
Pharmacokinetic Assessment 
10.3.1 Pharmacokinetic Analysis 
For each subject, the following PK parameters will be calculated, whenever possible, based on 
the concentrations of BVD-523, BVD-0513A, and BVD-0502A+BVD-0503A in plasma and 


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concentrations of total radioactivity in plasma and whole blood, using noncompartmental 
methods performed using Phoenix WinNonlin (Certara USA, Inc.) Version 6.4 or higher: 
Parameter 
Definition 
Cmax 
maximum observed concentration 
Tmax 
time to maximum concentration 
AUC0-t 
area under the concentration-time curve calculated using the linear 
trapezoidal rule from Hour 0 to the last measurable concentration 
AUC0-12 
area under the concentration-time curve calculated using the linear 
trapezoidal rule from Hour 0 to Hour 12 
AUC0-24 
area under the concentration-time curve calculated using the linear 
trapezoidal rule from Hour 0 to Hour 24 
AUC0- 
area under the concentration-time curve extrapolated to infinity, 
calculated using the formula: 
AUC0- = AUC0-t + 
 
where Ct is the last measurable concentration and Z is the apparent 
terminal elimination rate constant 
% AUCextrap 
percentage of AUC0- determined by extrapolation 
Z 
apparent terminal elimination rate constant, where Z is the 
magnitude of the slope of the linear regression of the log 
concentration versus time profile during the terminal phase 
t1/2 
terminal phase half-life, where t1/2 = natural log (2)/ Z 
CL/F 
apparent oral clearance (for BVD-523 only) 
Vz/F 
apparent volume of distribution (for BVD-523 only) 
AUC0-∞ Blood /Plasma Ratio 
AUC0-∞ of total radioactivity in whole blood/AUC0-∞ of total 
radioactivity in plasma 
AUC0-∞ Plasma BVD-523/ Total 
AUC0-∞ of nonradiolabeled BVD-523 in plasma/AUC0-∞ of total 
Z
t
λ
C


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Radioactivity Ratio 
radioactivity in plasma 
AUC0-12 Blood/Plasma Total 
Radioactivity Ratio 
AUC0-12 of total radioactivity in whole blood/AUC0-12 of total 
radioactivity in plasma 
AUC0-12 Plasma BVD-523/ Total 
Radioactivity Ratio 
AUC0-12 of nonradiolabeled BVD-523 in plasma/AUC0-12 of total 
radioactivity in plasma 
AUC0-24 Blood/Plasma Total 
Radioactivity Ratio 
AUC0-24 of total radioactivity in whole blood/AUC0-24 of total 
radioactivity in plasma 
AUC0-24 Plasma BVD-523/ Total 
Radioactivity Ratio 
AUC0-24 of nonradiolabeled BVD-523 in plasma/AUC0-24 of total 
radioactivity in plasma 
AUC0-∞ Plasma Metabolites/ 
Total Radioactivity Ratio 
AUC0-∞ of nonradiolabeled metabolites in plasma/AUC0-∞ of total 
radioactivity in plasma 
AUC0-12 Plasma Metabolites/ 
Total Radioactivity Ratio 
AUC0-12 of nonradiolabeled metabolites in plasma/AUC0-12 of total 
radioactivity in plasma 
AUC0-24 Plasma Metabolites/ 
Total Radioactivity Ratio 
AUC0-24 of nonradiolabeled metabolites in plasma/AUC0-24 of total 
radioactivity in plasma 
 
In addition, the following PK parameters will be calculated, whenever possible, for each subject 
based on the urine concentrations of BVD-523 and total radioactivity. Parameters for BVD-523 
in urine will be calculated and reported by the Covance EC Biometrics PK group; parameters for 
total radioactivity (except CLR, which will be calculated for BVD-523 only) will be calculated 
and reported by the Covance Radioanalysis group. Urinary parameters for total radioactivity will 
also be presented in the CSR tables. 


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Parameter 
Definition 
Aeu 
amount excreted in urine over sampling interval (t1-t2) where t1 
and t2 are the start and end times of the sampling interval, 
respectively 
Cumulative Aeu 
cumulative amount excreted in urine, calculated as the sum of the 
amount excreted in urine for each collection interval 
CLR 
renal clearance, where CLR = Aeu/AUC0-∞ (for BVD-523 only) 
% Feu 
percent of dose excreted in urine over sampling interval (t1-t2), 
where % Excreted = 100 (Aeu/dose) 
Cumulative % Feu 
cumulative percent of dose excreted in urine, calculated as the sum 
of the percent of dose excreted in urine for each collection interval 
 
The following PK parameters will be calculated, whenever possible, for each subject based on 
the fecal concentrations of total radioactivity. Parameters for total radioactivity will be reported 
by the Covance Radioanalysis group in the Radioanalysis report. Fecal parameters for total 
radioactivity will also be presented in the CSR tables. 
Parameter 
Definition 
Aef 
amount excreted in feces over sampling interval (t1-t2) 
Cumulative Aef 
cumulative amount excreted in feces, calculated as the sum of the 
amount excreted in feces for each collection interval 
% Fef 
percent of dose excreted in feces over sampling interval (t1-t2), 
where % Excreted = 100 (Aeu/dose) 
Cumulative % Fef 
cumulative percent of dose excreted in feces, calculated as the sum 
of the percent of dose excreted in feces for each collection interval 
 
Additional PK parameters may be determined where appropriate. 


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Pharmacokinetic analysis will, where possible, be carried out using actual postdose times 
recorded in the raw data. If actual times are missing, nominal times may be used with sponsor 
approval.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Cmax and Tmax will be obtained directly from the plasma concentration-time profiles.   
For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest Tmax will be reported.  
The amount excreted in urine (Aeu) for each urine collection interval will be calculated as the 
product of urine concentration and urine weight; Cumulative Aeu 0-x hour will be calculated by 
summing the Aeu values for each collection interval over the 0-x hour period. 
In addition to the PK and radioanalysis results, a discussion of the results of metabolite 
characterization will be included in the CSR however no tables, figures, or listings will be 
generated.  The quantitation of parent and metabolites (concentrations and/or percent of dose), as 
applicable, other applicable metabolite characterization results (representative chromatograms, 
proposed metabolite structures, etc.), and any PK parameters calculated from the 
radiochromatography data will be reported in the Metabolite Profiling and Identification report. 
Radiochromatography PK parameters may be summarized in the CSR along with PK parameters 
determined from the bioanalytical data. 
10.3.1.1 Criteria For Handling Concentrations below the Limit of Quantification in 
Pharmacokinetic Analysis 
Concentration values that are below the lower level of quantification (BLOQ) will be set to zero, 
with defined exceptions as follows; 
 Any embedded BLOQ value (between 2 quantifiable concentrations) and BLOQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
 If there are late positive concentration values following 2 BLOQ concentration values in 
the apparent terminal phase, these values will be evaluated. If these values are considered 
to be anomalous, they will be set to missing. 


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 If an entire concentration-time profile is BLOQ, the profile will be excluded from the PK 
analysis. 
 If a predose concentration is missing, this value may be set to zero with sponsor approval. 
10.3.1.2 Criteria for the Calculation of an Apparent Terminal Phase  Half-Life 
 Number of Data Points 
- At least 3 data points will be included in the regression analysis and preferably should 
not include Cmax. 
 Goodness of Fit 
- When assessing terminal  phases, the R2 adjusted value will be used as a measure of the 
goodness of fit of the data points to the determined line.  
- An terminal phase  half-life will only be calculated if the R2 adjusted value of the 
regression line is greater than or equal to 0.7. 
 Period of Estimation 
- Time period used for the estimation of apparent terminal phase  half-lives, where 
possible, will be over at least 2 half-lives.  
- Where an elimination half-life is estimated over a time period of less than 2 half-lives, 
it will be flagged in the data listings at the discretion of the Pharmacokineticist, and the 
robustness of the value should be discussed in the study report. 
 Calculation of AUC 
- The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive plasma concentrations above the lower limit of quantification (LLOQ), 
with at least 1 of these concentrations following Cmax. Exceptions may be made for 
metabolites. 
- For any partial AUC determination (ie, AUC0-12 and AUC0-24), nominal time will 
generally be used for the end of the interval. Actual times for partial AUC intervals 
may be used at the discretion of the Pharmacokineticist.  


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- AUC0- values where the percentage extrapolation is less than 20% will be reported. 
AUC0- values where the percentage extrapolation is  20% to 30% will be flagged and 
included in the descriptive statistics, whilst AUC0- values where the percentage 
extrapolation is greater than 30% will be reported but excluded from descriptive 
statistics.   
 Anomalous Values 
- If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis based on the 
Covance SOP. However, the exclusion of data must have strong justification and will 
be documented in the raw data and study report. 
- Positive predose value(s) greater than 5% of Cmax may be excluded from the summary 
statistics of PK tables and statistical analysis at the discretion of the Pharmacokineticist 
and BioMed Valley Discoveries Inc. 
10.3.2 Presentation of Pharmacokinetic Data 
10.3.2.1 Presentation of Pharmacokinetic Plasma Drug Concentration Data 
The following rules will be applied if there are values that are BLOQ or if there are missing 
values (eg, no result [NR]) in a plasma concentration data series to be summarized. 
 For the calculation of summary statistics, BLOQ values will be set to zero. 
 If an embedded BLOQ value is considered anomalous within the concentration-time 
profile, this value will be excluded from the summary statistics. 
 Where there is NR, these will be set to missing. 
 If there are less than 3 values in the data series, only the min, max, and n will be presented. 
The other summary statistics will be denoted as not calculated (NC). BLOQ is considered a 
value. 
 If all the values are BLOQ, then the arithmetic mean, arithmetic SD, median, min, and max 
will be presented as zero. 


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 If the value of the arithmetic mean or median is below the LLOQ, these values will be 
presented as zero. 
10.3.2.2 Presentation of Pharmacokinetic Parameters 
  For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing. 
 The AUC values will be set to NC if they have been calculated using fewer than 
3 concentrations, and/or 3 concentrations if the last is Cmax (exception made for 
metabolites). 
10.3.3 Pharmacokinetic Statistical Methodology 
Descriptive statistics (arithmetic mean, SD, median, min, max, and number of observations) will 
be calculated for the PK parameters. No formal statistical analyses are planned. 
10.4 
Safety and Tolerability Assessments 
10.4.1 Adverse Events 
A baseline sign and symptom is defined as an AE that starts after the subject has provided 
written informed consent and that resolves prior to the first dosing occasion, or an AE that starts 
prior to the first dosing occasion and does not increase in severity after dosing. A 
treatment-emergent AE (TEAE) is defined as an AE that occurs postdose or that is present 
predose and becomes more severe postdose.  
Nonserious AE information observed before dosing will not be listed as an AE in the eCRF but 
will be listed as medical history instead, unless the AE becomes more severe postdose, in which 
case it will be recorded as an AE in the eCRF. Serious AEs will be recorded from the time the 
subject signs the ICF until study completion. 
All AEs will be listed. The TEAEs will be summarized by treatment, severity, and relationship to 
the study drug. The frequency (the number of TEAEs, the number of subjects experiencing a 
TEAE, and the percentage of subjects experiencing a TEAE) of TEAEs will be summarized by 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. 
The summary and frequency TEAE tables will be presented for all causalities and for those 
TEAEs considered related to the study drug (those that have a relationship of at least possibly 
related to study treatment). Any severe or serious AEs will be tabulated. For any AEs that change 


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severity ratings the AE will be included only once under the maximum severity rating in the 
summaries.    
10.4.2 Clinical Laboratory Parameters 
Clinical chemistry, hematology data will be listed. In addition, all clinical chemistry panel, 
hematology, and UA data outside the clinical reference ranges will be listed by parameter. Any 
clinical chemistry, hematology, and urinalysis (UA) values outside the clinical reference ranges 
will be flagged on the individual subject data listings. 
10.4.3 Vital Signs 
The vital signs, including systolic blood pressure, diastolic blood pressure, pulse rate, and 
temperature data will be summarised by time point, together with changes from baseline. Figures 
of mean vital signs and mean change from baseline profiles will be presented by time point.  
Vital signs values outside the clinical reference ranges will be flagged on the individual subject 
data listings. Repeat and unscheduled readings will be handled as defined in Section 10.1.2.  
10.4.4 Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the Fridericia correction (QTcF), the PR and QT intervals, the QRS 
duration, and heart rate. The ECG data will be listed only. Values for ECG parameters outside 
the clinical reference ranges will be flagged on the individual subject data listings. 
10.4.5 Other Assessments 
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed. 
10.4.6 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
11. INTERIM ANALYSES 
No interim statistical analyses are planned. 


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12. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol-specified statistical analyses. 
13. DATA PRESENTATION 
13.1   Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.” 
14. REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.