Clinical trial NCT01781429
Conditions: Advanced Solid Tumors
Sponsor: BioMed Valley Discoveries, Inc
Start date: 2013-03-01; Completion date: 2018-09-01
Enrollment: 136 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open-label, multi-center Phase 1/2 study will assess the safety, pharmacokinetics, and pharmacodynamics of escalating doses of BVD-523 in patients with advanced malignancies. The study also seeks to demonstrate target modulation and early signs of clinical response in select patient populations.

Detailed description:
The study is being performed to assess the safety and tolerability of BVD-523

In Part 1 of the study, an accelerated dose escalation plan will be used to establish dose limiting toxicities, maximum tolerated dose, and the recommended Phase 2 dose.

In Part 2 of the study, additional patients with particular tumor types and/or cancers harboring specific genetic mutations will be recruited for treatment at the Recommended Phase 2 Dose. Patients may also be assessed pharmacodynamic measures in healthy or malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic measures.

Arms: arm 1: None
Interventions: intervention 1: BVD-523
Intervention descriptions: intervention 1: Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle

Protocol documents:
Prot_000.pdf: 
BVD-523 
 
BioMed Valley Discoveries, Inc. 
Clinical Study Protocol: BVD-523-01 
 
 
 
 
CONFIDENTIAL 
Page 1 
 
CLINICAL STUDY PROTOCOL 
PHASE 1 DOSE-ESCALATION, SAFETY, PHARMACOKINETIC AND 
PHARMACODYNAMIC STUDY OF BVD-523 IN PATIENTS WITH 
ADVANCED MALIGNANCIES 
BVD-523-01 
 
Drug Development Phase: 
Phase 1 
Investigational Product: 
BVD-523 
Indication: 
Advanced Malignancies 
Sponsor: 
BioMed Valley Discoveries, Inc. 
4520 Main St. 16th Floor 
Kansas City, MO 64111 
 
Protocol Version and Date: 
Amendment 7, 11 April 2016 
 
Conduct:  In accordance with the ethical principles that originate from the Declaration of 
Helsinki and that are consistent with International Conference on Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. 
 
CONFIDENTIAL INFORMATION 
This document is the sole property of BioMed Valley Discoveries, Inc.  This document 
and any and all information contained herein has to be considered and treated as 
strictly confidential.  This document shall be used only for the purpose of the disclosure 
herein provided.  No disclosure or publication shall be made without the prior written 
consent of BioMed Valley Discoveries, Inc. 
 
 
 




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Clinical Study Protocol: BVD-523-01 
 
 
 
 
CONFIDENTIAL 
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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol amendment 7 for Study No. 
BVD-523-01 dated 11 April 2016 and will adhere to the study requirements as presented, 
including all statements regarding confidentiality.  In addition, I will conduct the Study in 
accordance with current Good Clinical Practices and applicable FDA regulatory 
requirements: 
Name of Principal Investigator:   
<Enter Name and Title> 
<Enter Clinic> 
<Enter Address> 
Phone: <Enter Phone Number> 
Fax: <Enter Fax Number> 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 


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BioMed Valley Discoveries, Inc. 
Clinical Study Protocol: BVD-523-01 
 
 
 
 
CONFIDENTIAL 
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PROTOCOL SYNOPSIS 
Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental 
Phase:  Phase 1 
Title of Study: 
Phase 1 Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 
in Patients with Advanced Malignancies 
Protocol Number: 
BVD-523-01 
Indication: 
Advanced malignancies 
Objectives:  
Primary objective: 
To define the safety and tolerability of BVD-523 in patients with advanced malignancies by 
determining the dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the 
recommended Phase 2 Dose (RP2D). 
Secondary objectives: 
To determine the pharmacokinetic profile of BVD-523 and selected metabolites in patients 
with advanced malignancies. 
To investigate any preliminary clinical effects on tumor response assessed by physical or 
radiological exam (RECIST 1.1). 
Exploratory objective(s): 
To evaluate pharmacodynamic marker (biomarker) measures. 
Methodology: 
Open-label, dose-escalation, multicenter Phase 1 study with dose-escalation phase (Part 1) 
and cohort expansion phase (Part 2). 


BVD-523 
 
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Clinical Study Protocol: BVD-523-01 
 
 
 
 
CONFIDENTIAL 
Page 5 
Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental 
Phase:  Phase 1 
Diagnosis and Criteria for Inclusion: 
Patients eligible for inclusion in this trial have to fulfill all of the following criteria: 
1. 
Provide signed and dated informed consent prior to initiation of any study-related 
procedures that are not considered standard of care (SOC). 
2. 
Male or female patients aged ≥ 18 years. 
3. 
Patients with metastatic or advanced-stage malignant tumor, confirmed histologically, 
for whom no therapy exists that would be curative.  
4. 
ECOG performance status of 0 (fully active, able to carry out all pre-disease activities 
without restriction) or 1 (unable to perform physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature), measured within 72 hours 
before the start of treatment. 
5. 
Predicted life expectancy of ≥ 3 months. 
6. 
Adequate renal function [creatinine ≤ 1.5 times ULN (upper limit of normal)] or GFR of 
≥ 50mL/min. 
7. 
Adequate hepatic function [total bilirubin ≤ 1.5 times ULN; AST (aspartate 
transaminase) and ALT (alanine transaminase) ≤ 3 times ULN or ≤ 5 times ULN if due 
to liver involvement by tumor. 
8. 
Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x109cells/L; 
absolute neutrophil count ≥ 1.5x109 cells/L). 
9. 
Adequate cardiac function, > institutional lower limit of normal e.g., left ventricular 
ejection fraction (LVEF) of > 50% as assessed by multi-gated acquisition (MUGA) or 
ultrasound/echocardiography (ECHO); corrected QT interval (QTc) < 470 ms. 
10. Contraception: 
• For women: Negative pregnancy test for females of child-bearing potential; must be 
surgically sterile, postmenopausal (no menstrual cycle for at least 12 consecutive 
months), or compliant with a medically approved contraceptive regimen during and 
for 3 months after the treatment period.  Abstinence is not considered an adequate 
contraceptive regimen. 
• For men: Must be surgically sterile, or compliant with a medically approved 
contraceptive regimen during and for 3 months after the treatment period. 
11. Willing and able to participate in the trial and comply with all trial requirements. 
12. For Part 2 of the Study ONLY: 
• Patient must be diagnosed with specific tumor types and histologies. 
• Patient must bear tumors that harbor specific classes of genetic mutations. 
• Patients must have measurable disease by RECIST 1.1. 
 


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CONFIDENTIAL 
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Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental 
Phase:  Phase 1 
Criteria for Exclusion: 
Patients who fulfill one or more of the following criteria will not be eligible for inclusion in 
this trial: 
1. 
Gastrointestinal (GI) condition that could impair absorption of study medication 
(specific cases e.g., remote history of GI surgery, may be enrolled after discussion with 
the medical monitor) or inability to ingest study medication. 
2. 
Uncontrolled or severe intercurrent medical condition. 
3. 
Known uncontrolled brain metastases.  Stable brain metastases either treated or being 
treated with a stable dose of steroids/anticonvulsants, with no dose change in the 
previous 4 weeks, can be allowed. 
4. 
Any cancer-directed therapy (chemotherapy, hormonal therapy, biologic or 
immunotherapy, etc.) within 28 days or 5 half-lives, (whichever is shorter).  Patients 
previously treated with radiotherapy must have recovered from the acute toxicities 
associated with such treatment. 
5. 
Major surgery within 4 weeks prior to first dose. 
6. 
Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) 
prior to the first dose of BVD-523.  A minimum of 10 days between termination of the 
investigational drug and administration of BVD-523 is required, unless a dose escalation 
of BVD-523.  In addition, any drug-related toxicity except alopecia should have 
recovered to Grade 1 or less. 
7. 
Pregnant or breast-feeding women. 
8. 
Any evidence of serious active infections. 
9. 
Any important medical illness or abnormal laboratory finding that would increase the 
risk of participating in this study (based on the investigator’s judgment). 
10. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR). 
11. Concurrent therapy with any other investigational agent. 
12. Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6 and 
CYP3A4, or strong inducers of CYP3A4 (for list of non-permitted drugs, see 
Appendix 1).  
13. Concomitant malignancies or previous malignancies with less than 2 years disease-free 
interval at the time of enrollment (except non-melanoma skin cancer, cervical cancer in 
situ, prostate cancer with undetectable PSA).  Other concurrent malignancies that are 
indolent and do not require active treatment must be discussed with the medical monitor 
prior to enrollment. 
 
 


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CONFIDENTIAL 
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Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental 
Phase:  Phase 1 
Test Product, Dose and Mode of Administration: 
Part 1: BVD-523, starting at 10 mg, with escalating dose levels, twice daily for 21 days, oral.  
Part 2: BVD-523, recommended Phase 2 dose (RP2D), twice daily for 21 days, oral. 
Concomitant Medications: 
Necessary supportive care such as antiemetics, antidiarrheals, etc., will be allowed.  Certain 
other medications such as stable doses of steroids for brain metastases may also be allowed. 
Drugs that are strong inhibitors of CYP1A2, CYP2D6 and CYP3A4, or strong inducers of 
CYP3A4, will not be allowed during the study (for list of non-permitted drugs, see 
Appendix 1). 
Study Duration: 
Part 1: 10 to 18 months, Part 2: 18 to 24 months 
Criteria for Evaluation: 
Safety: 
Vital signs, physical examination, ophthalmology examination, clinical chemistry, 
hematology, urinalysis, electrocardiograms (ECG), and Holter monitoring. 
Efficacy: 
Tumor measurements (anti-tumor activity as evaluated using RECIST 1.1). 
Pharmacokinetics: 
Blood, urine, and tissue biopsy (as indicated) BVD-523 and selected metabolite 
concentration levels. 
Pharmacodynamics: 
Evaluation of multiple biomarkers to characterize drug response (pRSK, pERK, Ki67, 
Caspase-3, and circulating tumor DNA).  Additional biomarkers may be identified and 
measured as appropriate.  Tumor genotyping by DNA analysis will be performed to identify 
somatic alterations, relying on either available archived tissue or freshly-collected samples.  


BVD-523 
 
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Clinical Study Protocol: BVD-523-01 
 
 
 
 
CONFIDENTIAL 
Page 8 
Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental 
Phase:  Phase 1 
Statistical Methods: 
The sample size for Part 1 of this study was determined by clinical rather than statistical 
considerations.  Approximately 40 patients will be treated in Part 1 of this study (Dose 
Escalation Phase) to establish dose limiting toxicities (DLT), maximum tolerated dose 
(MTD), and the recommended Phase 2 dose (RP2D). 
The purpose of Part 2 of this first in human research is to document that there is some 
evidence of a response.  Upon completion of Part 1 of this study, up to approximately 105 
evaluable patients with certain cancer types and/or characterized genetic alterations will be 
treated with the RP2D (which may be the same or lower than the MTD).  The observation of 
DLTs in more than 33% of patients in any Part 2 cohort with at least 6 patients enrolled at 
any time during Part 2 will trigger temporary stopping of patient enrollment and revision of 
the definition of the MTD and potentially RP2D in the specific cohort.  Subsequent patients 
will be treated with a dose lower than the initial MTD and this dose will be determined in 
discussion with the Clinical Investigators, the Medical Monitor, and the Sponsor. 
Enrollment of up to 15 evaluable patients in each cohort provides an 80% probability of 
seeing at least one positive response if the true response rate is at least 10%.  Allowing for a 
low response rate in these patient cohorts is appropriate based on unmet medical need. 
 


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Clinical Study Protocol: BVD-523-01 
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE .....................................................................2 
PRINCIPAL INVESTIGATOR’S AGREEMENT ...................................................................3 
PROTOCOL SYNOPSIS ..........................................................................................................4 
ABBREVIATIONS AND DEFINITION OF TERMS............................................................14 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Study Drug .............................................................................................................18 
1.2 
Indication ...............................................................................................................18 
1.3 
Background to the Disease .....................................................................................19 
1.4 
Safety Experience (Pre-Clinical and Clinical) .......................................................20 
1.4.2 
Pharmacology Studies ..................................................................................23 
1.4.3 
Preclinical Toxicity and Safety Studies .......................................................23 
2 
RATIONALE FOR THE STUDY ...................................................................................25 
2.1 
Rationale for the Doses and the Dosing Regimen .................................................25 
3 
STUDY DESIGN.............................................................................................................26 
3.1 
Study Design Overview .........................................................................................26 
3.1.1 
Study Objectives ..........................................................................................26 
3.1.1.1 
Primary Objective ..............................................................................26 
3.1.1.2 
Secondary Objectives.........................................................................26 
3.1.1.3 
Exploratory Objectives ......................................................................26 
3.1.2 
Study Design ................................................................................................26 
3.1.3 
Summary of Dose Escalation .......................................................................29 
3.1.4 
Definition of MTD, DLT, and RP2D...........................................................29 
3.1.4.1 
Definition of Maximum Tolerated Dose (MTD) ...............................29 
3.1.4.2 
Definition of Dose Limiting Toxicity (DLT).....................................29 
3.1.4.3 
Definition of Recommended Phase 2 Dose (RP2D) ..........................30 
3.2 
Safety Monitoring Committee ...............................................................................30 
3.3 
Safety Review Meetings ........................................................................................30 
3.4 
Stopping Rules .......................................................................................................30 
3.5 
Study Endpoints .....................................................................................................30 
3.5.1 
Primary Endpoint(s) .....................................................................................30 
3.5.2 
Secondary Endpoint(s) .................................................................................31 
3.5.3 
Exploratory Endpoint(s)...............................................................................31 


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3.6 
Blinding and Randomization .................................................................................31 
4 
SELECTION OF PATIENTS ..........................................................................................32 
4.1 
Number of Patients ................................................................................................32 
4.2 
Recruitment ............................................................................................................32 
4.3 
Inclusion Criteria ...................................................................................................32 
4.4 
Exclusion Criteria ..................................................................................................33 
5 
STUDY PLAN AND PROCEDURES ............................................................................35 
5.1 
Study Patient Number ............................................................................................35 
5.2 
Description of Study Visits for Part 1 ....................................................................36 
5.2.1 
Visit 1 (Day -14 to -1); Screening................................................................36 
5.2.2 
Visit 2 (Day 1 ± 0); Baseline/Drug Dispensing/Initiation of Treatment .....37 
5.2.3 
Visit 3 (Day 8 ± 1) .......................................................................................38 
5.2.4 
Visit 4 (Day 15 ± 1) .....................................................................................38 
5.2.5 
Visit 5 (Day 22 ± 1 of Cycle 1, first day of Cycle 2) ...................................39 
5.2.6 
End of Treatment Visit.................................................................................39 
5.2.7 
30-day Safety Visit ......................................................................................40 
5.2.8 
Unscheduled Visits ......................................................................................40 
5.3 
Study Visits for Part 1 Cycle 2 ..............................................................................40 
5.4 
Description of Study Visit for Part 1 Cycle 3 and Each Subsequent Cycle of 
Part 1 ......................................................................................................................40 
5.4.1 
Cycle 3 and Subsequent Cycles Visit (Day 1 ± 1 of each cycle) .................40 
5.5 
Description of Study Visits for Part 2 ....................................................................41 
6 
METHODS OF ASSESSMENT AND ENDPOINTS .....................................................43 
6.1 
Demographic Data .................................................................................................43 
6.2 
Medical History .....................................................................................................43 
6.3 
Concomitant Medications ......................................................................................43 
6.4 
Physical Examination.............................................................................................43 
6.5 
Safety Assessments ................................................................................................44 
6.6 
Pharmacokinetics ...................................................................................................45 
6.7 
Pharmacodynamics ................................................................................................45 
6.8 
Efficacy ..................................................................................................................45 
6.9 
Pharmacokinetic Procedures ..................................................................................46 
6.9.1 
Blood Sampling and Processing ..................................................................46 
6.9.2 
Urine Sampling and Processing ...................................................................46 
6.9.3 
Pharmacokinetic Endpoints .........................................................................47 


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7 
DISCONTINUATION CRITERIA .................................................................................51 
7.1 
Early Discontinuation of the Study ........................................................................51 
7.2 
Early Discontinuation of Individual Patients .........................................................51 
8 
TREATMENT .................................................................................................................53 
8.1 
Dosing and Administration of Study Medication ..................................................53 
8.1.1 
Dispensing Directions ..................................................................................53 
8.1.2 
Dosing Information ......................................................................................53 
8.1.3 
Dosing Instructions for the Study Participants ............................................54 
8.2 
Rescue Medications and Concomitant Treatments ................................................55 
8.3 
Treatment Compliance ...........................................................................................55 
9 
ADVERSE EVENT MANAGEMENT ...........................................................................56 
9.1 
Definition of an Adverse Event .............................................................................56 
9.2 
Definition of a Serious Adverse Event ..................................................................56 
9.3 
Recording of Adverse Events and Serious Adverse Events ..................................57 
9.4 
Intensity of Adverse Events ...................................................................................57 
9.5 
Relationship of Adverse Events to Study Drug .....................................................58 
9.6 
Follow-Up of Adverse Events and Serious Adverse Events .................................58 
9.7 
Poststudy Adverse Events and Serious Adverse Events ........................................58 
9.8 
Regulatory Aspects of Adverse Event Reporting ..................................................59 
9.8.1 
Overdose ......................................................................................................59 
9.8.2 
Pregnancies ..................................................................................................59 
10 STATISTICAL METHODS ............................................................................................61 
10.1 
General Considerations ..........................................................................................61 
10.1.1 
Statistical and Analytical Plans ....................................................................61 
10.1.2 
Determination of Sample Size .....................................................................61 
10.1.3 
Blinding and Randomization .......................................................................61 
10.2 
Analysis Datasets ...................................................................................................62 
10.2.1 
Population to be Analyzed ...........................................................................62 
10.2.2 
Modified Intent-to-treat ...............................................................................62 
10.2.3 
Per Protocol ..................................................................................................62 
10.2.4 
Definition of Study Days .............................................................................62 
10.3 
Data Presentation ...................................................................................................62 
10.3.1 
Demographic ................................................................................................62 
10.3.2 
Baseline Characteristics ...............................................................................63 
10.3.3 
Medical History and Physical Examination .................................................63 


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10.3.4 
Concomitant Medications or Treatments .....................................................63 
10.3.5 
Primary Endpoint .........................................................................................63 
10.3.6 
Secondary Endpoints ...................................................................................64 
10.3.7 
Pharmacokinetic Data ..................................................................................64 
10.3.8 
Safety Data ...................................................................................................64 
10.3.9 
Adverse Events (AE) ...................................................................................64 
10.4 
Changes in the Conduct of the Study or Planned Analysis ...................................64 
11 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ........................................65 
11.1 
Declaration of Helsinki ..........................................................................................65 
11.2 
Good Clinical Practice ...........................................................................................65 
11.3 
Institutional Review Boards/Ethics Committees ...................................................65 
11.4 
Regulatory Authority Approval .............................................................................65 
11.5 
Pre-study Documentation Requirements ...............................................................65 
11.6 
Informed Consent...................................................................................................65 
11.7 
Patient Confidentiality and Disclosure ..................................................................66 
11.8 
Collection, Monitoring and Auditing of Study Documentation, and Data 
Storage ...................................................................................................................66 
11.9 
Disclosure of Information ......................................................................................67 
11.10 Discontinuation of the Study .................................................................................67 
11.11 Study Report, Publication Policy and Archiving of Study Documentation ...........67 
11.11.1 Study Report and Publication Policy ...........................................................67 
11.11.2 Study Documents .........................................................................................68 
11.11.3 Archiving of Documents ..............................................................................68 
12 REFERENCES ................................................................................................................69 
 


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Clinical Study Protocol: BVD-523-01 
 
 
 
 
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LIST OF IN-TEXT TABLES 
Table 3.1. 
Study Medication Dosing and Pharmacokinetics/Pharmacodynamics 
Chart .................................................................................................................28 
Table 3.2. 
Summary of Dose Escalation ...........................................................................29 
Table 6.1. 
Part 1 and 2: Schedule of Assessments and Procedures ..................................48 
Table 6.2. 
Pharmacokinetic Parameters to be Estimated after Dose 1 and at Steady 
State..................................................................................................................50 
Table 10.1. 
Per Cycle Study Visit Definitions ....................................................................62 
 
LIST OF APPENDICES 
Appendix 1 
Non-permitted concomitant Medications ........................................................73 
 
 


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Clinical Study Protocol: BVD-523-01 
 
 
 
 
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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase (SGPT) 
AST 
aspartate transaminase (SGOT) 
AUC 
area under the plasma concentration-time curve 
b.i.d. 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CFB 
change from baseline 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
cm 
centimeter 
Cmax 
maximum concentration 
CMC 
carboxymethylcellulose 
CRF 
case report form 
CSR 
central serous retinopathy 
CT 
computed tomography 
CV 
curriculum vitae 
CYP 1A2 
cytochrome P450 isoform 1A2 
CYP 2D6 
cytochrome P450 isoform 2D6 
CYP 3A4 
cytochrome P450 isoform 3A4 
dL 
deciliter 
DLT 
dose limiting toxicity 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 
EOS 
end-of-study 
ERK 
extracellular signal-regulated kinase 
°F 
degrees Fahrenheit 
%F 
absolute bioavailability 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
good clinical practice 


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Abbreviation 
Definition 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HCl 
hydrochloride 
HDL 
high-density lipoprotein 
hERG 
human ether-a-go-go related gene 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
IRB 
institutional review board 
ITT 
intent-to-treat 
LD 
largest diameter 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLOQ 
lower limit of quantification 
LVEF 
left ventricular ejection fraction 
LS 
least squares 
µg 
microgram 
m2 
square meters 
MAPK 
mitogen-activated protein kinase 
MEDDRA® 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen-activated protein kinase/extracellular signal-related kinase 
mg 
milligram 
mL 
milliliter 
mmHg 
millimeters of mercury 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multigated acquisition 
NA 
not applicable 
NOEL 
no observed effect level 
ng 
nanogram 
NSCLC 
non-small cell lung cancer 
PD 
progressive disease 
PI 
principal investigator 
PI3K 
phosphatidylinositol 3-kinase 
PK 
pharmacokinetics 
PSA 
prostate-specific antigen 
PT 
prothrombin time 


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Abbreviation 
Definition 
PTT 
partial thromboplastin time 
q.d. 
once daily 
QTc 
corrected QT interval 
RBC 
red blood cell 
RECIST 
response evaluation criteria in solid tumors (version 1.1) 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAS 
statistical analysis systems 
SD 
standard deviation 
SEM 
standard error of the mean 
SMC 
safety monitoring committee 
SOC 
standard of care 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WO 
Washout 
 


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1 
INTRODUCTION 
A critical hallmark of cancer is the activation of cell-growth signaling cascades independent 
of appropriate growth stimuli (Hanahan 2000).  A canonical example of a cell growth control 
circuit is the mitogen-activated protein kinase, or MAPK, pathway.  Here, surface receptors 
activated by growth ligands signal via downstream effectors in a linear relay system: RAS 
family GTPases activate RAF family protein kinases, which in turn trigger a phosphorylation 
cascade involving MEK and ERK family kinases.  ERK kinases activate an array of direct 
effectors that ultimately translate growth signaling into essential cellular functions including 
cell division and cell survival. 
Aberrant activation of the MAPK pathway is frequently observed in cancer.  Often, 
components of the MAPK pathway undergo direct genetic mutation, causing constitutive 
activation of the signaling cascade in the absence of appropriate ligands.  For example, 
members of the RAS GTPase family (KRAS, NRAS, and HRAS) were among some of the 
first endogenous oncogenes demonstrated to exhibit spontaneous, activating mutations in a 
variety of cancers, including pancreatic, colorectal and non-small cell lung malignancies 
(McCoy 1983).  Later, auto-activating mutations in MAPK protein kinase BRAF were 
identified in over fifty percent of all late stage melanoma patients (Davies 2002).  MEK 
mutations are rarer, occurring at a frequency of 8% in melanomas (Nikolaev 2012); while 
ERK mutations resulting in tumorigenesis were only recently reported (Deschenes-Simard 
2014).  Aberrant activation of the MAPK signaling cascade may be present in a large 
proportion of cancers, and direct MAPK pathway mutations may account for a 
preponderance of “driver” mutations in specific cancers.   
The US Food and Drug Administration has recently approved two selective BRAF inhibitors, 
vemurafenib and dabrafenib, as monotherapies for patients with BRAFV600-mutant metastatic 
melanoma.  Though response rates can be as high as 50%, duration of response is often 
measured in months, not years.  The MEK1/2 inhibitor trametinib is also approved as a 
monotherapy in this setting, but is more commonly used in combination with a BRAF 
inhibitor.  First-line use of trametinib administered in combination with dabrafenib offers an 
even greater improvement in overall survival compared with vemurafenib monotherapy, 
without increased overall toxicity (Robert 2015), highlighting the potential usefulness of 
simultaneously targeting multiple stages of the MAPK signaling pathway.  This therapeutic 
combination was also associated with a lower incidence of MEK inhibitor-associated rash 
and BRAF inhibitor-induced hyperproliferative skin lesions compared with each single agent 
alone (Flaherty 2012).  Recently, a phase III trial also demonstrated significant improvements 
in overall survival (25.1 vs. 18.7 months, hazard ratio [HR] 0.71, P = 0.0107), progression-
free survival (PFS) (11.0 vs. 8.8 months, HR 0.67, P = 0.0004), and overall response (69% 
vs. 53%; P = 0.0014) with dabrafenib plus trametinib versus dabrafenib alone in patients with 
BRAFV600Lys/Glu mutation-positive melanoma (Long 2015).  Similarly, significant 
improvements in PFS (9.9 vs. 6.2 months, HR 0.51, P < 0.001) and the rate of complete 
response (CR) or partial response (PR) (68% vs. 45%; P < 0.001) has been demonstrated 
with the combination of vemurafenib plus cobimetinib compared with vemurafenib alone 
(Larkin 2014).  Based on these and related findings, the combination of a BRAF inhibitor 


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plus an MEK inhibitor has since become a standard targeted treatment option for patients 
with metastatic melanoma containing BRAFV600 mutations.  
Though BRAF/MEK-targeted combination therapy has significantly prolonged PFS 
compared with single-agent therapeutic options, patients still eventually develop resistance 
and disease progression after ~9 to 11 months (Robert 2015, Flaherty 2012, Long 2015).  
Several mechanisms of acquired resistance to BRAF inhibition have been previously 
identified, including the generation of BRAF splicing variants, BRAF amplification, 
development of MEK1 or NRAS mutations, and upregulation of bypass pathways (Poulikakos 
2011, Corcoran 2010, Nazarian 2010, Shi 2014, Johannessen 2010).  Central to these 
mechanisms of resistance is the resultant reactivation of ERK signaling, which enables the 
rapid recovery of MAPK pathway signaling and escape of tumor cells from BRAF inhibitor 
therapy (Paraiso 2010).  Furthermore, alterations in the MAPK signaling pathway have also 
been shown to confer resistance to BRAF/MEK inhibitor combination therapy, including 
MEK1 or MEK2 mutations and BRAF amplification (Wagle 2011, Wagle 2014, Ahronian 
2015).  ERK inhibition alone or in combination may have the potential to overcome or avoid 
resistance from upstream mutations, as it is the final target of the MAPK signaling pathway.  
The ERK family kinases are MAPK signaling components that have yet to be therapeutically 
targeted.  BVD-523 is a small-molecule inhibitor of ERK kinases that we plan to test in 
various treatment settings.  Understanding the safety and efficacy of BVD-523 will bolster 
the armamentarium of targeted therapies that can be used against the activated MAPK 
signaling pathway in cancer. 
1.1 
STUDY DRUG 
BVD-523 is a small molecule that potently inhibits both ERK1 and ERK2 protein kinases in 
the sub-nanomolar range, while not significantly inhibiting any of an array of kinases even at 
1000-fold greater concentrations.  BVD-523 potently inhibits growth and survival in cultured 
cancer cell lines; melanoma, colorectal and pancreatic lines harboring BRAF or RAS 
mutations are among those most susceptible to the drug.  In animals bearing ectopic tumor 
xenografts, orally administered BVD-523 is effective as a single agent, again preferentially in 
cancers where activating mutations in the MAPK pathway cause abundant ERK kinase 
activation. 
BVD-523 will be administered orally in humans.  The HCl salt of BVD-523 was selected for 
manufacture of drug product in capsule form. 
More information is available in the Investigator’s Brochure for BVD-523. 
1.2 
INDICATION 
Initial indications for BVD-523 are advanced malignancies, especially those known to harbor 
activating genetic mutations in components of the MAPK pathway such as the BRAF, ERK 
or MEK kinases, or members of the RAS GTPase family.  Given this biological rationale and 
relevant supportive data, melanoma, lung, colon, and pancreatic cancers are potential 
indications for future development. 


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1.3 
BACKGROUND TO THE DISEASE 
Contemporary cancer therapy seeks to leverage a molecular level understanding of disease to 
rationally target isolated cancer types, often with agents specifically designed to correct well-
characterized cellular, biochemical or genetic aberrations.  The modern view of cancer as a 
fundamentally genetic disease has greatly aided the invention and development of several 
such “targeted” therapies.  For instance, a common mutation found in chronic myelogenous 
leukemia produces the BCR-ABL oncogene, and direct inhibition of this gene product using 
the kinase inhibitor drug imatinib/Gleevec™ (Ren 2005) provides substantial benefit to 
patients.  Similarly, the observation of genetic amplification and/or overexpression of EGFR 
(Putz 1999), ErbB2 (Hynes 2005) and Flt-3 (Tse 2000) receptor tyrosine kinase genes led to 
therapeutics that inhibit each in a potent and specific fashion, and likewise offer 
improvements to standard of care (erlotininb/Tarceva™ [Perez-Soler 2004]; 
gefitinib/Iressa™ [Herbst 2004]; cetuximab/Erbitux [Graham 2004]).  For these and other 
targeted therapies, clinical benefit is accompanied by a safety profile broadly favorable 
compared to cytotoxic drugs: this occurs because each therapy spares healthy tissue, but 
damages cancer tissue where oncogenic mutations and malignant cell processes are confined. 
A unique array of oncogenic mutations cluster in the mitogen-activated protein kinase, or 
MAPK, pathway, a key signal transduction cascade that controls cell-growth signaling in 
many tissues (Sebolt-Leopold 2004a, Chang 2003, Hilger 2002, Kohno 2003, Smalley 2003).  
Activating mutations in RAS GTPase family members are found in ~30% of all cancers 
(Bos 1989), with particularly high incidence in pancreatic (90%) (Almoguera 1988) and 
colon (50%) cancer (Salhab 1989).  Activating somatic missense mutations of BRAF are 
frequent in melanomas (up to 80%) (Pollock 2002, Gorden 2003), papillary thyroid (36%) 
(Xu 2003), colon (up to 18%) (Ikenoue 2003), and ovarian (14%) (Hsu 2004) cancers.  Less 
frequently, activating mutations have also been observed in MEK family kinases, which are 
the direct substrates of RAF kinases.  MEK kinases phosphorylate and activate the ERK 
kinase gene family.  ERK kinases phosphorylate numerous proteins that act as MAPK 
pathway “effectors”; these substrates directly promote cell division, reduce cell death, and 
increase cell motility and cell differentiation (Chang 2003, Sebolt-Leopold 2004b).  To date, 
spontaneous activating mutations in ERK kinases have not been observed in human cancers.  
Nonetheless, abundant ERK phosphorylation reflecting elevated MAPK signaling is 
frequently observed in cancer contexts where extracellular growth factors are elevated 
(Wan 2004), or where activating mutations in RAS, BRAF, or MEK genes have occurred. 
In this setting, therapies targeted against MAPK pathway components have been rationally 
applied in cancers that show activation of the signaling cascade following genetic mutation.  
Notably, vemurafenib (ZELBORAF®), is an inhibitor of mutated BRAF that, when dosed in 
patients with metastatic melanoma harboring specific BRAF activating mutations, induces 
tumor regression and improves overall survival in this defined patient population 
(Flaherty 2010, Sosman 2012, Chapman 2011). 
The development of additional therapies that can modulate MAPK pathway activity in cancer 
is desirable for several reasons.  First, all drugs exhibit a unique spectrum of side effects that 
often influences their therapeutic utility.  Despite some findings suggestive of 
mechanism-related events, the incidence and severity of both BRAF and MEK inhibitor 


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associated toxicities may uniquely indicate their use in particular patients.  Likewise, given 
the potential for drug-drug interactions, and an increasing emphasis on polypharmacy in 
targeted oncology regimens, it is desirable to have multiple unique agents with discrete 
pharmacology and prescribing characteristics, even when they may share a common, 
redundant target or modes of inhibition in a pathway. 
Additionally, a more fundamental and prominent problem drives the need for additional 
MAPK pathway modulators: increasingly, multiple inhibitors in the pathway exhibit the 
phenomenon of acquired drug resistance (Nazarian 2010, Poulikakos 2011, Shi 2012, 
Hatzivassiliou 2012).  Acquired resistance may limit the clinical efficacy of MAPK directed 
agents even when their initial activity is promising.  The severe consequences and complex 
biology of acquired resistance in patients treated with MAPK signaling inhibitors suggest 
that additional, novel agents targeting the pathway may display improved durability and 
overall efficacy (Hatzivassiliou 2012). 
Given this background, we plan to assess the safety and efficacy of BVD-523, which is a 
potent and selective inhibitor of the ERK family kinases.  Drugs targeting other components 
of the MAPK pathway exhibit promising therapeutic activity, while also being limited by 
unique toxicities and limited duration of efficacy.  Targeting the downstream MAPK kinase, 
ERK, could possibly evoke a unique and desirable balance of durable efficacy and suitable 
tolerability.  As such, BVD-523 may represent a valuable addition to the armamentarium of 
drugs useful for treating patients whose cancers exhibit the hallmarks of aberrant MAPK 
pathway activity. 
1.4 
 SAFETY EXPERIENCE (PRE-CLINICAL AND CLINICAL) 
Human experience with BVD-523 is limited to the ongoing BVD-523-01 and BVD-523-02 
studies, thus the entire safety profile of BVD-523 is not known at this time.  
Prominent treatement-emergent events in the BVD-523 program include effects on skin and 
the GI system.  Summary details for specific toxicities (both observed and potential) are 
provided below; additional information is presented in the BVD-523 Investigator’s Brochure. 
Dermatological Lesions 
Dermatological lesions have been seen in rodent GLP toxicology studies of BVD-523.  
Several of the following findings displayed exposure-dependent increases in incidence and/or 
severity: non-specific dermal inflammation, pustular dermatitis, epidermal ulceration and 
acanthosis.  These toxicities appeared to be associated with predominantly reversible 
pharmacodynamics, as the majority of findings were mild and/or of low incidence in animals 
that underwent dose cessation. 
In clinical studies, other drugs that inhibit components of the MAPK pathway exhibit 
cutaneous toxicity.  Multiple investigational inhibitors of MEK1/2 kinases exhibit exposure-
dependent, dose-limiting and reversible skin toxicities in a proportion of patients.  Specific 
toxicities include: non-specific rash and pruritus, acneiform dermatitis, epidermal fissure and 
paronychia.  Additionally, clinical experience with both investigational agents and approved 
drugs that primarily target BRAF kinase have displayed exposure-dependent and reversible 


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skin toxicities in a proportion of treated patients; relevant lesions here include 
keratoacanthoma-type squamous cell carcinomas, non-cancerous hyperkeratosis and actinic 
keratosis. 
A similar pattern of cutaneous toxicity has been observed in patients treated with BVD-523 
in this first-in-man study, with approximately two thirds of patients experiencing rash and/or 
pruritus and one patient with a history of squamous cell carcinoma developing a squamous 
cell carcinoma while on treatment with BVD-523.  Rash has been treated with topical and/or 
oral agents (e.g., steroids, antibiotics), and dose reductions/interruptions as needed.  One 
patient (dosed at 900 mg b.i.d.) in BVD-523-01, experienced an event of grade 3 erythema 
multiforme that was considered related to BVD-523 and that resulted in dose interruption.  
Similarly, one patient (dosed at 750 mg b.i.d.) in BVD-523-02 experienced an event of grade 
3 erythema multiforme that was considered related to BVD-523 and that resulted in the 
discontinuation of study drug. 
Gastrointestinal Effects 
Preclinical toxicity studies of BVD 523 have provided evidence of exposure-related, 
reversible gastrointestinal toxicities, and nausea, vomiting and diarrhea have been observed 
at high frequency in both BVD-523-01 and BVD-523-02, in some cases occurring in 
association with dehydration and elevated creatinine/renal insufficiency.  Nausea, vomiting 
and diarrhea have been managed with BVD-523 dosing interruptions and supportive 
medications as needed and, in some cases, dose reduction of BVD-523 has been undertaken.  
Gastrointestinal hemorrhage (both upper and lower) has been reported in the BVD-523 
program with the majority of events assessed as unrelated to study agent. 
Hepatic and Renal Effects 
Related events of mild, moderate and severe elevated AST and/or ALT have also been 
observed in the BVD-523 clinical program and have been managed with interruption of study 
agent followed in some instances by dose reduction.  Related events of mild, moderate and 
severe increased creatinine have also been observed, sometimes in conjuction with vomiting, 
diarrhea and dehydration.  Management has consisted of study agent interruption, re-
hydration and, in some instances, dose reduction or discontinuation of study drug. 
Hematological Effects 
Hematological effects observed in a rat repeat dose study included lowered reticulocyte 
counts, mean corpuscular volume, platelet counts (in females only) and increased neutrophil, 
monocyte, basophil and large unstained cell counts.  In dogs the clinical pathology findings 
were consistent with inflammation (increased white blood cell count, neutrophils, fibrinogen 
and globulin) and decreased albumin and hemorrhage (decreased red cell mass).  Anemia has 
been noted in the BVD-523 program.  One case of possibly related, grade 3, reversible, 
thrombotic thrombocytopenia purpura was reported in a patient with melanoma while 
receiving BVD-523 at a dose of 450 mg b.i.d. 


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In order to monitor for potential hematologic toxicity in humans, routine clinical laboratory 
hematology tests, should be performed and any indication of abnormalities may result in 
further investigations. 
Phototoxicity 
BVD-523 exhibits an absorbance peak in the range of UV-A/UV-B light, specifically at 
~320 nm.  Clinical studies of other drugs that modulate MAPK pathway components have 
exhibited skin phototoxicity. 
Beyond dermatological monitoring (above), potential risks of direct phototoxicities induced 
by BVD-523 will be further minimized by advising that patients minimize sun exposure, use 
broad-spectrum sunscreens, and wear sunglasses.  In this first-in-man Phase 1 study, a low 
number of patients treated with BVD-523 have experienced grade 1 and 2 photosensitivities 
classified as possibly related and related to study drug.  Patients will be informed that 
relevant sun exposure may occur even through glass, such as while driving. 
Ophthalmological Effects 
Preclinical toxicology studies of BVD-523 have not revealed any exposure-dependent 
ophthalmological toxicities; however, clinical studies of MEK1/2 kinase inhibitors highlight 
ocular toxicities that may reflect mechanistically attributable risks observable in a proportion 
of patients.  Of particular concern are the following dose-limiting toxicities comprising 
exposure-dependent, serious adverse events during clinical studies: retinal vein occlusion, 
retinal detachment and related vision abnormalities.  In this ongoing first-in-man Phase 1 
study, patients treated with BVD-523 have experienced visual changes, including 
dimmed/blurry vision and unspecified vision changes. In addition, one patient (dosed at 900 
mg b.i.d.), experienced an event of central serous retinopathy.   While it is not definitively 
understood whether ocular toxicities reflect primary pharmacology associated with global 
inhibition of the MAPK pathway, specific management and exclusion criteria are defined in 
this clinical protocol, as the toxicities could potentially severely and irreversibly impact 
patient well-being. 
Cardiac Effects 
The balance of preclinical evidence suggests BVD-523 has a low, but observable, potential to 
cause QT prolongation.  Given potentially unique species sensitivity, as well as possibly 
unknown consequences following chronic dosing, patients dosed with BVD-523 will be 
monitored for potential QTc prolongation and related cardiotoxicities, including 12 hour 
Holter monitoring following dosing on days 1 and 15.  There has been one event of possibly 
related, grade 3 heart failure in a patient with melanoma which occurred after having 
received 10 days of study drug (600 mg b.i.d.). 
Tissue Mineralization 
Tissue mineralization has been observed in rodent toxicology studies of BVD-523.  The 
incidence and severity of mineralization was dose-dependent and effects were observed in 
1 or more tissues at toxic doses.  In animals in which mineralization occurred after treatment 


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with BVD-523, significantly increased serum phosphorus and modestly decreased serum 
calcium were seen; these effects were not observed in animals in which there was no 
mineralization. 
Tissue mineralization has been reported in rodents with other compounds that target the 
MAPK pathway and published studies suggest that the MAPK pathway is a negative 
regulator of matrix mineralization both in vitro and in vivo. 
Routine clinical laboratory tests, including blood chemistry analyses for calcium and 
inorganic phosphate, will be performed and any indication of abnormalities may result in 
further investigations.  A clinical monitoring strategy similar to this was previously 
employed for related drugs that target the MAPK pathway. 
1.4.2 
Pharmacology Studies 
BVD-523 is highly efficacious in vivo when administered as a single agent in ectopic 
xenograft models of colon, pancreatic and melanoma cancers, 3 tumor types in which ERK is 
known to be highly activated.  Notably, partial regression was achieved in a colon cancer 
model (Colo205) when the compound was administered at 50 mg/kg (b.i.d.).  Biomarker 
analyses confirmed that improved efficacy obtained at higher doses of BVD-523 correlated 
with increasing ERK inhibition. 
1.4.3 
 Preclinical Toxicity and Safety Studies 
When BVD-523 was characterized using in vitro screens against 66 receptors and ion 
channels no toxicologically significant interactions were identified.  Additionally, BVD-523 
was negative in bacterial mutation and in vivo micronucleus screening assays, so BVD-523 is 
not considered to have a significant genetic toxicology risk.   
While BVD-523 modestly inhibits the hERG current (IC50 3.4 µM), no significant effects 
were seen in action potentials recorded from dog Purkinje fibers exposed to up to 10 μg/mL, 
and no significant cardiovascular findings were observed upon acute oral dosing of the 
compound at dose levels up to 50 mg/kg in dogs (Cmax = 17.3 µM).  Thus BVD-523 is 
considered to have a low potential to cause QT prolongation in patients, but, as stated, the 
study will monitor for signs of cardiovascular effects of BVD-523 in humans. 
No significant cytochrome P450 (CYP) inhibition has been observed with the compound.  
In vitro studies suggest that the compound is metabolized primarily via oxidation by multiple 
CYPs, including 3A4, 2D6, and 1A2.  Furthermore, no significant CYP induction was 
observed after up to 14 days drug treatment in rats, nor during in vitro studies with human 
hepatocytes.  These data suggest a limited potential for drug-drug interactions. 
BVD-523 HCl salt is orally available in multiple species (absolute bioavailability %F = 23% 
in dog to 100 % in monkey) when formulated as a simple suspension in 1% 
carboxymethylcellulose (CMC) and has a half-life of 2−4 hours across all species. 
BVD-523 was administered to male and female Sprague-Dawley rats in several toxicology 
studies: a GLP study for up to 28 days at dose levels up to 50 mg/kg/day twice daily; for up 


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to 14 days at dose levels up to 100 mg/kg twice daily; and for up to 5 days at dose levels up 
to 150 mg/kg/dose once daily.  The incidence and severity of mineralization seen in these 
studies was dose-dependent and effects were observed in 1 or more tissues at toxic doses.  In 
animals in which mineralization occurred after treatment with BVD-523, significantly 
increased serum phosphorus and modestly decreased serum calcium were seen; these effects 
were not observed in animals in which there was no mineralization.  Therefore, the risk of 
tissue mineralization can be assessed by serum phosphorus and calcium monitoring.  A 
clinical monitoring strategy similar to this was previously employed for related drugs that 
target the MAPK pathway because those compounds likewise elicited mineralization in 
rodents. 
When BVD-523 was administered to male and female Sprague-Dawley rats for up to 28 days 
at a dose level of 25 or 50 mg/kg twice daily, it was poorly tolerated.  Although most clinical 
signs and clinical pathology findings reversed following 4 weeks of recovery, skin lesions 
and histopathology findings persisted in many tissues at both dose levels after the recovery 
phase.  Based on these findings, 25 and 50 mg/kg twice daily dose levels were considered 
severely toxic.  Administration of 12.5 mg/kg twice daily for 28 days was generally well-
tolerated by rats of both sexes; however, this dose level was associated with test article-
related findings that included: swelling in the neck; decreased forelimb strength; multiple 
clinical pathology findings; enlarged lymph nodes, spleen, and mammary gland.  Based on 
these findings, the severely toxic dose in 10% of the animals (STD10) for BVD-523 when 
administered for up to 28 days in Sprague-Dawley rats is 12.5 mg/kg given twice daily 
(25 mg/kg/day).  On Day 28 of the dosing phase, this dose level corresponded with a Cmax of 
28700 and 15323 ng/mL and AUC0-12 of 264868 and 124341 hr.ng/mL for males and 
females, respectively. 
BVD-523 was administered to male and female beagle dogs for up to 28 days at dose levels 
of 15, 5, or 2 mg/kg twice daily.  Initial analysis of the toxicity profile observed shows that 
BVD-523 was well tolerated in dogs.  The rat was designated the most sensitive species and 
rat data were used to calculate the starting dose in man. 
BVD-523 has a measured UV absorbance at 320 nm, which means that it can absorb both 
UV-A and UV-B.  BVD-523 may therefore act as a photosensitizing agent in man.  
Based on the data accumulated to date, BVD-523 possesses a toxicology profile which 
presents no impediment to its development as an anti-cancer agent. 
For further information, please refer to the BVD-523 Investigator’s Brochure. 


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2 
RATIONALE FOR THE STUDY 
The overall purpose of this study is to support the development of an oral formulation of 
BVD-523 for the treatment of patients with advanced cancers.  BVD-523 is a highly potent, 
selective, and pharmacologically active inhibitor of ERK family kinases.  The compound has 
demonstrated efficacy as a single agent in preclinical models of colon, pancreatic and 
melanoma cancers (Section 1.4.2), and has potential for application alone or in combination 
with existing cancer chemotherapeutics. 
This first-in-human study is being performed to assess the safety and tolerability of BVD-523 
given orally, twice daily for 21-day cycles.  The pharmacokinetics and pharmacodynamics of 
BVD-523 will also be explored after the first doses administered on Day 1, at steady state on 
Day 15, at the end of the first cycle of treatment (Day 22), and as indicated after completion 
of Cycle 1.  Pharmacokinetic, pharmacodynamics, and/or Holter measurements may be 
suspended pending review of accumulated patient experience.  
2.1 
RATIONALE FOR THE DOSES AND THE DOSING REGIMEN 
The dosing regimen combines both accelerated titration and standard cohort dose escalation 
schemata, which will be used jointly to identify the maximum tolerated dose (MTD) and 
recommended Phase 2 dose (RP2D) of BVD-523 in human patients. 
The proposed human Phase 1 starting dose for BVD-523 is derived from 28-day GLP 
toxicology studies performed in rodent and non-rodent species and calculated as described in 
Senderowicz 2010.  Specifically, our results indicated that toxicity in rodents would be used 
to establish starting dose in patients.  The severely toxic dose in 10% of the animals (STD10) 
for BVD-523 when administered for up to 28 days in Sprague-Dawley rats was determined to 
be 12.5 mg/kg dosed twice daily (25 mg/kg/day).  A standard 10-fold reduction of this dose 
was scaled to establish a starting dose of 13.5 mg twice-daily of BVD-523 (free base 
equivalents) or 14.6 mg twice-daily of BVD-523, based on an average body surface area of 
1.8 m2.  
Consistent with current clinical practice and dosing convenience, the proposed starting dose 
for the Phase 1 clinical study with BVD-523 in cancer patients is 10 mg twice-daily 
(20 mg/day).   
Since there are no pre-clinical data to suggest that flat dosing will lead to greater inter-patient 
PK variability, flat milligram dosing without adjustment for body size will be used in this 
study (Mathijssen 2007).  The effects of weight and body surface area on PK may be studied 
retrospectively as part of the PK analysis. 


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3 
STUDY DESIGN 
3.1 
STUDY DESIGN OVERVIEW 
This is an open-label, multi-center Phase 1 study to assess the safety, pharmacokinetics, and 
pharmacodynamics of escalating doses of BVD-523 in patients with advanced malignancies.  
The study will be conducted at up to 15 sites. 
3.1.1 
Study Objectives 
3.1.1.1 
Primary Objective 
To define the safety and tolerability of BVD-523 in patients with advanced malignancies by 
determining the dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the 
recommended Phase 2 Dose (RP2D). 
3.1.1.2 
Secondary Objectives 
• To determine the pharmacokinetic profile of BVD-523 and selected metabolites in 
patients with advanced malignancies 
• To investigate any preliminary clinical effects on tumor response assessed by 
physical or radiological exam (RECIST 1.1) 
3.1.1.3 
Exploratory Objectives 
• To evaluate pharmacodynamic marker (biomarker) measures 
3.1.2 
Study Design 
This clinical study comprises 2 parts: 
• Part 1: Dose-escalation Phase 
• Part 2: Cohort Expansion Phase 
 
Part 1 – Dose-escalation Phase:  An accelerated dose escalation plan will be used to establish 
dose limiting toxicities (DLT), maximum tolerated dose (MTD), and the recommended 
Phase 2 dose (RP2D).  One to 6 patients per treatment cohort will be assigned to receive 
sequentially higher oral doses of BVD-523 on a twice daily schedule (b.i.d.) for 21 days (a 
“Cycle”), starting at a dose of 10 mg twice daily.  Patients will receive twice-daily oral doses 
of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation 
satisfying another withdrawal criterion is noted.  Treatment cycles will occur consecutively 
without interruption, except when necessary to manage toxicities. 
Patients with advanced-stage solid tumors only (no hematological malignancies) will be 
enrolled in the dose-escalation phase of the study.  The study will initially be conducted as an 
accelerated single patient design, followed by a standard 3 + 3 design, informed by the 


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accrued safety experience throughout the study (see Table 3.2 below).  All dose-escalation 
decisions will be based on Cycle 1 safety data. 
In the accelerated single patient phase, 1 patient will be enrolled in a cohort and an 
evaluation of dose escalation will take place after the patient has completed the 21-day 
treatment cycle.  If the patient exhibits no Grade 2 or greater adverse events, dose escalation 
in a 100% increment and enrollment will continue with a single patient per cohort.  However, 
when one patient experiences a ≥ Grade 2 toxicity (excluding alopecia or diarrhea), this 
cohort and subsequent cohorts will be expanded to at least 3 patients each following the 
classic 3 + 3 design and dose escalation increments will be reduced from 100% to a 
maximum of 50%, as determined by discussion with the Clinical Investigators, the Medical 
Monitor, and the Sponsor.  Doses will not be escalated unless the patient(s) receiving the 
highest current dose has been observed for at least 3 weeks. 
The classic 3 + 3 design will be conducted as follows.  Initially, 3 patients will be enrolled to 
a cohort; the occurrence of a single drug-related DLT in one of these 3 patients will prompt 
enrollment of up to an additional 3 patients to that same cohort i.e., 3 + 3.  When more than 
1 DLT occurs in ≤ 6 patients in a dosing cohort, dose escalation will be stopped and this dose 
level will be identified as the non-tolerated dose.  Doses between the non-tolerated dose and 
the preceding lower dose, where ≤ 1 DLT occurred, may be explored to define the MTD.  
This strategy allows for a rigorous determination of MTD, especially if the dose increase that 
resulted in determination of the non-tolerated dose is relatively large (i.e., > 50%). 
At any time during the study, the Sponsor and Investigators may request that cohorts should 
be enlarged or that exploration of intermediate doses between 2 planned escalation steps 
should be explored.  Such requests will be discussed with the Sponsor and Medical Monitor, 
and should be based on all data existing at that time, including determinations of 
pharmacokinetics, pharmacodynamics, and cumulative toxicity.  Before each escalation, 
investigators will be consulted to ensure that all involved agree with the escalation decision.  
In addition, once the RP2D is defined, intra-patient dose escalation to the RP2D will be 
allowed after a patient has completed at least 1 cycle at their assigned dose and only if the 
patient has experienced no toxicity above Grade 1, upon request by the PI and discussion 
with the Medical Monitor and the Sponsor.  
Part 2 – Cohort-expansion Phase:  Additional patients with particular tumor types and/or 
cancers harboring specific genetics will be recruited for treatment at the Recommended 
Phase 2 Dose (RP2D).  Patients must have measurable disease by RECIST 1.1.  Patients will 
receive twice daily oral doses of BVD-523 in 21-day treatment cycles until disease 
progression, unacceptable toxicity, or another withdrawal criterion is met (Section 7.2).  
Treatment cycles will occur consecutively without interruption except when necessary to 
manage toxicities. 
Total enrollment for Part 2 is targeted at approximately 105 evaluable patients.  Patients will 
be enrolled into 1 of 7 treatment groups.  Group assignments are made according to the 
following disease characteristics, which correspond to specific inclusion and exclusion 
criteria for Part 2. 


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• Group 1: Patients with BRAF mutated cancer, except those with colorectal or non-small 
cell lung cancers, not previously treated with BRAF and/or MEK inhibitors; n < 15 
• Group 2: Patients with BRAF mutated colorectal cancer, not previously treated with 
BRAF and/or MEK inhibitors; n < 15 
• Group 3: Patients with BRAF mutated melanoma who have progressed or are refractory 
to BRAF and/or MEK inhibitors; n < 15 
• Group 4: Patients with NRAS mutated melanoma, not previously treated with BRAF 
and/or MEK inhibitors; n < 15  
• Group 5: Patients with MEK mutated cancer, not previously treated with BRAF and/or 
MEK inhibitors; n < 15 
• Group 6: Patients with BRAF mutated non-small cell lung cancer, not previously treated 
with BRAF and/or MEK inhibitors; n < 15 
• Group 7: Patients with ERK mutated cancer, not previously treated with BRAF and/or 
MEK inhibitors; n < 15 
 
Initial enrollment targets for each group may be modified to respond to accrued safety, 
clinical effect, pharmacokinetic, and pharmacodynamic data.  The decision to expand 
enrollment in one or more groups will be made through consultation among the Principal 
Investigators, the Medical Monitor and the Sponsor.  
Table 3.1. 
Study Medication Dosing and Pharmacokinetics/Pharmacodynamics Chart  
 
Study Days 
1 
8 
15 
22 
BVD-523 Dosing1 
X 
X 
X 
X 
Pharmacokinetics Sampling 
X 
 
X 
X 
Pharmacodynamics Sampling2 
X 
 
X 
 
1 
Dosing is twice daily in 21-day cycles until disease progression.  Patients may be treated beyond disease 
progression for additional 21-day cycles at the same dose level at the Investigator’s discretion.  However it 
is particularly important in patients for which FDA approved BRAF and/or MEK inhibitors are indicated 
that BVD-523 treatment NOT be continued beyond tumor progression.  Study medication for a week of 
dosing will be dispensed at each visit (± 1 day for Cycles 1 and 2, ± 2 days for later cycles).  For treatment 
cycles after Cycle 2, study medication for 3 weeks of dosing will be dispensed.  Additional medication may 
be dispensed to ensure uninterrupted dosing, if needed. 
2 
Pharmacodynamic sampling should only be completed in those patients that consent to optional biopsy. 
Those patients that do not consent to this collection do not need to have pharmacodynamics samples taken.  


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3.1.3 
Summary of Dose Escalation 
Table 3.2. 
Summary of Dose Escalation  
Observed Safety Outcomes 
Action 
Single Patient Cohorts 
AEs ≤ Gr 1 
• Continue testing with single patient cohorts 
• Escalate by 100% to next dose level  
One AE ≥ Gr 2 (excluding alopecia or 
diarrhea) 
• Expand current and subsequent cohorts to ≥ 3patients 
• Escalate by ≤ 50% to next dose level 
1 DLT  
• Expand cohort up to 6 patients 
Standard Escalation Cohorts (3−6 patients) 
No DLTs 
• Escalate by ≤ 50% to next dose level 
1 DLT in 3 patients 
• Expand cohort up to 6 patients 
1 DLT in 6 patients 
• Escalate by ≤ 50% to next dose level 
> 1 DLT in ≤ 6 patients 
• Stop dose escalation 
Note: DLT (see Section 3.1.4.2) is defined as any BVD-523 related toxicity in the first 21 days of treatment that 
results in: 
1. 
≥ Grade 4 hematologic toxicity for > 1 day 
2. 
Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding 
3. 
≥ Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain and rash 
(these become DLTs if the AE persists despite adequate treatment), a doubling of AST/ALT in patients 
with grade 2 ALT/AST at baseline 
4. 
A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite 
adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for > 7 days) due to BVD-523-related 
toxicity. 
 
Each cohort can only begin when the previous cohort has completed treatment to at least the 
end of Week 3 without fulfilling a criterion that would prevent dose escalation.   
Although dose escalation decisions may be taken upon review of the data from Cycle 1, 
safety data will be collected from all patients continuing treatment and reviewed periodically 
by the Safety Monitoring Committee.  Any detected cumulative toxicity may require later 
dose reductions or other action as appropriate, including having an effect on the RP2D. 
3.1.4 
Definition of MTD, DLT, and RP2D 
3.1.4.1 
Definition of Maximum Tolerated Dose (MTD) 
MTD is defined as the highest dose cohort at which ≤ 33% of patients experience BVD-523 
related DLTs in the first 21 days of treatment. 
3.1.4.2 
Definition of Dose Limiting Toxicity (DLT) 
DLT is defined as BVD-523 related toxicity in the first 21 days of treatment that results in: 
• ≥ Grade 4 hematologic toxicity for > 1 day 


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• Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with 
bleeding 
• ≥ Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, 
pain, and rash (these become DLTs if the AE persists despite adequate treatment), a 
doubling of AST/ALT in patients with grade 2 ALT/AST at baseline 
• A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for 
rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for 
> 7 days) due to BVD-523-related toxicity 
3.1.4.3 
Definition of Recommended Phase 2 Dose (RP2D) 
The Recommended Phase 2 Dose (RP2D) may be as high as the MTD and will be 
determined in discussion with the Clinical Investigators, the Medical Monitor, and the 
Sponsor.  Observations related to pharmacokinetics, pharmacodynamics, and any cumulative 
toxicity observed after multiple cycles may be included in the rationale supporting the RP2D. 
3.2 
SAFETY MONITORING COMMITTEE 
An internal Safety Monitoring Committee (SMC) will be set up to review the safety of 
BVD-523 as the study progresses.  The SMC will consist of Clinical Investigators, the 
Medical Monitor and BVD representatives.  The SMC will review any serious Adverse Event 
(SAE) that occurs during the study, and will examine the safety of each dose level of 
BVD-523, including toxicities that may occur in later cycles of treatment.   
3.3 
SAFETY REVIEW MEETINGS 
The safety review will be performed in all stages of the dose escalation: 
1. Prior to starting each new dose level after the initial cohort. 
2. To stop the dose escalation if the MTD has been reached. 
 
3.4 
STOPPING RULES 
The entire study or treatment of individual patients may be stopped under defined 
circumstances as outlined in Section 7. 
3.5 
STUDY ENDPOINTS 
3.5.1 
Primary Endpoint(s) 
Safety 
• Evaluation of the DLTs of BVD-523 
• Determination of MTD of BVD-523 
• Determination of RP2D of BVD-523 
• Evaluation of treatment-related AEs of BVD-523 


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3.5.2 
Secondary Endpoint(s)  
Pharmacokinetics 
• Evaluation of pharmacokinetic parameters of BVD-523 and selected metabolites in 
patients with advanced malignancies. 
Efficacy 
• Preliminary clinical effects on tumor response assessed by physical or radiological 
exam (RECIST 1.1). 
3.5.3 
Exploratory Endpoint(s) 
Pharmacodynamics 
• Evaluation of multiple biomarkers to characterize response to drug (pRSK, pERK, 
Ki67, Caspase-3, and circulating tumor DNA).  Additional biomarkers may be 
identified and measured as appropriate.  Tumor genotyping by DNA analysis will be 
performed to identify somatic alterations, relying on either available archived tissue 
or freshly-collected samples. 
3.6 
BLINDING AND RANDOMIZATION 
This study is designed as an open-label study.  All patients will receive treatment with orally 
administered BVD-523.   


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4 
SELECTION OF PATIENTS 
4.1 
NUMBER OF PATIENTS 
In this Phase 1 study up to 40 patients with advanced solid tumors will be enrolled in Part 1.  
One to six patients per treatment cohort will be assigned to receive sequentially higher oral 
doses of BVD-523.  
The purpose of Part 2 of this first in human research is to document that there is some 
evidence of a response.  Upon completion of Part 1 of this study, up to approximately 105 
evaluable patients with certain cancer types and/or characterized genetics will be assigned to 
1 of 7 treatment arms and treated with the RP2D determined in Part 1 (which may be the 
same or lower than the MTD).  The observation of DLTs in more than 33% of patients in any 
Part 2 cohort with at least 6 patients enrolled at any time during Part 2 will trigger temporary 
stopping of patient enrollment and revision of the definition of the MTD and potentially 
RP2D in the specific cohort.  Subsequent patients will be treated with a dose lower than the 
initial MTD and this dose will be determined in discussion with the Clinical Investigators, 
the Medical Monitor, and the Sponsor. 
Enrollment of up to 15 evaluable patients in each cohort provides an 80% probability of 
seeing at least one positive response if the true response rate is at least 10%.  Allowing for a 
low response rate in these patient cohorts is appropriate based on unmet medical need.   
In Part 2 of the study, patients who withdraw at any time preceding the 1st protocol-specified 
tumor measurement evaluation at the end of Cycle 2 (except for study drug-related AE) will 
be replaced. 
4.2 
RECRUITMENT 
Three to 10 study centers will enroll up to 40 patients for Part 1. 
In addition to the sites supporting Part 1 studies, sites may be added (up to 15 total sites) to 
enroll up to approximately 105 evaluable patients for Part 2 of the study. 
4.3 
INCLUSION CRITERIA 
Patients eligible for inclusion in this trial have to fulfill all of the following criteria: 
1. Provide signed and dated informed consent prior to initiation of any study-related 
procedures that are not considered standard of care (SOC). 
2. Male or female patients aged ≥ 18 years. 
3. Patients with metastatic or advanced-stage malignant tumor, confirmed histologically, for 
whom no therapy exists that would be curative.   
4. ECOG performance status of 0 (fully active, able to carry out all pre-disease activities 
without restriction) or 1 (unable to perform physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature), measured within 72 hours 
before the start of treatment. 


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5. Predicted life expectancy of ≥ 3 months. 
6. Adequate renal function [creatinine ≤ 1.5 times ULN (upper limit of normal)] or GFR of 
≥ 50 mL/min. 
7. Adequate hepatic function [total bilirubin ≤ 1.5 times ULN; AST (aspartate transaminase) 
and ALT (alanine transaminase) ≤ 3 times ULN or ≤ 5 times ULN if due to liver 
involvement by tumor]. 
8. Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 109 cells/L; 
absolute neutrophil count ≥ 1.5 x 109 cells/L). 
9. Adequate cardiac function, > institutional lower limit of normal  e.g., left ventricular 
ejection fraction (LVEF) of > 50% as assessed by multi-gated acquisition (MUGA) or 
ultrasound/echocardiography (ECHO); corrected QT interval (QTc) < 470 ms. 
10. Contraception: 
• For women: Negative pregnancy test for females of child-bearing potential; must be 
surgically sterile, postmenopausal (no menstrual cycle for at least 12 consecutive 
months), or compliant with a contraceptive regimen during and for 3 months after 
the treatment period.  Abstinence is not considered an adequate contraceptive 
regimen. 
• For men: Must be surgically sterile, or compliant with a medically approved 
contraceptive regimen during and for 3 months after the treatment period. 
11. Willing and able to participate in the trial and comply with all trial requirements. 
12. For Part 2 of the Study ONLY: 
• Patient must be diagnosed with specific tumor types and histologies (Section 3.1.2). 
• Patient must bear tumors that harbor specific classes of genetic mutations. 
• Patients must have measurable disease by RECIST 1.1. 
4.4 
EXCLUSION CRITERIA 
Patients who fulfill one or more of the following criteria will not be eligible for inclusion in 
this trial: 
1. Gastrointestinal (GI) condition that could impair absorption of study medication (specific 
cases e.g., remote history of GI surgery, may be enrolled after discussion with the 
medical monitor), or inability to ingest study medication. 
2. Uncontrolled or severe intercurrent medical condition. 
3. Known uncontrolled brain metastases.  Stable brain metastases either treated or being 
treated with a stable dose of steroids/anticonvulsants, with no dose change in the previous 
4 weeks, can be allowed. 
4. Any cancer-directed therapy (chemotherapy, hormonal therapy, biologic or 
immunotherapy, etc.) within 28 days or 5 half-lives, (whichever is shorter).  Patients 
previously treated with radiotherapy must have recovered from the acute toxicities 
associated with such treatment. 
5. Major surgery within 4 weeks prior to first dose. 
6. Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) 
prior to the first dose of BVD-523.  A minimum of 10 days between termination of the 
investigational drug and administration of BVD-523 is required.  In addition, any drug-
related toxicity except alopecia should have recovered to Grade 1 or less. 


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7. Pregnant or breast-feeding women. 
8. Any evidence of serious active infections. 
9. Any important medical illness or abnormal laboratory finding that would increase the risk 
of participating in this study (based on the investigator’s judgment). 
10. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR). 
11. Concurrent therapy with any other investigational agent. 
12. Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6 and 
CYP3A4, or strong inducers of CYP3A4 (for list of non-permitted drugs, see 
Appendix 1). 
13. Concomitant malignancies or previous malignancies with less than 2 years disease-free 
interval at the time of enrollment (except non-melanoma skin cancer, cervical cancer in 
situ, prostate cancer with undetectable PSA).  Other concurrent malignancies that are 
indolent and do not require active treatment must be discussed with the medical monitor 
prior to enrollment. 
 
 


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5 
STUDY PLAN AND PROCEDURES 
This clinical study will consist of 2 parts.  In Part 1, patients with advanced solid tumors will 
receive sequentially higher oral doses of BVD-523.   
In Part 2, patients will be assigned to 1 of 7 treatment groups based on specific tumor and 
clinical characteristics and will be treated at the Recommended Phase 2 Dose determined in 
Part 1.   
To characterize the pharmacokinetic properties of BVD-523 in patients, blood, urine, and 
tissue biopsy (as indicated) samples will be obtained/analyzed during Cycle 1 of Part 1, and 
during additional cycles in Part 1 and/or Part 2 as indicated.  
Multiple pharmacodynamics biomarkers will be used to measure response to drug treatment, 
including evaluation of pRSK, pERK, Ki67, Caspase-3, and circulating tumor DNA.  
Biomarker samples/measurements will be obtained during Cycle 1 of Part 1, and during 
additional cycles in Part 1 and/or Part 2 based on accumulated experience (appropriate 
control samples/measurements will be taken prior to patient receiving their first dose). 
Tumor assessments will be made by CT/MRI/Physical Exam prior to dose initiation, at the 1st 
protocol-specified tumor measurement evaluation at the end of Cycle 2 and then every 2-3 
cycles, and at End of Treatment.   
All patients will be screened and eligibility determined prior to enrollment and start of study 
treatment. 
5.1 
STUDY PATIENT NUMBER 
In Part 1, up to forty patients are expected to be enrolled. 
In Part 2 of the study, up to approximately 105 evaluable patients with measurable disease 
will be enrolled: 
• Group 1: Patients with BRAF mutated cancer, except those with colorectal or non-small 
cell lung cancers, not previously treated with BRAF and/or MEK inhibitors; n < 15 
• Group 2: Patients with BRAF mutated colorectal cancer, not previously treated with 
BRAF and/or MEK inhibitors; n < 15 
• Group 3: Patients with BRAF mutated melanoma who have progressed or are refractory 
to BRAF and/or MEK inhibitors; n < 15 
• Group 4: Patients with NRAS mutated melanoma, not previously treated with BRAF 
and/or MEK inhibitors; n < 15  
• Group 5: Patients with MEK mutated cancer, not previously treated with BRAF and/or 
MEK inhibitors; n < 15 


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• Group 6: Patients with BRAF mutated non-small cell lung cancer, not previously treated 
with BRAF and/or MEK inhibitors; n < 15 
 
• Group 7: Patients with ERK mutated cancer, not previously treated with BRAF and/or 
MEK inhibitors; n < 15 
 
5.2 
DESCRIPTION OF STUDY VISITS FOR PART 1 
Procedures performed in the first cycle are specified in Table 6.1.  Patients receiving multiple 
cycles of treatment will not have blood drawn for pharmacokinetic and pharmacodynamic 
measurements after Cycle 1 unless additional pharmacokinetic and pharmacodynamic data 
are deemed necessary after initial analysis. 
5.2.1 
Visit 1 (Day -14 to -1); Screening 
The following procedures will be performed at Visit 1 (Screening): 
• Obtain written informed consent (before start of any study related procedures that are 
not standard of care) including optional consents for additional future analyses (Note: 
informed consent may be obtained up to -28 days to allow flexibility in scheduling of 
the screening procedures). 
• Evaluate all inclusion and exclusion criteria to ensure that patients meet all inclusion 
criteria and none of the exclusion criteria. 
• Review medical history including all previous cancer treatments. 
• Record prior (within previous 28 days) and concomitant medications including 
start/stop dates, indication, dose and frequency. 
• Record demographic data including date of birth, age, gender, race, ethnicity and 
smoking status. 
• Measure and record height and weight.  
• Perform and record physical examination. 
• Assess and record performance status (ECOG) within 7 days before start of treatment. 
• Record vital signs.  Measure body temperature, systolic/diastolic blood pressure (BP) 
and pulse rate. 
• Collect blood for a serum pregnancy test for female patients who are not 
postmenopausal or surgically sterile. 
• Assess and record current disease status (computed tomography [CT] or other 
measurements to be defined). This may be performed within 28 days before start of 
treatment (Visit 2). 
• Collect blood samples for blood chemistries, hematology and creatinine clearance (In 
all instances throughout the study, when creatinine clearance is calculated, the 
Cockcroft-Gault formula should be used.) within 7 days before start of treatment, 
analyze, review and report any clinically significant abnormalities to medical monitor 
before dosing. 
• Perform and record ophthalmology examination. 


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• Obtain a 12-lead electrocardiogram (ECG), ECHO cardiogram or MUGA for LVEF. 
• Collect urine samples for urinalysis within 7 days before start of treatment. 
• For patients enrolled in Part 2 of the study, a tumor biopsy and blood may be required 
to obtain tumor genetic information required to confirm eligibility (e.g., BRAF, 
MEK, RAS, or ERK mutation). 
• For patients who have given consent for optional research tests involving the 
collection of tumor tissue and plasma samples for circulating tumor DNA analysis, 
collect tumor biopsy and plasma samples prior to first dose of BVD-523. 
5.2.2 
Visit 2 (Day 1 ± 0); Baseline/Drug Dispensing/Initiation of Treatment 
The following procedures will be performed at Visit 2 (Baseline): 
Visit 1 (Screening) laboratory assessments (including Chemistry, Hematology and 
Urinalysis), ECOG and physical exams completed within 7 days prior to the Cycle 1 Day 1 
visit do not need to be repeated pre-dose at this visit.  Female patients with a negative serum 
pregnancy test result within 24 hours of the Cycle 1 Day 1 visit may have a urine pregnancy 
test performed pre-dose on C1D1. 
• Review all inclusion and exclusion criteria to ensure that patients meet all inclusion 
criteria and none of the exclusion criteria. 
• Review medical history.  
• Record medications including start/stop dates, indication, dose and frequency. 
• Perform and record physical examination. 
• Assess and record performance status (ECOG). 
• Record vital signs (body temperature, systolic/diastolic BP and pulse rate). 
• ONLY if the screening pregnancy test was performed more than 1 day previously, 
collect urine for a urine pregnancy test for female patients who are not 
postmenopausal or surgically sterile. 
• Attach Holter monitor for QTc assessment. 
• Collect pre-dose blood samples for pharmacokinetic and pharmacodynamic analyses 
• In Part 2, pharmacodynamic samples only need to be taken if the patient has 
consented to the optional research tests involving collection of tumor tissue. 
• Collect pre-dose urine samples for pharmacokinetic analyses. 
• Collect pre-dose blood samples for blood chemistries, hematology and creatinine 
clearance. 
• Collect pre-dose urine samples for urinalysis. 
• Administer first dose of BVD-523. 
• Collect post-dose blood samples for pharmacokinetic and pharmacodynamic 
analyses. 
• In Part 2, pharmacodynamic samples only need to be taken if the patient has 
consented to the optional research tests involving collection of tumor tissue. 
• Collect post-dose urine samples for pharmacokinetic analyses. 
• Perform and record Holter monitoring during pharmacokinetic sampling. 


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• Assess and record AEs. 
• Dispense study drug and instruct patients how to take study drug. 
• Inform patients of the potential photosensitizing effects of BVD-523 and instruct 
them to avoid sunlight and wear protective clothes, sunglasses, and apply sunblock 
when outside, including when driving a car.  
5.2.3 
Visit 3 (Day 8 ± 1) 
• Review medical history. 
• Record concomitant medications including start/stop dates, indication, dose and 
frequency taken after Visit 2. 
• Perform and record targeted physical examination as appropriate. 
• Assess and record performance status (ECOG). 
• Record vital signs.  Measure body temperature, systolic/diastolic BP and pulse rate. 
• Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• Collect urine samples for urinalysis.   
• Obtain all unused study drug from patient. 
• Assess study drug compliance by pill count. 
• Obtain a 12-lead ECG. 
• Assess and record AEs. 
• Administer BVD-523 and dispense drug supply for self-dosing. 
5.2.4 
Visit 4 (Day 15 ± 1) 
• Review medical history. 
• Record medications including start/stop dates, indication, dose and frequency taken 
after Visit 3. 
• Perform and record targeted physical examination as appropriate. 
• Assess and record performance status (ECOG). 
• Assess and record AEs. 
• Record vital signs (body temperature, systolic/diastolic BP and pulse rate). 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by pill count. 
• Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• Collect urine samples for urinalysis. 
• Attach Holter monitor for QTc assessment. 
• Collect pre-dose urine samples for pharmacokinetic analyses. 
• Collect pre-dose blood samples for pharmacokinetic and pharmacodynamic analyses. 
• In Part 2, pharmacodynamic samples only need to be taken if the patient has 
consented to the optional research tests involving collection of tumor tissue. 
• Administer BVD-523 and dispense drug supply for self-dosing. 
• Collect post-dose blood samples for pharmacokinetic and pharmacodynamic 
analyses. 


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• In Part 2, pharmacodynamic samples only need to be taken if the patient has 
consented to the optional research tests involving collection of tumor tissue 
• Collect post-dose urine samples for pharmacokinetic analyses. 
• Perform and record Holter monitoring during pharmacokinetic sampling. 
• For patients who have given consent for optional research tests involving the 
collection of tumor tissue, collect tumor tissue sample (may be collected 1 day before 
or up to 2 days after the visit). 
 
Note: If the patient has not completed at least 5 days of continuous dosing before the 
visit, Holter monitoring, pharmacokinetic sampling, pharmacodynamic sampling, and 
optional research tests (for patients who have given consent) should not be completed. 
Patients may be asked to complete these assessments at a future study visit. 
5.2.5 
Visit 5 (Day 22 ± 1 of Cycle 1, first day of Cycle 2) 
• Review medical history including all cancer treatments received since previous visit. 
• Record medications including start/stop dates, indication, dose and frequency taken 
after Visit 4. 
• Perform and record targeted physical examination as appropriate. 
• Assess and record performance status (ECOG). 
• Record vital signs.  Measure body temperature, systolic/diastolic BP and pulse rate. 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by reviewing pill count. 
• Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• Collect urine samples for urinalysis. 
• Perform urine pregnancy test for female patients who are not postmenopausal or 
surgically sterile.  If urine test is positive, collect blood for a serum pregnancy test.  
• Collect a pre-dose blood sample for pharmacokinetic analyses. 
• Administer BVD-523 and dispense drug supply for self-dosing for Cycle 2 if 
appropriate. 
• Assess and record disease status, including safety, pharmacokinetics, and 
pharmacodynamics.   
• Assess and record AEs. 
• For patients who have given consent for optional research tests involving the 
collection of plasma samples for circulating tumor DNA analysis, collect plasma 
samples. 
5.2.6 
End of Treatment Visit 
At the time of study drug discontinuation, the End of Treatment Visit should be completed 
for all patients as soon as possible after the last dose of study drug, and every effort should be 
made to perform all procedures. 
• Review medical history. 


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• Record medications including start/stop dates, indication, dose and frequency. 
• Perform and record physical examination. 
• Assess and performance status (ECOG). 
• Record vital signs.  Measure body temperature, systolic/diastolic BP and pulse rate. 
• Perform and record ophthalmology examination. 
• Perform urine pregnancy test for female patients who are not postmenopausal or 
surgically sterile.  If urine test is positive, collect blood for a serum pregnancy test. 
• Assess and record disease status.  CT/MRI/Physical Exam for tumor assessment to be 
performed if the previous CT/MRI scan was conducted more than 21 days earlier. 
• Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• Collect urine samples for urinalysis. 
• Assess and record AEs. 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by reviewing pill count. 
 
5.2.7 
30-day Safety Visit 
Patients will be asked to return for a visit or contacted by phone for a follow-up assessment 
at 30 ± 3 days after the last dose of study drug is taken, or earlier if subsequent therapy is 
initiated before 30 ± 3 days.  Information concerning only SAEs and AEs will be collected at 
this visit.  
5.2.8 
Unscheduled Visits 
Additional visits can be performed as appropriate and at the discretion of the investigator.  
Testing may include any previously described assessment including timed pharmacokinetics 
and pharmacodynamics collections. 
5.3 
STUDY VISITS FOR PART 1 CYCLE 2 
Cycle 2 visits and procedures are similar to Cycle 1, although no 
pharmacokinetic/pharmacodynamic measurements will be made unless specifically requested 
by Investigator.  Refer to Table 6.1 for Cycle 2 assessments and procedures. 
5.4 
DESCRIPTION OF STUDY VISIT FOR PART 1 CYCLE 3 AND 
EACH SUBSEQUENT CYCLE OF PART 1 
Cycle 3 and subsequent cycles have one scheduled visit per cycle.  No 
pharmacokinetic/pharmacodynamic measurements will be made unless the Visit 4 or Visit 5 
measurements were missed due to dosing interruption or unless specifically requested by 
Investigator.  Refer to Table 6.1 for Cycle 3 assessments and procedures. 
5.4.1 
Cycle 3 and Subsequent Cycles Visit (Day 1 ± 1 of each cycle) 
• Review medical history. 


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• Record medications including start/stop dates, indication, dose and frequency taken 
since previous visit. 
• Perform and record targeted physical examination as appropriate. 
• Assess and record performance status (ECOG). 
• Measure weight in kg. 
• Record vital signs.  Measure body temperature, systolic/diastolic BP and pulse rate. 
• Perform ECG if appropriate (Patients with a normal ECG during Cycle 1 need not 
have repeat ECGs during subsequent cycles). 
• Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• Collect urine samples for urinalysis. 
• Perform urine pregnancy test for female patients who are not postmenopausal or 
surgically sterile. If urine test positive, test, collect blood for a serum pregnancy test. 
• Assess and record disease status (CT/MRI/Physical Exam every 2-3 cycles and other 
measurements to be defined). 
• Assess and record AEs. 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by reviewing pill count. 
• Dispense BVD-523 with timing and quantity to ensure continuous treatment. 
• For patients who have given consent for optional research tests involving the 
collection of tumor tissue and plasma samples for circulating tumor DNA analysis, 
tumor biopsy and plasma samples may be collected after disease progression. 
 
5.5 
DESCRIPTION OF STUDY VISITS FOR PART 2 
Study procedures for Part 2 will be the same as those for Part 1 with three exceptions:  
• Urine pharmacokinetics will be discontinued at the completion of Part 1, and 
• Blood pharmacokinetics, blood pharmacodynamics, and Holter monitoring may be 
discontinued prior to completion of Part 2 based on accumulated patient experience, 
and 
• Based on accumulated patient experience, in Part 2, pharmacodynamic samples 
only need to be taken if the patient has consented to the optional research tests 
involving collection of tumor tissue. 
• The 1st protocol-specified tumor measurement evaluation will be performed at the end 
of Cycle 2 and then every 2-3 cycles. 
 
If clinical experience gained in Part 1 requires significant deviations in Part 2 from the 
procedures in Part 1, these changes will be addressed in a protocol amendment.  
During the Cohort Expansion phase (Part 2) of the study an alternative BVD-523 capsule 
formulation may be evaluated.  The new drug product contains the same investigational drug 
substance (BVD-523) in the same dosage form and strength as the initial powder-in-capsule 
drug product; however it also contains standard excipients commonly used in immediate 


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release solid dosage forms and is therefore not expected to alter the bioavailability of the 
drug substance.  


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6 
METHODS OF ASSESSMENT AND ENDPOINTS 
All trial data will be recorded on the eCRFs (TEMPOTM). 
6.1 
DEMOGRAPHIC DATA 
At Visit 1 (Screening), patient demographic data will be collected.  These include: year 
of birth, age, gender, race, ethnicity, tumor type and molecular abnormalities when 
available or required for Part 2. 
6.2 
MEDICAL HISTORY 
At Visit 1 (Screening) a complete medical history will be obtained from each patient.  For 
female patients of child-bearing potential, the date of the last menstrual period should be 
noted.  Data will be reviewed at Visit 2 (Baseline) and updated at subsequent visits. 
6.3 
CONCOMITANT MEDICATIONS 
Detailed history of medications and procedures will be documented for each patient at Visit 1 
(Screening) and Visit 2 (Baseline).  Concomitant medications (especially changes in 
medication) will be documented for each patient at each scheduled visit.  Medications which 
are known to be strong inhibitors of CYP3A4, CYP2D6 and CYP1A2, or strong inducers of 
CYP3A4, are not permitted during the study (for list of non-permitted drugs, see 
Appendix 1). 
6.4 
PHYSICAL EXAMINATION 
• Height in centimeters (cm) will be measured at Visit 1 (Screening). 
• Body weight in kilogram (kg) will be measured at screening and at the beginning of 
each cycle. 
• Body temperature will be measured at each visit. 
• Systolic and diastolic BP and pulse rate will be measured with the patient in a supine 
position.  Blood pressure should be assessed on the same arm during the study. 
 
Full physical examination evaluations at screening should include general appearance, skin, 
neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological examinations.  Subsequent targeted physical exams should include body 
systems as appropriate. 
Information about the physical examination must be present in the source documentation at 
the study site.  The result of the physical examination prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions Case Report Form.  
Clinically relevant findings made after the start of study drug, which meet the definition of an 
adverse event, must be recorded on the Adverse Event Case Report Form. 


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6.5 
SAFETY ASSESSMENTS 
Safety evaluations will be conducted at baseline, on Days 8, 15, 22, 29, 36, 43, and, in 
patients who continue treatment, every 3 weeks or if clinically indicated thereafter.  These 
evaluations will include a physical examination, electrocardiography in subjects with a 
clinically significant abnormal ECG in Cycle 1 (by ECG and Holter monitoring [Holter for 
12 ± 2 hours during PK sampling days]), and clinical laboratory studies.  An ophthalmologic 
assessment will be conducted at baseline, at the end of study and at other visits by an 
ophthalmologist if clinically indicated.  Patients experiencing dermatological AEs considered 
to be possibly related to BVD-523 should have digital photographs and punch biopsies taken 
of the affected skin, if they have given formal informed consent.  The following clinical 
laboratory tests will be performed: 
• Hematology: hemoglobin, hematocrit, white blood cells (WBC) count with 
differential, red blood cells (RBC) count, erythrocyte sedimentation rate (ESR) and 
platelet count. 
• Blood Chemistry: albumin, alkaline phosphatase (ALP), total bilirubin, calcium, 
chloride, creatinine, glucose, inorganic phosphorus, potassium, total protein, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP), 
lactic dehydrogenase (LDH), sodium and blood urea nitrogen (BUN) uric acid. 
• If the total bilirubin concentration is increased above 1.5 times the upper normal 
limit, total bilirubin should be differentiated into the direct and indirect reacting 
bilirubin. 
• Cholesterol, HDL, LDL and triglycerides levels will be measured at screening and 
the first day of each cycle only. 
• Urinalysis:  specific gravity, pH, semi-quantitative "dipstick" evaluation of glucose, 
protein, bilirubin, ketones, leukocytes, and blood. Abnormal findings by dipstick will 
trigger a full microscopic examination including RBC, WBC and casts. 
 
Blood chemistry will be analyzed at each trial center by a certified laboratory and a report of 
the laboratory values will be sent to the trial center.  The investigator will review the 
laboratory reports before dosing and appropriate action taken to address any clinically 
significant abnormal values.  Laboratory parameters for which clinically significant values 
are noted will be re-measured on the appropriate clinical follow-up arranged by the 
investigator.  Values will be monitored until stabilized, or the laboratory value returns to a 
clinically acceptable range (regardless of relationship to study medication).  Any laboratory 
value that remains abnormal at the end-of-study (EOS) and that is considered clinically 
significant will be followed according to accepted medical standards for up to 30 days or 
until resolution of the abnormality. 
Ophthalmologic examinations include best-corrected visual acuity, visual field examination 
intraocular pressure, external eye examination, and dilated fundoscopy.  For additional 
details refer to study manual). 
Toxicity will assessed using the National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.03. 


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6.6 
PHARMACOKINETICS 
Please refer to Section 6.9.  
PK blood and urine samples may be sent to a third party vendor (for submission instructions, 
see Study Manual). 
6.7 
PHARMACODYNAMICS 
Multiple biomarkers intended to demonstrate inhibition of the molecular target, and 
mechanism of action will be investigated, including pRSK, pERK, Ki67, Caspase-3, and 
circulating tumor DNA.  Additional biomarkers and DNA sequence analysis may be 
identified and measured as appropriate. 
In Part 1, pharmacodynamics blood samples will be taken pre-dose and 4 hours 
(± 10 minutes) post-dose.  In the event of intra-patient dose escalation, additional 
pharmacodynamics samples may be obtained at investigator discretion or sponsor request.  In 
Part 2, pharmacodynamics blood samples will be taken according to the Part 1 schedule, but 
only in those patients consenting to optional research tests involving collection of tumor 
tissue and blood/plasma samples.  
Tumor genotyping by DNA analysis may be performed in patients in Part 1 and Part 2 to 
identify somatic alterations.  Collection of tumor tissue may also be obtained from selected 
patients within 3 days (1 day before, 2 days after) of the C1D15 visit day. Additional tissue 
samples for analysis may also be obtained from selected patients after disease progression.  
Paired tumor tissue and blood samples will be obtained at baseline.  Tissue may consist of 
formalin-preserved samples obtained at previous surgery or new biopsy tissue in patients 
with accessible tumors. 
Tissue and blood samples may be sent to a third party vendor (for submission instructions, 
see Study Manual). 
6.8 
EFFICACY 
Tumor measurements based on physical examination will occur at baseline and on the first 
day of each treatment cycle.  Tumor assessments will be made by CT/MRI/Physical Exam 
prior to dose initiation, at the 1st protocol-specified tumor measurement evaluation at the end 
of Cycle 2 and then every 2-3 cycles, and at End of Treatment.  Imaging will be performed 
on the abdomen, chest, pelvis and the site of the primary tumor if elsewhere.  The same 
imaging modality used for an individual patient (i.e., CT or MRI) at Screening should be 
maintained throughout the study.  The findings will be assessed according to the Response 
Evaluation Criteria in Solid Tumors (RECIST version 1.1).  The response criteria are defined 
as follows: 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 


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• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
1 or more new lesions is also considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
CT and MRI scans may be submitted to a central third party vendor for review (for 
submission instructions, see Study Manual).  
6.9 
PHARMACOKINETIC PROCEDURES 
6.9.1 
Blood Sampling and Processing 
In Part 1, samples for PK analysis of BVD-523 and selected metabolites will be obtained 
from all patients during their first cycle of treatment (Cycle 1).  In Part 2, samples for PK 
analysis of BVD-523 and selected metabolites will be obtained from all patients during their 
first cycle of treatment (Cycle 1) until the sponsor determines sampling will be discontinued 
based on accumulated patient experience.  Additional PK samples may also be obtained in 
the event of an SAE, AE, or intra-patient dose-change at the Investigator’s or sponsor’s 
request. 
At Visit 2 (Baseline) blood samples will be collected prior to dosing, and then at 0.5, 1 
(± 5 minutes), 2, 4, 6, 8 (± 10 minutes), and 12 hours (± 2 hours) post-dose after the 
administration of the first dose of the first cycle.  At Day 15 (Visit 4; at steady-state) blood 
samples will be collected prior to dosing and then 0.5, 1 (± 5 minutes), 2, 4, 6, 8 
(± 10 minutes), and 12 hours (± 2 hours) post-dose.  A single sample will be collected on 
Day 22 prior to dosing on that day.  Comprehensive information on blood sample acquisition, 
handling and storage are to be found in the Study Manual.  Sample tube labels include the 
patient identification number/protocol code, sample number and visit number. 
For storage and shipping instructions refer to Study Manual. The analytical laboratory will 
measure plasma concentrations of BVD-523 using a validated method.  
6.9.2 
Urine Sampling and Processing 
At Visit 2 (Baseline), urine samples will be collected pre-dose.  Total urine for the 1–6-hour 
and 6–12 ± 2-hour time periods post-dose after the administration of the first dose of the first 
cycle will also be collected.  At Day 15 (Visit 4; at steady-state) urine samples will be 
collected pre-dose and then post-dose for the 1–6-hour and 6–12 ± 2-hour time periods. 
For storage and shipping instructions refer to the Study Manual.  The analytical laboratory 
will measure urine concentrations of BVD-523 using a validated method. 


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Urine samples for PK will not be collected during Part 2 of the study.   
Samples will be stored at the study center until shipment under appropriate conditions to the 
analytical laboratory (refer to study manual).  The analytical laboratory will measure urine 
concentrations of BVD-523 using a validated method. 
6.9.3 
Pharmacokinetic Endpoints 
Blood, urine, (as indicated) BVD-523 and selected metabolite (blood samples only) 
concentration levels will be measured at specified timepoints. 
Table 6.2 lists the various parameters that will be calculated. 


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Table 6.1. 
Part 1 and 2: Schedule of Assessments and Procedures 
 
Cycle 1 
Day 1 through 21 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21 day cycles, visit 
on 1st day of cycle 
 
Visit  
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 -X 
Tx 
Final Study Visit/ Early 
Discontinuation 
Visit Day 
-14 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ± 1 
36 ± 1 
43 ± 1 
 
Informed consent* 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history1 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
 
 
 
Measure height (cm) 
X 
 
 
 
 
 
 
 
 
Measure weight (kg) 
X 
X 
 
 
X 
 
 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmology exam2 
X 
 
 
 
 
 
 
 
X 
Pregnancy test3,4 
X 
X3 
 
 
X4 
 
 
X4 
X4 
Study drug dispensed 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug administration5 
 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic samples6,7 
 
X7 
 
X6 
X6 
 
 
 
 
Pharmacodynamic samples6,7,8 
 
X7 
 
X6 
 
 
 
 
 
Tumor measurements9 
X 
 
 
 
 
 
 
X 
X 
Clinical lab tests10  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG)11 
X 
 
X 
 
 
 
 
 
 
Holter monitoring12 
 
X 
 
X 
 
 
 
 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance by pill count 
 
 
X 
X 
X 
X 
X 
X 
X 
Obtain unused drug  
 
 
X 
X 
X 
X 
X 
X 
X 
ECHO cardiogram or MUGA 
X 
 
 
 
 
 
 
 
 


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Table footnotes: 
*Note: informed consent may be obtained up to -28 days to allow flexibility in scheduling of the screening procedures. 
1 
Full medical history at screening, review/update of history only at subsequent visits. 
2 
Ophthalmological examinations will be performed by an ophthalmologist at screening, at End of Treatment and if clinically indicated. 
3 
ONLY if the screening serum pregnancy test was performed more than 1 day previously. 
4 
After screening and baseline, urine pregnancy test which if positive, confirm with serum test. 
5 
Study drug to be taken twice daily, first dose in clinic on days when PK sampling occurs i.e. Cycle 1 on Visit 2 (Day 1), Visit 4 (Day 15) and morning dose 
of Cycle 2 on Visit 5, remaining doses on all other days to be self-administered by patient. 
6 
In Part 1PK and pharmacodynamic blood samples plus PK urine samples will be taken concurrently on Day 1 and Day 15 along with QTc extractions from 
the Holter monitoring.  PK blood samples will be collected prior to first dose and at 0.5 hours, 1 hour (both ± 5 minutes), 2 hours, 4 hours, 6 hours, 8 hours 
(all ± 10 minutes), and 12 hours (± 2 hours) post first dose. Blood samples for pharmacodynamic assessment will be collected pre-dose and 4 hours post–
dose (±10 minutes).  PK urine samples will be collected prior to first dose and for the 1–6-hour and 6–12 ± 2-hour time periods post first dose on Day 1 and 
Day 15.  On Day 22, PK and pharmacodynamic samples will be collected prior to the first dose of that day.  In Part 2, urine PK will not be performed and 
blood PK, blood pharmacodynamic, and Holter monitoring will be performed until the sponsor determines they will be discontinued based on accumulated 
patient experience.  
7 
PK and pharmacodynamic blood and urine samples are required, and paired tumor tissue and blood samples are to be obtained at baseline where feasible.  
Tumor genotyping by DNA analysis may be performed to identify somatic alteration.  Additional tissue or plasma DNA samples for analysis may also be 
obtained from selected patients prior to first dose, at steady-state during treatment, or dose change, and/or after disease progression. 
8 
In Part 2, pharmacodynamic samples only need to be taken if the patient has consented to the optional research tests involving collection of tumor tissue. 
9 
Tumor assessments will be made by CT/MRI/Physical Exam prior to dose initiation if the patient does not have a recent CT/MRI/Physical Exam on record 
within 28 days before start of treatment (Visit 2), at the 1st protocol-specified tumor measurement evaluation at the end of Cycle 2 and then every 2-3 cycles, 
and at End of Treatment if the previous CT/MRI/Physical Exam was conducted 21 or more days earlier.  The same imaging modality used for an individual 
patient (i.e., CT or MRI) at Screening should be maintained throughout the study. 
10 
Chemistry (to include calcium and inorganic phosphorus), hematology and urinalysis.  After Cycle 2, clinical chemistry (to include calcium and inorganic 
phosphorus), hematology and urinalysis may be performed once per cycle or more frequently at the investigator’s discretion. 
11 
Patients with a normal ECG in Cycle 1 need not have repeat ECGs in subsequent cycles. 
12 
Holter monitoring for 12±2 hours during PK sampling. 


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Table 6.2. 
Pharmacokinetic Parameters to be Estimated after Dose 1 and at Steady State 
Cmax 
Peak plasma concentration determined manually by visual inspection of plasma concentration vs. time figures on the untransformed (linear) 
scale of measurement 
tmax 
Time to reach the peak plasma concentration determined manually by visual inspection of plasma concentration vs. time figures on the 
untransformed (linear) scale of measurement 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours post-dosing, calculated by linear/log trapezoidal method 
AUC1-12 
Area under the plasma concentration-time curve from 1 to 12 hours post-dosing, calculated by linear/log trapezoidal method (for use in 
calculating CLr) 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to time of last observation after dosing calculated by linear/log trapezoidal 
method 
λz 
Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-
time curve.  The correlation coefficient (r2) for the goodness of the fit of the regression line through the data points has to be 0.85 or higher, 
for the value to be considered reliable.  If the WinNonlin data points are not on the linear portion of the terminal slope, the data points will be 
selected manually prior to calculation of lambda z 
t1/2 
Terminal half-life, defined as 0.693 (ln 2) divided by lambda z 
U1-12 
Amount excreted in urine calculated from Time 1 to 12 hours 
CLr 
Renal clearance, U1-12 divided by AUC1-12 
Ae% 
Percentage of the dose excreted in the urine, U1-12 divided by the dose and multiplied by 100. 
 


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7 
DISCONTINUATION CRITERIA 
7.1 
EARLY DISCONTINUATION OF THE STUDY 
It is agreed that for reasonable cause, either the investigator or the Sponsor may terminate 
this study, provided a written notice is submitted at a reasonable time in advance of intended 
termination; if by the investigator notice is to be submitted to BioMed Valley Discoveries, 
Inc., and if by the Sponsor, notice will be provided to each investigator.  
If a severe local reaction or drug-related SAE occurs at any time during the study, the Safety 
Monitoring Committee will review the case immediately.  
The study will be immediately suspended and no additional BVD-523 doses administered 
pending review and discussion of all appropriate study data by the SMC if 1 or more patients 
at any dose level develop any of the following adverse events deemed to be possibly, 
probably or definitely related to BVD-523 by the Investigator and/or Medical Monitor, based 
upon close temporal relationship or other factors: 
• Death 
• Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia, or 
respiratory distress) 
 
The study will not be restarted until all parties have agreed to the course of action to be taken 
and the IRB/EC has been notified. 
7.2 
EARLY DISCONTINUATION OF INDIVIDUAL PATIENTS 
Patients are to be withdrawn from the study for any of the following reasons: 
• Withdrawal of informed consent 
• Disease progression (at the discretion of the PI).  However it is particularly important 
in patients for which FDA approved BRAF and/or MEK inhibitors are indicated that 
BVD-523 treatment NOT be continued beyond tumor progression. 
• Unacceptable toxicity 
• Changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the PI 
• Patient non-compliance as assessed by the investigator 
• Patient has a positive serum pregnancy test (withdrawal is required) 
• Patient is lost to follow-up 
 
Patients will also to be withdrawn at any time if the investigator concludes that it would be in 
the patient’s best interest for any reason.  Protocol violations do not lead to patient 
withdrawal unless they constitute a significant risk to the patient’s safety.  


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Patients can voluntarily withdraw from the trial for any reason at any time.  They are to be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or 
became lost to follow up for any reason. 
In Part 1 of the study, patients who withdraw at any time preceding the last visit of Cycle 1 
(Day 22) will constitute an early discontinuation and must be replaced in order to ensure 
proper data accrual for dose escalation decisions.  A patient who experiences a DLT in 
Course 1 and withdraws before Day 22 either because of the toxicity or otherwise, will 
nonetheless have that DLT counted in the assessment of potential cohort expansion and/or 
dose escalation (see Table 3.2). 
In Part 2 of the study, patients who withdraw at any time preceding the 1st protocol-specified 
tumor measurement evaluation at the end of Cycle 2 (except for study drug-related AE) will 
be replaced. 
The investigator must determine the primary reason for a patient’s withdrawal from the study 
and record this information on the eCRF. 


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8 
TREATMENT 
The safety and PK of BVD-523 will be tested in sequentially increasing doses starting at 
10 mg twice daily, initially in single-patient cohorts (for tabular summary, see Table 3.2).  
Dose escalations of BVD-523 will occur in 100% increments in single-patient cohorts until 
one patient experiences a ≥ Grade 2 toxicity (excluding alopecia or diarrhea).  This cohort 
and subsequent cohorts will be expanded to at least 3 patients each and subsequent dose-
escalation increments will be reduced from 100% to a maximum of 50%, as determined by 
discussion with the Clinical Investigators, the Medical Monitor, and the Sponsor.  If one 
patient in a 3-patient cohort experiences a DLT as defined in Table 3.2, up to 3 additional 
patients will be treated at this dose level.  If more than one DLT occurs in ≤ 6 patients, this 
dose level will be defined as the non-tolerated dose and dose escalation will be stopped. 
Doses will not be escalated unless the patient(s) receiving the highest current dose have been 
observed for at least 3 weeks and dose-limiting side effects have been reported in less than 
2 of 6 patients assigned to a given dose.  Before each escalation, Clinical Investigators will 
be consulted to ensure that all involved agree with the escalation decision.  Once the RP2D 
has been identified, up to 40 additional patients with pre-defined tumor types will be treated 
at this dose. 
Patients experiencing DLT or unacceptable toxicity will have their treatment interrupted until 
the toxicity returns to ≤ Grade 1 or pre-treatment baseline, whichever is more severe.  
Resumption of BVD-523 treatment may then be at the next lower dose level tested or at a 
20–30% dose decrease, aligning with capsule dose availability. 
During Part 2 of the study, intrapatient dose modifications are allowed, including dose 
reductions/interruptions as needed and re-escalations up to and including RP2D, at Clinical 
Investigators’ discretion. 
8.1 
DOSING AND ADMINISTRATION OF STUDY MEDICATION 
8.1.1 
Dispensing Directions 
Dispensing instruction will be provided in Pharmacy Instructions in the Study Manual. 
8.1.2 
Dosing Information 
BVD-523 is to be taken twice daily orally for 21 days, at 12 ± 2-hour intervals.  The study 
medication should be taken with 8 ounces of water at the same time each day on an empty 
stomach i.e., fasting (30-60 minutes before food or 2 hours after food).  All capsules, if more 
than one is taken at each dosing time, should be taken within 10 minutes.  A patient that is 
observed to vomit an intact capsule after dosing in the clinic during the PK measurements 
may receive a substitute dose of drug.  However, patients should be instructed NOT to take a 
substitute capsule if vomiting occurs after self-dosing at home.  Patient dosing dates and 
times will be collected. 
Since this is a first-in-human study no human toxicity has yet been experienced and, 
therefore, dose modifications for any toxicity seen will necessarily have to be developed as 


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data are accrued. However, patients experiencing DLT or unacceptable toxicity will have 
their treatment interrupted until the toxicity returns to ≤ Grade 1 or pre-treatment baseline, 
whichever is more severe.  BVD-523 treatment may then be re-initiated at the next lower 
dose level which has been safely tested or at a 20–30% dose decrease, aligning with capsule 
dose availability.  Such dose adjustments will be done in consultation with the Investigators 
and Medical Monitor of the study. 
Each cohort can only begin when the previous cohort has completed treatment to at least the 
end of Week 3 without fulfilling a criterion that would prevent dose escalation.   
Although dose escalation decisions may be taken upon review of the data from Cycle 1, 
safety data will be collected from all patients continuing treatment and reviewed periodically 
by the Safety Monitoring Committee.  Any detected cumulative toxicity may require later 
dose reductions or other action as appropriate, including having an effect on the RP2D. 
In addition, once the RP2D is defined, intra-patient dose escalation to the RP2D will be 
allowed after a patient has completed at least one cycle at their assigned dose and only if the 
patient has experienced no toxicity above Grade 1, upon request by the PI and discussion 
with the Medical Monitor and the Sponsor. 
8.1.3 
Dosing Instructions for the Study Participants 
Patients will be instructed to take their study medication twice daily at 12 ± 2-hour intervals.  
The study medication should be taken with 8 ounces of water at the same time each day on 
an empty stomach (30-60 minutes before food or 2 hours after food).  All capsules, if more 
than one is taken at each dosing time, should be taken within 10 minutes.   
Drug Storage 
Information will be provided in the Study Manual.  
Drug Accountability 
The investigator or trial staff will verify the integrity of the clinical trial supplies (storage 
conditions, correct amount received, condition of shipment, kit numbers, etc.) according to 
Standard Operating Procedures. 
The following data will be tracked on the drug accountability log provided by the Sponsor: 
• Date received 
• Lot number 
• Bottle number 
• Date dispensed 
• Patient number 
• Identification of the person dispensing the drug, with date 
 


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Records of study medication (used, lost, destroyed, and returned containers, individual 
capsules) should be made at each visit in the eCRF.  Drug accountability and reconciliation 
will be checked by the site monitor during site visits and at completion of study treatment. 
Any drug remaining in opened dispensing containers will be destroyed after the site monitor 
has verified drug accountability at the site, unless Institutional SOPs prohibit storage of 
unused or waste drug.  Unused and unopened study medication will be returned by the site 
monitor to the Sponsor. 
8.2 
RESCUE MEDICATIONS AND CONCOMITANT TREATMENTS  
All medications administered from 28 days prior to the commencement of study treatment 
(Day 1) through the end of treatment will be recorded on the eCRF.  Any changes of dosages 
of medication will also be noted. 
8.3 
TREATMENT COMPLIANCE 
The investigator will dispense the study medication only for use by patients enrolled in the 
study as described in this protocol.  The study medication is not to be used for reasons other 
than those described in this protocol. 
The investigator or other study staff will supervise study drug treatment given in the clinic 
and instruct the patient on study medication self-administration at Visit 2 (Baseline).  Patients 
will be asked to bring their study medication container with them at the each visit and 
compliance with protocol-defined study drug intake will be checked by pill count.  In case of 
non-compliance the patients will be instructed again.  


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9 
ADVERSE EVENT MANAGEMENT 
9.1 
DEFINITION OF AN ADVERSE EVENT 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient 
administered a medicinal product that does not necessarily have a causal relationship with 
this treatment.  An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the study (investigational) 
product.  This includes an exacerbation of pre-existing conditions or events, intercurrent 
illnesses, drug interaction, or the significant worsening of the indication under investigation 
that is not recorded elsewhere in the eCRF under specific efficacy assessments.  Anticipated 
fluctuations of pre-existing conditions, including the disease under study that does not 
represent a clinically significant exacerbation or worsening, need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study.  
AE information will be elicited by asking the patient a nonleading question, for example, 
“Have you experienced any new or changed symptoms since we last asked/since your last 
visit?” AEs should be reported on the appropriate page of the eCRF. 
9.2 
DEFINITION OF A SERIOUS ADVERSE EVENT 
A Serious Adverse Event (SAE) is any untoward medical occurrence that occurs at any dose 
(including after the ICF is signed and prior to dosing) that: 
• Results in death 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical 
reasons) or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
 
Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent 1 of the outcomes listed in this definition.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in-patient hospitalization, or the development 
of drug dependency or drug abuse. 
Hospitalizations for elective surgery or other medical procedures that are not related to a 
treatment-emergent AE are not considered SAEs. 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal during the study or within the 
safety reporting period (see below).  If the malignancy has a fatal outcome during the study 


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or within the safety reporting period, then the event should be reported using the term 
“disease progression” with a CTCAE severity of Grade 5. 
9.3 
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
Recording and reporting of adverse events should be in accordance with the current FDA 
“Guidance for Industry and Investigators Safety Reporting Requirements for INDs and 
BA/BE Studies”. 
Any AE is to be recorded in the eCRF.  In order to avoid vague, ambiguous, or colloquial 
expressions, the AE should be recorded in standard medical terminology rather than the 
patient’s own words.  Whenever possible, the investigator should combine signs and 
symptoms that constitute a single diagnosis. 
The existence of an AE may be concluded from a spontaneous report of the patient; from the 
physical examination; or from special tests e.g., ECG, laboratory assessments, or other study-
specified tests (source of AE). 
The reporting period begins from the time that the patient provides informed consent through 
and including 30 calendar days after the last administration of BVD-523.  AEs may occur in 
the specified follow-up period.  Any SAE occurring after the reporting period must be 
promptly reported if a causal relationship to the investigational drug is suspected.  If the 
patient begins a new anticancer therapy, the safety reporting period ends at the time the new 
treatment is started, however, death must always be reported when it occurs during the 30-
day reporting period irrespective of intervening treatment. 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug.  The action taken and the outcome must also be recorded. 
9.4 
INTENSITY OF ADVERSE EVENTS 
The severity of the AE will be graded according to the NCI CTCAE Grading Scale Version 
4.03 (see the NCI CTCAE web page at http://ctep.cancer.gov for details).  For AEs not 
covered by NCI CTCAE, the severity will be characterized as “mild”, “moderate”, or 
“severe” according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily 
activities. 
• Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities. 
• Severe events interrupt the patient’s usual daily activities. 
 


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9.5 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY DRUG 
The investigator will provide an assessment as to whether or not the AE was related to study 
drug, as outlined below.  
Unrelated 
The adverse event is unlikely to have been caused by study drug. 
Possibly related 
It is unclear whether the adverse event may have been caused by 
study drug.  
Related 
The adverse event is likely to have been caused by study drug.  
 
9.6 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All AEs occurring during the study are to be followed up in accordance with good medical 
practice until they are resolved, stabilized or judged no longer clinically significant or, if a 
chronic condition, until fully characterized.  Any AEs that are considered drug-related 
(possibly related, related) must be followed until resolution or until stabilization. 
9.7 
POSTSTUDY ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All unresolved AEs should be followed by the investigator until the events are resolved, the 
patient is lost to follow-up, or the AE is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each patient to report any subsequent event(s) that the patient, or 
the patient’s personal physician, believes might reasonably be related to participation in this 
study.  Prior to the conclusion of the study at the site the investigator should notify the Safety 
Associate (see Section 9.8) of any death or AE occurring at any time after a patient has 
discontinued or terminated study participation that may reasonably be related to this study.  
After study conclusion the investigator should notify BioMed Valley Discoveries, Inc., of 
any death or AE they are aware of occurring at any time after a patient has discontinued or 
terminated study participation that may reasonably be related to this study.  BioMed Valley 
Discoveries, Inc., should also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived offspring of a 
patient that has participated in this study. 
The investigator should notify Clinipace Worldwide, Inc. (CPWW) of any death or AE 
occurring at any time after a patient has discontinued or terminated study participation that 
may reasonably be related to this study.  BioMed Valley Discoveries, Inc., should also be 
notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that has participated in 
this study. 


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9.8 
REGULATORY ASPECTS OF ADVERSE EVENT REPORTING 
Unexpected serious suspected adverse reactions that the Sponsor believes have at least a 
reasonable possibility to be related to study drug are subject to expedited reporting to FDA.  
ALL SAEs must be entered into the eCRF within 24 hours of first knowledge of the event by 
study personnel.  It is important that the investigator provide his/her assessment of 
relationship to study drug at the time of the initial report.  Entry of an SAE into the eCRF 
triggers an automatic alert to the CPWW safety team.  The following information must be 
reported on the eCRF SAE report form: 
• Protocol number 
• Site and/or Investigator number 
• Patient number 
• Demographic data 
• Brief description of the event 
• Onset date and time 
• Resolution date and time, if the event resolved 
• Current status, if event not yet resolved 
• Any concomitant treatment and medication 
• Investigator’s assessment of whether the SAE was related to Investigative product 
• Outcome of the event if available 
 
The CPWW Safety Associate will contact the site for clarification of data entered onto the 
eCRF, or to obtain missing information.  In the event of questions regarding SAE reporting, 
the site may contact: 
Safety Associate  
Clinipace Worldwide, Inc.  
safety@clinipace.com 
 
BioMed Valley Discoveries, Inc., or their designee CPWW, is responsible for submitting 
reports of AEs associated with the use of the drug that are serious, unexpected and to have at 
least a reasonable possibility of having been caused by the drug, to FDA according to 
21 CFR 312.32 and current guidance.  All investigators participating in ongoing clinical 
studies with the study medication will receive copies of these reports for prompt submission 
to their Institutional Review Board (IRB) or Ethics committee (EC). 
9.8.1 
Overdose 
No information on treatment of overdose of BVD-523 is currently available. 
9.8.2 
Pregnancies  
Pregnancy per se is not considered an AE unless there is cause to believe that the 
investigational drug may have interfered with the effectiveness of a contraceptive 


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medication.  Hospitalization for normal delivery of a healthy newborn should not be 
considered a SAE.   
Each pregnancy in a patient or partner of a patient on BVD-523 must be reported to the 
Sponsor within 24 hours of learning of its occurrence.  If a patient becomes pregnant, study 
drug administration must be discontinued immediately.  The pregnancy should be followed 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.  Follow-up and documentation must occur even if the patient 
withdraws from the study or the study is completed. 
The avoidance of pregnancy or fathering a child is suggested for 3 months following the 
discontinuation of BVD-523 therapy.  No information is currently available regarding the 
effects of BVD-523 on fertility, gestation or subsequent child development.  


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10 STATISTICAL METHODS 
10.1 
GENERAL CONSIDERATIONS 
10.1.1 
Statistical and Analytical Plans 
A formal detailed statistical analysis plan (SAP) will be created prior to the review of any 
data. 
The purpose of this Phase 1 dose escalation study is to determine the maximum tolerated 
dose (MTD), the dose limiting toxicity (DLT), and the recommended Phase 2 dose (RP2D) 
of orally administered BVD-523.  Groups of 1−6 patients will be treated at each dose level 
until the maximum tolerated dose is reached.  All patients meeting the eligibility criteria and 
receiving at least 1 dose of BVD-523 will be evaluable for safety. 
10.1.2 
Determination of Sample Size 
The sample size for Part 1 of this study was determined by clinical rather than statistical 
considerations.  Approximately 40 patients will be treated in Part 1 of this study (Dose 
Escalation Phase) to establish dose limiting toxicities (DLT), maximum tolerated dose 
(MTD), and the recommended Phase 2 dose (RP2D). 
The purpose of Part 2 of this first in human research is to document that there is some 
evidence of a response.  Upon completion of Part 1 of this study, up to approximately 105 
evaluable patients with certain cancer types and/or characterized genetic alterations and/or 
MAPK pathway activation will be treated with the RP2D (which may be the same or lower 
than the MTD).  The observation of DLTs in more than 33% of patients in any Part 2 cohort 
with at least 6 patients enrolled at any time during Part 2 will trigger temporary stopping of 
patient enrollment and revision of the definition of the MTD and RP2D in the specific cohort.  
Subsequent patients will be treated with a dose lower than the initial RP2D and this dose will 
be determined in discussion with the Clinical Investigators, the Medical Monitor, and the 
Sponsor. 
Enrollment of up to 15 evaluable patients in all cohorts provides an 80% probability of 
seeing at least one positive response if the true response rate is at least 10%.  Allowing for a 
low response rate in these patient cohorts is appropriate based on unmet medical need.    
Up to 15 study centers are expected to enroll patients for this study. 
10.1.3 
Blinding and Randomization 
This clinical study is open-label, and all patients enrolled will be treated with BVD-523. 


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10.2 
ANALYSIS DATASETS 
10.2.1 
Population to be Analyzed 
The safety population will consist of all patients receiving at least 1 dose of study 
medication. 
10.2.2 
Modified Intent-to-treat 
The modified intent-to-treat (mITT) population will consist of all patients who have a 
screening visit/sign the informed consent. 
10.2.3 
Per Protocol 
The per-protocol (PP) population will consist of all patients of the mITT population who 
completed the 1st protocol-specified tumor measurement evaluation (except for study drug-
related AE) without major protocol violations. 
10.2.4 
Definition of Study Days 
In each treatment cycle, a total of 5 visits are planned for Part 1 of this clinical study.  
Patients in Part 2 of the study will receive a total of up to 5 visits per treatment Cycle.  The 
study visits are defined in Table 10.1 and summarized in Table 6.1. 
Table 10.1. 
Per Cycle Study Visit Definitions 
Visit Description 
Study Day 
Visit 1: Screening* 
Day -14 to -1 
Visit 2: Baseline / Randomization / Drug Dispensing / Initiation of Treatment 
Day 1 ± 0 
Visit 3: Treatment Phase 
Day 8 ± 1 
Visit 4: Treatment Phase 
Day 15 ± 1 
Visit 5: Final Visit 
Day 22 ± 1 
*Note: informed consent may be obtained up to -28 days to allow flexibility in scheduling of the screening 
procedures. 
10.3 
DATA PRESENTATION 
10.3.1 
Demographic 
Demographic characteristics of patients will be summarized in appropriate tables and 
analyzed with descriptive statistics. 
The following characteristics will be summarized in the mITT, PP, and safety population: 
• Age 
• Gender 
• Race 


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• Ethnicity 
• Tumor type 
• Tumor mutation status  
10.3.2 
Baseline Characteristics 
Baseline characteristics will be summarized in appropriate tables and with descriptive 
statistics. 
The following characteristics will be summarized in the mITT, PP, and safety population:  
• Body weight 
• Height 
• ECOG performance status 
• Previous chemotherapy 
• Previous immunotherapy 
 
10.3.3 
Medical History and Physical Examination 
Descriptive statistics will be generated to summarize data.  For continuous variables, 
descriptive statistics may include the number of patients, mean, standard deviation, median, 
minimum, maximum; frequencies and percentages may be displayed for categorical data. 
10.3.4 
Concomitant Medications or Treatments 
The number and percentage of patients taking concomitant medication will be summarized.  
All data will be recorded as follows: 
• Prior use ended before first day of trial medication 
• Concomitant use on or after first day of trial medication (initiation date, stop date) 
 
10.3.5 
Primary Endpoint 
MTD 
Please see Section 3.1.4.1 for the determination of MTD. 
RP2D 
Please see Section 3.1.4.3 for the determination of RP2D. 


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10.3.6 
Secondary Endpoints 
Anti-tumor Activity as Evaluated Using RECIST Criteria 
Disease response will be summarized in tabular format showing the number and percent of 
patients in each dose level. 
No formal efficacy analysis will be conducted. 
10.3.7 
Pharmacokinetic Data 
Blood and Urine BVD-523 and Selected Metabolite Concentration Levels 
Systemic BVD-523 exposure as measured in blood and urine samples will be summarized 
per time point by means of descriptive statistics.  Measured concentrations will be presented 
by a by-patient listing, sorted by site, patient identifier and dose. 
10.3.8 
Safety Data 
All safety summaries will be provided for the Safety population. 
Summaries for safety variables (physical examinations, vital signs, clinical laboratory 
analyses) will be given.  All safety variables will be presented in by-patient listings, sorted by 
site and patient identifier. 
10.3.9 
Adverse Events (AE) 
Adverse events will be coded using the MedDRA coding dictionary.  A listing of all events, 
with seriousness, severity, relationship, sequelae and begin and end times will be provided.  
Narratives for any serious adverse events will be provided.  
Deaths, serious adverse events (SAEs), and AEs leading to discontinuation of trial 
medication will be summarized by primary system organ class (SOC) and preferred terms.  
Listings will be provided. 
10.4 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the Sponsor, the IRB/IEC and the Health Authorities. 


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11 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
11.1 
DECLARATION OF HELSINKI 
The Investigator will ensure that this Study is conducted in accordance with the most recent 
revision of the Declaration of Helsinki.  
11.2 
GOOD CLINICAL PRACTICE 
The Study will be conducted according to the study protocol and to Standard Operating 
Procedures (SOPs) that meet the guidelines provided by the International Conference on 
Harmonization (ICH) for Good Clinical Practice in clinical studies.  
11.3 
INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES 
Before implementing this study, the protocol, the proposed patient informed consent forms 
and other information for the patients, must be reviewed by a properly constituted committee 
or committees responsible for approving clinical studies.  The IRB/IEC written, signed 
approval letter/form must contain approval of the designated investigator, the protocol 
(identifying protocol title, date and version number), and of the patient informed consent 
form (date, version).  
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the Sponsor, the IRB/IEC and the Health Authorities. 
11.4 
REGULATORY AUTHORITY APPROVAL 
Before implementing this study, the protocol must be approved by the relevant regulatory 
authority. 
11.5 
PRE-STUDY DOCUMENTATION REQUIREMENTS 
To be provided. 
11.6 
INFORMED CONSENT 
The investigator must fully inform the patient of all pertinent aspects of the trial including the 
written information approved/favorably assessed by the IRB/IEC. 
Prior to the start of the pre-study examination, the written informed consent form must be 
signed and personally dated by the patient and by the physician who conducted the informed 
consent discussion.  One copy of the written information and signed consent form must be 
given to each patient and 1 copy must be retained in the investigator's study records. 
Additionally, consent will be requested to obtain/retain a blood sample for future analysis as 
warranted by our rapidly-advancing understanding in this field.  Each patient’s Informed 
Consent document will reflect that samples collected may be used for pharmacogenomic 
investigations. 


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11.7 
PATIENT CONFIDENTIALITY AND DISCLOSURE 
Data on patients collected on eCRFs during the trial will be documented in an anonymous 
fashion and the patient will only be identified by the patient number, and by his/her initials if 
also required.  If, as an exception, it is necessary for safety or regulatory reasons to identify 
the patient, all parties are bound to keep this information confidential. 
The investigator will guarantee that all persons involved will respect the confidentiality of 
any information concerning the trial patients.  All parties involved in the study will maintain 
strict confidentiality to assure that neither the person nor the family privacy of a patient 
participating in the trial is violated.  Likewise, the appropriate measures shall be taken to 
prevent access of non-authorized persons to the trial data.   
11.8 
COLLECTION, MONITORING AND AUDITING OF STUDY 
DOCUMENTATION, AND DATA STORAGE 
Collection of Data and Monitoring Procedures 
This study will use a 21 CFR Part 11 compliant electronic data capture system (TEMPOTM) 
An electronic case report form (eCRF) is used for data recording  All data requested on the 
eCRF must be entered and all missing data must be accounted for.   
The data will be checked for completeness and correctness as it is entered by the real-time 
online checks applied by TEMPOTM.  Off-line checks will also be run to perform any 
additional data review required.  Discrepancy reports will be generated accordingly and 
transferred to the study center for resolution by the investigator or his/her designee. 
Accurate and reliable data collection will be assured by verification and cross–check of the 
eCRF against the investigator’s records by the study monitor (source document verification), 
and the maintenance of a study drug–dispensing log by the investigator. 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Sponsor 
representative will review the protocol and case report forms with the investigators and their 
staff.  During the study a monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the case report forms, the adherence to the protocol 
and to Good Clinical Practice, the progress of enrollment.  The monitor will ensure during 
on-site visits that study medication is being stored, dispensed and accounted for according to 
specifications.  Key trial personnel must be available to assist the monitors during these 
visits. 
The investigator must give the monitor access to relevant hospital or clinical records, to 
confirm their consistency with the case report form entries.  No information in these records 
about the identity of the patients will leave the study center.  Monitoring standards require 
full verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs and the recording of primary efficacy and safety variables.  
Additional checks of the consistency of the source data with the eCRFs are performed 
according to the study-specific monitoring plan. 


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Auditing Procedure 
In addition to the routine monitoring procedures the Sponsor or the regulatory authority can 
conduct an audit or an inspection (during the study or after its completion) to evaluate 
compliance with the protocol and the principles of Good Clinical Practice.   
The investigator agrees that representatives of the Sponsor and Regulatory Authorities will 
have direct access, both during and after the course of this study, to audit and review all 
study-relevant medical records. 
Retention of Documents 
The investigator must maintain source documents for each patient in the study, consisting of 
all demographic and medical information, including laboratory data, electrocardiograms, etc., 
and keep a copy of the signed informed consent form.  All information on case report forms 
must be traceable to these source documents in the patient's file.  Data without a written or 
electronic record will be defined before trial start and will be recorded directly on the case 
report forms, which will be documented as being the source data.  
11.9 
DISCLOSURE OF INFORMATION 
All information provided to the investigator by BioMed Valley Discoveries, Inc., or their 
designee, will be kept strictly confidential.  No disclosure shall be made except in accordance 
with a right of publication granted to the investigator. 
No information about this study or its progress will be provided to anyone not involved in the 
study other than to BioMed Valley Discoveries, Inc., or its authorized representatives, or in 
confidence to the IRB, or similar committee, except if required by law. 
11.10 DISCONTINUATION OF THE STUDY 
It is agreed that, for reasonable cause, either the investigator or BioMed Valley Discoveries, 
Inc., may terminate the investigator’s participation in this study after submission of a written 
notice.  BioMed Valley Discoveries, Inc. may terminate the study at any time upon 
immediate notice for any reason, including the Sponsor’s belief that discontinuation of the 
study is necessary for the safety of patients. 
11.11 STUDY REPORT, PUBLICATION POLICY AND ARCHIVING OF 
STUDY DOCUMENTATION 
11.11.1 
Study Report and Publication Policy 
An ICH-compliant integrated clinical and statistical report will be prepared upon completion 
of the study and data analysis.  The results of the study will be published in a relevant peer-
reviewed journal, with authorship status and ranking designated according to the 
acknowledged contributions of participating investigators, institutions and the Sponsor.  


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11.11.2 
Study Documents 
The investigator must maintain source documents for each patient in the study, consisting of 
all demographic and medical information, including laboratory data, electrocardiograms, etc., 
and keep a copy of the signed informed consent form.  All information on the e-case report 
forms must be traceable to these source documents in the patient's file.  Data without a 
written or electronic record will be defined before trial start and will be recorded directly on 
the e-case report forms, which will be documented as being the source data. 
11.11.3 
Archiving of Documents 
Essential documents, as listed below, must be retained by the investigator for as long as 
needed to comply with national and international regulations.  The Sponsor will notify the 
investigator(s)/institution(s) when the study-related records are no longer required.  The 
investigator agrees to adhere to the document retention procedures by signing the protocol.  
Essential documents include: 
1. IRB/IEC/REB approvals for the study protocol and all amendments 
2. All source documents and laboratory records 
3. CRF copies (electronic copies on a CDROM) 
4. Patients' informed consent forms (with study number and title of trial) 
5. FDA form 1572 
6. Any other pertinent study document 
 


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36. Sebolt-Leopold JS (a). Herrera R. Targeting the mitogen-activated protein kinase cascade 
to treat cancer. Nat Rev Cancer. 2004;(12):937−47. 
37. Sebolt-Leopold JS (b). MEK inhibitors: a therapeutic approach to targeting the Ras-MAP 
kinase pathway in tumors. Curr Pharm Des. 2004;10(16):1907−14. 
38. Senderowicz AM. Information needed to conduct first-in-human oncology trials in the 
United States: a view from a former FDA medical reviewer. Clin Canc Res. 2010;16: 
1719–25. 
39. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies 
(V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat 
Commun. 2012;3:724. 
40. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, et al. Acquired resistance and 
clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 
2014;4:80–93. 
41. Smalley KS. A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? 
Int J Cancer. 2003;104(5):527−32. 
42. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced 
melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707−14. 
43. Tse KF, Mukherjee G, Small D. Constitutive activation of FLT3 stimulates multiple 
intracellular signal transducers and results in transformation. Leukemia. 
2000;(10):1766−76. 


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Clinical Study Protocol: BVD-523-01 
 
 
 
 
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44. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, et al. Dissecting 
therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin 
Oncol. 2011;29:3085–96. 
45. Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, et al. 
MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired 
resistance to combined RAF/MEK inhibition. Cancer Discov. 2014;4:61–8. 
46. Wan PT, Garnett MJ, Roe SM, , et al. Mechanism of activation of the RAF-ERK 
signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855−67. 
47. Xu X, Quiros RM, Gattuso P,et al. High prevalence of BRAF gene mutation in papillary 
thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 2003;63(15):4561−7. 
 
 


BVD-523 
 
BioMed Valley Discoveries, Inc. 
Clinical Study Protocol: BVD-523-01 
 
 
 
 
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APPENDIX 1 
NON-PERMITTED CONCOMITANT MEDICATIONS 
INHIBITORS 
INHIBITORS 
INHIBITORS 
3A 
2D6 
1A2 
indinavir 
bupropion 
fluvoxamine 
nelfinavir 
fluoxetine 
ciprofloxacin 
ritonavir 
paroxetine 
enoxacin 
mibedfradil1 
quinidine 
 
clarithromycin 
 
 
itraconazole 
 
 
ketoconazole 
 
 
voriconazole 
 
 
nefazodone 
 
 
saquinavir 
 
 
telithromycin 
 
 
boceprevir 
 
 
conivaptan 
 
 
posaconazole 
 
 
telaprevir 
 
 
lopinavir/ritonavir 
 
 
Grapefruit juice2  
 
 
INDUCERS 
3A 
carbamazepine 
phenytoin 
rifampin 
Avasimibe3 
St. John’s Wort4 
1. Withdrawn from the United States marker because of safety reasons 
2. The effect of grapefruit juices varies widely among brands and is concentration-, dose-, and preparation- 
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low does, single strength).  
3. Not a marketed drug 
4. The effect of St John’s wort varies widely and is preparation-dependent. 
 
Strong Inhibitors: ≥ 5-fold increase in AUC or > 80% decrease in CL 
Strong Inducers: ≥ 80% decrease in AUC 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
abeling/ucm093664.htm#classInhibit    Accessed 4-5-16    Table dated 10-27-14 

SAP_001.pdf: 
 
 
 
DOCUMENT: 
Statistical Analysis Plan  
PROTOCOL NUMBER: BVD-523-01 
 
PHASE 1 DOSE-ESCALATION, SAFETY, 
PHARMACOKINETIC AND PHARMACODYNAMIC 
STUDY OF BVD-523 IN PATIENTS WITH ADVANCED 
MALIGNANCIES 
SAP VERSION: 
Final 
SAP DATE: 
23 June 2017 
PROTOCOL DATE: 
Original:            3 December 2012 
Amendment 1: 16 January 2013 
Amendment 2: 26 March 2013 
Amendment 3: 16 August 2013 
Amendment 4: 18 June 2014 
Amendment 5: 27 May 2015 
Amendment 6: 1 February 2016 
Amendment 7: 11 April 2016 
SPONSOR: 
BioMed Valley Discoveries, Inc. 
4520 Main St. 16th Floor 
Kansas City, Mo 64111 
PREPARED BY: 
Clinipace Worldwide 
AUTHOR(S): 
Scott W. Miller, PhD 
Director, US Biostatistics 
Clinipace Worldwide 
 
 
 
 




Statistical Analysis Plan 
 
BioMed Valley Discoveries, Inc. 
BVD-523-01 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION .......................................................................................................6 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS .................................6 
2.1 
Study Objectives ................................................................................................6 
2.1.1 
Primary Objectives ...................................................................................6 
2.1.2 
Secondary Objectives ...............................................................................7 
2.1.3 
Exploratory Objectives ............................................................................7 
2.2 
Treatment Groups ..............................................................................................7 
2.3 
Study Endpoints .................................................................................................7 
2.3.1 
Primary Endpoints ...................................................................................7 
2.3.2 
Secondary Endpoints ...............................................................................7 
2.3.3 
Exploratory Endpoints .............................................................................8 
3 
STUDY DESIGN.........................................................................................................8 
3.1 
Overall Study Design .........................................................................................8 
3.2 
Schedule of Study Assessments .......................................................................11 
4 
SAMPLE SIZE CONSIDERATIONS .......................................................................14 
5 
ANALYSIS POPULATIONS ...................................................................................14 
5.1 
Safety ...............................................................................................................14 
5.2 
Modified Intent-to-Treat ..................................................................................14 
5.3 
Per-Protocol .....................................................................................................14 
5.4 
Pharmacokinetic ...............................................................................................14 
5.5 
Pharmacodynamic ............................................................................................15 
6 
CONSIDERATIONS FOR DATA ANALYSIS .......................................................15 
6.1 
Programming Environment ..............................................................................15 
6.2 
Strata and Covariates .......................................................................................15 
6.3 
Subgroups ........................................................................................................15 
6.4 
Multiple Comparisons and Multiplicity ...........................................................15 
6.5 
Significance Level ...........................................................................................15 
6.6 
Statistical Notation and Methodology .............................................................15 
7 
DATA HANDLING METHODS ..............................................................................16 
7.1 
Missing Data ....................................................................................................16 
7.1.1 
Date Values ............................................................................................16 
7.1.2 
Non-Date Values ....................................................................................16 
7.2 
Visit Windows .................................................................................................16 
7.3 
Data Derivations and Definitions.....................................................................16 


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8 
STUDY POPULATION ............................................................................................18 
8.1 
Subject Disposition ..........................................................................................18 
8.2 
Demographic Characteristics ...........................................................................18 
8.3 
Prior and Concomitant Medications ................................................................19 
8.4 
Medical History ...............................................................................................19 
8.4.1 
Previous Chemotherapy .........................................................................19 
8.4.2 
Previous Immunotherapy .......................................................................19 
8.5 
On Study Procedures........................................................................................20 
8.6 
Inclusion/Exclusion Criteria ............................................................................20 
8.7 
Treatment Compliance .....................................................................................20 
8.8 
Protocol Deviations ..........................................................................................20 
9 
EFFICACY ANALYSIS ...........................................................................................21 
10  SAFETY ....................................................................................................................21 
10.1 
Exposure to Study Drug ...................................................................................22 
10.2 
Adverse Events ................................................................................................22 
10.3 
Serious Adverse Events and Death ..................................................................24 
10.4 
Laboratory Evaluations ....................................................................................24 
10.5 
Vital Signs ........................................................................................................25 
10.6 
Electrocardiograms and Holter Monitoring .....................................................25 
10.7 
Ophthalmology Examinations .........................................................................25 
10.8 
Physical Examinations .....................................................................................26 
11  ADDITIONAL ANALYSES .....................................................................................26 
11.1 
Pharmacokinetic Analyses ...............................................................................26 
11.2 
Pharmacodynamics Analyses ...........................................................................27 
11.3 
Tumor Genotyping ...........................................................................................27 
12  INTERIM ANALYSIS ..............................................................................................28 
13  END-OF-STUDY-ANALYSIS .................................................................................28 
14  TABLE OF CONTENTS FOR DATA DISPLAYS ..................................................28 
15  REVISIONS TO SAP ................................................................................................37 
16  REFERENCES ..........................................................................................................38 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
CR 
Complete Response  
eCRF 
electronic Case Report Forms 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicities 
ECG 
Electrocardiograms  
ECOG 
Eastern Cooperative Oncology Group 
ITT 
Intent-to-Treat 
Min 
Minimum 
MITT 
Max 
Modified Intent-to-Treat 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities  
MTD 
Maximum Tolerated Dose 
NCI  
National Cancer Institute  
NE 
Not Evaluable 
PD 
Progressive Disease 
PE 
Physical Examination 
PK 
Pharmacokinetics  
PR 
Partial Response  
PP 
Per-Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
STD 
Standard Deviation 
SMC 
Safety Monitoring Committee  
TEAE 
Treatment Emergent Adverse Event 
VS 
Vital Signs 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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BioMed Valley Discoveries, Inc. 
BVD-523-01 
 
23JUN2017 
 
 
 
 
 
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1 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the 
summary and analysis of data from Protocol BVD-523-01.  Background information is 
provided for the overall study design and objectives.  The reader is referred to the study 
protocol and electronic case report forms (eCRFs) for details of study conduct and data 
collection. 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS 
2.1 
STUDY OBJECTIVES 
2.1.1 
Primary Objectives 
To define the safety and tolerability of BVD-523 in patients with advanced malignancies by 
determining the dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the 
recommended Phase 2 Dose (RP2D). 
 
A DLT is defined (per definition in protocol amendment 7)1 as a BVD-523 related toxicity 
in the first 21 days of treatment that results in: 
• ≥ Grade 4 hematologic toxicity for > 1 day; 
• Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding; 
• ≥ Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, 
pain, and rash (these become DLTs if the adverse event (AE) persists despite adequate 
treatment), a doubling of AST/ALT in patients with grade 2 ALT/AST at baseline; 
• A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, 
despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for > 7 days) due to 
BVD-523-related toxicity. 
 
                                                 
1 The original protocol, as well as amendments 1, 2, 3, and 4 defined DLTs slightly differently. In these 
amendments, a DLT was defined as above except for the following: 
 
≥ Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain, and rash 
(these become DLTs if the adverse event (AE) persists despite adequate treatment) 
 
“A doubling of AST/ALT in patients with grade 2 ALT/AST at baseline” was introduced in 
Amendment 5 
Treatment interruption DLTs were also defined slightly differently in different protocols: 
• For the original protocol and Amendments 1 & 2: A treatment interruption exceeding 3 days in Cycle 1 
due to drug-related toxicity (or inability to begin Cycle 2 for > 7 days) due to drug-related toxicity. 
• For Amendment 3: A treatment interruption exceeding 5 days in Cycle 1 due to drug-related toxicity 
(or inability to begin Cycle 2 for > 7 days due to drug-related AE) 
• For Amendment 4, 5, 6 & 7: A treatment interruption exceeding 5 days (or an interruption exceeding 7 
days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for > 7 days) due to 
BVD-523-related toxicity. 
 


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The MTD is defined as the highest dose cohort at which ≤33% of patients experience BVD-
523 related DLTs in the first 21 days of treatment. 
2.1.2 
Secondary Objectives 
Secondary objectives of this study are:  
• To determine the pharmacokinetic profile of BVD-523 and selected metabolites in 
patients with advanced malignancies 
• To investigate any preliminary clinical effects on tumor response assessed by physical or 
radiological exam (RECIST 1.1) 
2.1.3 
Exploratory Objectives 
• To evaluate pharmacodynamic marker (biomarker) measures 
• To investigate any preliminary clinical effects on tumor response assessed by FDG-PET 
radiological exam. 
According to the Note to File signed (11/02/2015), FDG-PET is no longer collected. At 
Amendment 7, the language was officially removed from the protocol.  
2.2 
TREATMENT GROUPS 
Treatment groups of the study consist of various dose level cohorts (starting at 10 mg twice 
daily (bid) for 21 days (a “Cycle”)) used in the dose-escalation phase of the study and the 
group number (Group 1 - Group 7 as specified in Section Error! Reference source not 
found.) used in the cohort expansion phase of the study and dosed at the RP2D. 
2.3 
STUDY ENDPOINTS 
2.3.1 
Primary Endpoints 
Safety 
• Evaluation of the DLTs of BVD-523 
• Determination of MTD of BVD-523 
• Determination of RP2D of BVD-523 
• Evaluation of treatment-related AEs of BVD-523 
2.3.2 
Secondary Endpoints 
Pharmacokinetics 
• Evaluation of pharmacokinetic parameters of BVD-523 and selected metabolites in 
patients with advanced malignancies 
Efficacy 
• Preliminary clinical effects on tumor response assessed by physical or radiological exam 
(RECIST [Response Evaluation Criteria In Solid Tumors] version 1.1) 


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2.3.3 
Exploratory Endpoints 
Pharmacodynamics: Evaluation of multiple biomarkers to characterize response to drug 
(pRSK, pERK, Ki67, Caspase-3, and circulating tumor DNA). Additional biomarkers may be 
identified during the study and measured as appropriate.  Tumor genotyping by DNA 
analysis will be performed to identify somatic alterations, relying on either available archived 
tissue or freshly-collected samples. 
 
3 
STUDY DESIGN 
3.1 
OVERALL STUDY DESIGN 
This is an open-label, multi-center Phase 1 study to assess the safety, pharmacokinetics, and 
pharmacodynamics of escalating doses of BVD-523 in patients with advanced malignancies. 
It will be conducted at up to 15 sites. This clinical study comprises 2 parts: Part 1: Dose-
escalation Phase and Part 2: Cohort Expansion Phase.   
 
Part 1: Dose-escalation Phase, An accelerated dose escalation plan will be used to establish 
DLT, MTD, and the RP2D. One to 6 patients per treatment cohort will be assigned to receive 
sequentially higher oral doses of BVD-523 on a twice daily schedule (b.i.d.) for 21 days (a 
“Cycle”), starting at a dose of 10 mg twice daily. Patients will receive twice-daily oral doses 
of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation 
satisfying another withdrawal criterion is noted. Treatment cycles will occur consecutively 
without interruption, except when necessary to manage toxicities. Up to 40 patients will be 
enrolled in Part 1.  Patients with advanced-stage solid tumors only (no hematological 
malignancies) will be enrolled in the dose-escalation phase of the study.  The study will 
initially be conducted as an accelerated single patient cohorts design, followed by a standard 
3 + 3 design, informed by the accrued safety experience throughout the study (see Table 1 
below). All dose-escalation decisions will be based on Cycle 1 safety data.  Patients who 
withdraw at any time preceding the last visit of Cycle 1 (Day 22) will constitute an early 
discontinuation and must be replaced in order to ensure proper data accrual for dose 
escalation decisions.  A patient who experiences a DLT in Course 1 and withdraws before 
Day 22 either because of the toxicity or otherwise, will nonetheless have that DLT counted in 
the assessment of potential cohort expansion and/or dose escalation.  Doses will not be 
escalated unless the patient(s) receiving the highest current dose has been observed for at 
least 3 weeks.  No intra-patient dose escalation was permitted under the original protocol or 
the first two amendments.  Starting under amendment three, intra-patient dose escalations 
were allowed; see protocol for details.     
 
Once the RP2D is defined, intra-patient dose escalation to the R2PD will be allowed after a 
patient has completed at least 1 cycle at their assigned dose and only if the patient has 
experienced no toxicity above Grade 1, upon request by the PI and discussion with the 
Medical Monitor and the Sponsor. 
 


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Table 1: 
Summary of Dose Escalation  
Single Patient Cohorts 
Observed Safety Outcomes 
Action 
AEs ≤ Gr 1 
 Continue testing with single patient cohorts 
 Escalate by 100% to next dose level  
One AE ≥ Gr 2 (excluding alopecia or 
diarrhea) 
 Expand current and subsequent cohorts to ≥ 3 patients 
 Escalate by ≤ 50% to next dose level 
1 DLT  
 Expand cohort up to 6 patients 
 
Standard Escalation Cohorts (36 patients) 
Observed Safety Outcomes 
Action 
No DLTs 
 Escalate by ≤ 50% to next dose level 
1 DLT in 3 patients 
 Expand cohort up to 6 patients 
1 DLT in 6 patients 
 Escalate by ≤ 50% to next dose level 
> 1 DLT in ≤ 6 patients 
 Stop dose escalation 
 
When more than 1 DLT occurs in ≤ 6 patients in a dosing cohort, dose escalation will be 
stopped and this dose level will be identified as a non-tolerated dose.  Doses between the 
non-tolerated dose and the preceding lower dose, where ≤ 1 DLT occurred, may be explored 
to define the MTD.  
 
In Part 2 – Cohort-expansion Phase, an additional (approximately 105) patients with 
particular tumor types and/or cancers harboring specific genetic mutations (as specified in 
patient groups 1-7 below) will be recruited for treatment at the RP2D.  Patients must have 
measurable disease by RECIST 1.1. Patients will receive twice daily oral doses of BVD-523 in 
21-day treatment cycles until disease progression, unacceptable toxicity, or another withdrawal 
criterion is met. Treatment cycles will occur consecutively without interruption except when 
necessary to manage toxicities. Intra-patient dose modifications are allowed, including dose 
reductions/interruptions as needed and re-escalations up to and including RP2D, at Clinical 
Investigator’s discretion. 
 Group 1: Patients with BRAF mutated cancer, except those with colorectal or non-
small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors; 
n≤15 
• Group 2: Patients with BRAF mutated colorectal cancer, not previously treated with 
BRAF and/or MEK inhibitors; n≤15 
• Group 3: Patients with BRAF mutated melanoma who have progressed or are 
refractory to BRAF and/or MEK inhibitors; n≤15 
• Group 4: Patients with NRAS mutated melanoma; not previously treated with BRAF 
and/or MEK inhibitors; n≤15 
• Group 5: Patients with MEK mutated cancer, not previously treated with BRAF 
and/or MEK inhibitors; n≤15 


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• Group 6: Patients with BRAF mutated non-small cell lung cancer, not previously 
treated with BRAF and/or MEK inhibitors; n≤15 
• Group 7: Patients with ERK mutated cancer, not previously treated with BRAF 
and/or MEK inhibitors; n < 15  
 
It is agreed that for reasonable cause, either the investigator or the Sponsor may terminate 
this study, provided a written notice is submitted at a reasonable time in advance of intended 
termination; if by the investigator notice is to be submitted to BioMed Valley Discoveries, 
Inc., and if by the Sponsor, notice will be provided to each investigator.  
If a severe local reaction or drug-related serious adverse event (SAE) occurs at any time 
during the study, the Safety Monitoring Committee (SMC) will review the case immediately.  
The study will be immediately suspended and no additional BVD-523 doses administered 
pending review and discussion of all appropriate study data by the SMC if 1 or more patients 
at any dose level develop any of the following adverse events deemed to be possibly, 
probably, or definitely related to BVD-523 by the Investigator and/or Medical Monitor, based 
upon close temporal relationship or other factors: 
• Death; 
• Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia, or 
respiratory distress). 
 
The study will not be restarted until all parties have agreed to the course of action to be taken 
and the IRB/EC has been notified. 
 
 
 
 


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3.2 
SCHEDULE OF STUDY ASSESSMENTS 
Table 3.1. 
Table of Study Assessments 
The schedule of study assessments and procedures for patients in both Part I and Part II of the study is shown below: 


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23JUN2017 
 
 
 
 
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Cycle 1 
Day 1 through 21 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21 day cycles, visit 
on 1st day of cycle 
 
Visit  
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 -X 
Tx 
Final Study Visit/ 
Early 
Discontinuation 
Visit Day 
-14 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1  
29 ± 1 
36 ± 1 
43 ± 1 
 
Informed  consent* 
X 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history1 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
 
 
 
Measure height (cm) 
X 
 
 
 
 
 
 
 
 
Measure weight (kg) 
X 
X 
 
 
X 
 
 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmology exam2 
X 
 
 
 
 
 
 
 
X 
Pregnancy test3,4 
X 
X3 
 
 
X4 
 
 
X4 
X4 
Study drug dispensed 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug administration5 
 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic samples6,7 
 
X7 
 
X6 
X6 
 
 
 
 
Pharmacodynamic samples6,7,8 
 
X7 
 
X6 
 
 
 
 
 
Tumor measurements9 
X 
 
 
 
 
 
 
X 
X 
Clinical lab tests10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG)11 
X 
 
X 
 
 
 
 
 
 
Holter monitoring12 
 
X 
 
X 
 
 
 
 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance by pill count 
 
 
X 
X 
X 
X 
X 
X 
X 
Obtain unused drug 
 
 
X 
X 
X 
X 
X 
X 
X 
ECHO cardiogram or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 


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Table footnotes:  
*Note: informed consent may be obtained up to -28 days to allow flexibility in scheduling of the screening procedures.  
1 Full medical history at screening, review/update of history only at subsequent visits.  
2 Ophthalmological examinations will be performed by an ophthalmologist at screening, at End of Treatment and if clinically indicated.  
3 ONLY if the screening serum pregnancy test was performed more than 1 day previously.  
4 After screening and baseline, urine pregnancy test which if positive, confirm with serum test.  
5 Study drug to be taken twice daily, first dose in clinic on days when PK sampling occurs i.e. Cycle 1 on Visit 2 (Day 1), Visit 4 (Day 15) and morning dose of 
Cycle 2 on Visit 5, remaining doses on all other days to be self-administered by patient.  
6 In Part 1PK and pharmacodynamic blood samples plus PK urine samples will be taken concurrently on Day 1 and Day 15 along with QTc extractions from the 
Holter monitoring. PK blood samples will be collected prior to first dose and at 0.5 hours, 1 hour (both ± 5 minutes), 2 hours, 4 hours, 6 hours, 8 hours (all ± 10 
minutes), and 12 hours (± 2 hours) post first dose. Blood samples for pharmacodynamic assessment will be collected pre-dose and 4 hours post–dose (±10 minutes). 
PK urine samples will be collected prior to first dose and for the 1–6-hour and 6–12 ± 2-hour time periods post first dose on Day 1 and Day 15. On Day 22, PK 
and pharmacodynamic samples will be collected prior to the first dose of that day. In Part 2, urine PK will not be performed and blood PK, blood pharmacodynamic, 
and Holter monitoring will be performed until the sponsor determines they will be discontinued based on accumulated patient experience.  
7 PK and pharmacodynamic blood and urine samples are required, and paired tumor tissue and blood samples are to be obtained at baseline where feasible. Tumor 
genotyping by DNA analysis may be performed to identify somatic alteration. Additional tissue or plasma DNA samples for analysis may also be obtained from 
selected patients prior to first dose, at steady-state during treatment and/or after disease progression.  
8 In Part 2, pharmacodynamic samples only need to be taken if the patient has consented to the optional research tests involving collection of tumor tissue. 
9 Tumor assessments will be made by CT/MRI/Physical Exam prior to dose initiation if the patient does not have a recent CT/MRI/Physical Exam on record within 
28 days before start of treatment (Visit 2), at the 1st protocol-specified tumor measurement evaluation at the end of Cycle 2 and then every 2-3 cycles, and at End 
of Treatment if the previous CT/MRI/Physical Exam was conducted 21 or more days earlier. The same imaging modality used for an individual patient (i.e., CT 
or MRI) at Screening should be maintained throughout the study.  
10 Chemistry (to include calcium and inorganic phosphorus), hematology and urinalysis. After Cycle 2, clinical chemistry (to include calcium and inorganic 
phosphorus), hematology and urinalysis may be performed once per cycle or more frequently at the investigator’s discretion.  
11 Patients with a normal ECG in Cycle 1 need not have repeat ECGs in subsequent cycles.  
12 Holter monitoring for 12±2 hours during PK sampling.  
 
 


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4 
SAMPLE SIZE CONSIDERATIONS 
For this Phase 1 dose escalation study, no formal sample size calculations have been 
performed; the sample size reflects practical considerations.  
Approximately 40 patients will be treated in Part 1 of this study (dose-escalation phase) to 
establish DLT, MTD, and the RP2D. 
After the completion of Part 1 of this study, up to 105 additional patients with certain cancer 
types and/or characterized genetic alterations and/or MAPK pathway activation will be 
treated with the RP2D (which may be the same or lower than the MTD) to determine if 
BVD-523 is effective as a single agent therapy.  The purpose of the second phase of this first 
in human research is to merely document that there is some evidence of a response (complete 
response or partial response per RECIST v 1.1). 
5 
ANALYSIS POPULATIONS 
Five analysis populations will be used to analyze the study data.  Below are details of each 
analysis population: 
5.1 
SAFETY 
The Safety Population consists of all patients receiving at least one dose of study medication. 
This population will be used to summarize demographics and baseline characteristics, 
previous and concomitant medication/therapies, treatment exposure and all safety endpoints 
including AE, physical examination (PE), ophthalmology examination, clinical laboratory 
tests (chemistry, hematology, and urinalysis), serum/urine pregnancy test, ECG, Holter 
monitoring, and vital signs (VS).   
5.2 
MODIFIED INTENT-TO-TREAT 
The modified Intent-To-Treat (mITT) Population is defined as all patients receiving at least 
one dose of study medication.  Subject demographics, disposition, and analysis population 
summaries will be tabulated using the mITT population.  
5.3 
PER-PROTOCOL 
The Per Protocol population consists of all patients from the modified ITT Population who 
have completed the first protocol-specified tumor measurement evaluation (except for study 
drug-related AE) without major protocol violations.  All protocol deviations will be reported, 
but prior to generating TFLs for either Part 1 or Part 2, the list of protocol deviations will be 
reviewed and each classified as either major or minor.  This population will be used to 
summarize clinical effects on tumor response using RECIST version 1.1 criteria. Analyses 
based on the PP population will be exploratory. 
5.4 
PHARMACOKINETIC 
The Pharmacokinetic (PK) Population is comprised of all patients who receive at least 1 dose 
of study drug and have sufficient and valid PK samples to estimate PK parameters (Cmax,  tmax, 


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AUC0-12, AUC0-last, λz, t1/2 ) for Day 1 and/or Day 15.  In Part 2, urine PK samples were not 
collected so urine PK analyses will only be presented for Part 1 subjects.  
Pharmacokinetic summaries will be based on the PK population (refer to Section 11.1 of this 
SAP).  
5.5 
PHARMACODYNAMIC 
The Pharmacodynamics (PD) Population is defined as patients in the Safety Population who 
provide at least one pharmacodynamic measurement from fluid and/or tumor samples for Day 
1 or Day 15, relative to pre-treatment levels.  
All pharmacodynamics data will be analyzed based on the pharmacodynamics population.  
6 
CONSIDERATIONS FOR DATA ANALYSIS 
6.1 
PROGRAMMING ENVIRONMENT 
All analyses will be conducted using SAS® version 9.2 or higher. 
6.2 
STRATA AND COVARIATES 
Not applicable. 
6.3 
SUBGROUPS 
The only planned subgroup analyses are the seven patient subgroups from Part 2 (see Section 
3.1 of this SAP). 
6.4 
MULTIPLE COMPARISONS AND MULTIPLICITY 
There are no planned adjustments for multiplicity.  
6.5 
SIGNIFICANCE LEVEL 
Unless otherwise noted, all statistical analyses will be conducted using the significance level 
(α) of 0.05 and utilize two-sided testing.  However, no inferential testing is prospectively 
planned for the current study data. 
6.6 
STATISTICAL NOTATION AND METHODOLOGY 
Unless stated otherwise, the term “descriptive statistics” refers to the number of patients (n), 
mean, median, standard deviation (STD), minimum (Min), and maximum (Max) for 
continuous data and frequencies and percentages for categorical data.  Min and Max values 
will be presented using the precision of the original value, means and medians will be 
rounded to 1 decimal place greater than the precision of the original value, and STDs will be 
rounded to 2 decimal places greater than the precision of the original value.  Percentages will 
be rounded to the nearest whole number.  For percentage values that are less than 1% but 
greater than 0%, they will be presented as “< 1%”.  Similarly, “> 99%” will be used to 
display percentages that are greater than 99% but less than 100%.  P-values will be presented 
with 3 decimal places and values less than 0.001 will be presented as < 0.001. 


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All data collected during the study will be included in data listings and will be displayed and 
sorted by study part, dose level, cohort/treatment group, patient number and then by 
date/time (including visit, cycle, and day), if any, for each patient number, unless otherwise 
noted. 
7 
DATA HANDLING METHODS 
7.1 
MISSING DATA 
7.1.1 
Date Values 
In cases of incomplete dates (e.g., pertaining to AE, concomitant medication, medical 
history, etc.), the missing component(s) will be assumed as the most conservative value(s) 
possible.  For example, if the start date has a missing day value, the first day of the month 
will be imputed for study day computations (i.e., treatment-emergent status, etc.).  If day is 
missing for an end date, the last day of the month will be imputed.  Similar logic will be 
assumed for missing month and year components.   
Date imputation will only be used for computational purposes e.g., treatment-emergent 
status, etc.  Actual data values as they appear in the original CRFs will be shown in the data 
listings. 
7.1.2 
Non-Date Values 
Every effort will be made to obtain the protocol-required data for all study assessments that 
are scheduled for each scheduled visit for all subjects who have been enrolled.  No data 
imputation will be applied to missing study data except for imputing visit dates to classify 
AE and concomitant medication data into the study phase of “pre-treatment,” “during 
treatment,” or “post-treatment.” 
7.2 
VISIT WINDOWS 
All study data will be presented at the nominal visit obtained from the eCRFs, if available.  
Study day is defined as (date of visit – date of treatment initiation + 1).  That is, study day 1 
indicates the date of treatment initiation.  In the case of early termination visit, date of the 
visit will be used to calculate the nominal visit for the analysis.  
 
If there are two or more assessments within a nominal visit, then the assessment that is 
closest to the scheduled time point/target day will be used in the analysis.  If there is more 
than one closest value, then the evaluation occurring after the target day and prior to the date 
of last dose will be used in the analysis. 
All values will be included in the data listings. 
7.3 
DATA DERIVATIONS AND DEFINITIONS 
General derivations that can be applied to any endpoint are defined below.  For specific 
derivations that can only be applied to a particular endpoint, they will be defined in the 
section describing the endpoint. 


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Baseline Definition 
Baseline measurement is defined as the last pre-treatment measurement obtained prior to the 
initial administration of BVD-523. 
 
Change from Baseline 
The change from baseline will be calculated by subtracting the baseline values from the 
individual post-procedure values.  If either the baseline or post-procedure value is missing, 
the change from baseline is set to missing as well. 


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8 
STUDY POPULATION 
Unless otherwise stated, all study population analyses will be performed on the Safety 
Population. 
8.1 
SUBJECT DISPOSITION 
The frequency and percentage of patients who receive at least one dose of BVD-523 or not, 
patients who have completed the study as per protocol or not, and patients who withdrew 
prematurely from the study with their reasons for discontinuation will be summarized by 
treatment group and overall (all treatment groups combined) for each study part2.  The total 
number of mITT patients in each treatment group for each study part will be used as the 
denominator for the calculation of percentages. 
 
The number and percentage of patients in each of the five analysis populations as specified in 
Section 5 will also be tabulated similarly. 
 
A listing of analysis population, study completion, and early termination with the primary 
reason for early withdrawal will also be provided. 
8.2 
DEMOGRAPHIC CHARACTERISTICS 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall for each study part using the mITT and Safety Populations.  
 
Demographic and baseline characteristics include, but are not limited to: age (years), age 
category (<65 and ≥65 years old), gender, ethnicity, race, weight (kg), height (cm), body 
mass index (BMI; kg/m2), Eastern Cooperative Oncology Group (ECOG) Performance 
Score, reproductive status, cancer type, tumor mutation status, type of scan (Echocardiogram 
or Multi-gated acquisition scan (MUGA)), left ventricular ejection fraction (LVEF) result, 
and molecular abnormalities when available.   
Age will be calculated in years from date of birth to the date of informed consent as an 
integer value.   BMI is calculated as weight / (height/100)2, where weight is in kg and height 
is in cm. 
                                                 
2 Part 1 and Part 2 use different categories.  Part 1 categories are: Death, Anaphylaxis (angioedema, 
hypotension, shock, bronchospasm, hypoxia, or respiratory distress), Withdrawal of Informed Consent, Disease 
Progression, Unacceptable Toxicity, Change in the Subject’s Condition that Renders the Subject Unacceptable 
for Further Treatment, At Least 3 Interruptions of BVD-523 Intake, Patient Becomes Pregnant, Patient is Lost 
to Follow-up, Other.  Part 2 categories are: Withdrawal of Informed Consent, Disease Progression (at the 
discretion of the PI).  However it is particularly important in patients for which FDA approved BRAF and/or 
MEK inhibitors are indicated that BVD-523 treatment NOT be continued beyond tumor progression, 
Unacceptable Toxicity, Changes in the Patient’s Condition Render the Patient Unacceptable for Further 
Treatment in the Judgment of the PI, Patient Non-Compliance as Assessed by the Investigator, Patient has a 
Positive Serum Pregnancy Test (Withdrawal is Required), Patient is Lost to Follow-up, Other.  


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8.3 
PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded according to the World Health Organization Drug Dictionary 
(WHO Drug, March 1, 2013).  Summary of all medications will then be using the WHO 
Drug ATC classification and preferred term. 
 
All medications taken, except for BVD-523, will be classified into prior or concomitant 
medications.  A prior medication is defined as any medication taken within 28 days prior to 
the initiation of BVD-523 irrespective of whether it is continued into the study.  A 
concomitant medication is defined as any medication taken after the initiation of BVD-523 
and up to 30 calendar days after the last administration of BVD-523. If a medication falls 
into both prior and concomitant time phase then it will be presented in both time phases.  All 
medications, except for BVD-523, will be summarized by WHO Drug ATC classification 
and preferred term with regards to treatment groups for each study part and time phase. 
 
At each level (WHO Drug ATC classification and Preferred Term) of summarization, a 
subject will be counted only once per drug class or preferred term.  For example, if a subject 
reports multiple concomitant medications with the same drug class, then that drug class will 
only be incremented by one. Similarly, if a subject reports multiple concomitant medications 
with the same preferred term, then that preferred term will only be incremented by one. 
Whether medications are taken for AEs or not will also be provided.  The medication with 
indication equals to the AE verbatim which also has “Concomitant Medications” as the 
response to the question of “Any Treatment Required?” will be deemed as the medication 
taken for the AE.  Medications taken for AEs will be tabulated by WHO Drug ATC 
classification and preferred term with regards to treatment groups for each study part. 
 
Subject listing of medications will also be presented by time phase. 
8.4 
MEDICAL HISTORY 
Medical history findings including change in medical condition since the last visit will be 
provided in a listing. 
8.4.1 
Previous Chemotherapy  
Previous chemotherapy information includes description of the chemotherapy, start/stop date, 
reason for therapy, best response from the therapy, total number of cycles completed, prior 
anthracycline use, prior XRT use, and delivery site.  They will be summarized by descriptive 
statistics by treatment group for each study part.  Listing of previous chemotherapy 
information will also be provided in the order of occurrences within a patient. 
8.4.2 
Previous Immunotherapy 
Previous immunotherapy data including type of immunotherapy (monoclonal antibodies, 
cancer vaccine, other immunotherapy), start/stop date, and reason for discontinuation 
(completed regimen, disease progression, other) will be listed by time of occurrence within a 
patient. 


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8.5 
ON STUDY PROCEDURES 
A listing of on study procedures including their purposes (prior medical condition, adverse 
event, other) will be provided. 
8.6 
INCLUSION/EXCLUSION CRITERIA 
Inclusion and exclusion criteria failures will be included in a data listing. 
8.7 
TREATMENT COMPLIANCE 
Patients will take BVD-523 orally twice daily for 21-day cycles until disease progression, 
unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is 
noted.  Patients may be treated beyond disease progression for additional 21-day cycles at the 
Investigators discretion. However it is particularly important in patients for which FDA 
approved BRAF and/or MEK inhibitors are indicated that BVD-523 treatment NOT be 
continued beyond tumor progression.  Treatment cycles will occur consecutively without 
interruption, except when necessary to manage toxicities.  No intra-patient dose escalation 
was permitted under the original protocol or the first two amendments.  Under amendment 
three, some intra-patient dose escalations were allowed.  Under amendment four, intra-
patient dose escalations are only allowed to bring subjects to the RP2D (after it is identified), 
if deemed medically appropriate and if the subject has not experienced any toxicity greater 
than Grade 1.  Some intra-patient dose escalation may occur.     
A listing of BVD-523 administration, dispensed, missed/interrupted dose, intra-patient dose 
escalations, returned, and compliance will also be provided. 
8.8 
PROTOCOL DEVIATIONS 
Protocol deviations in the following areas will be collected from the study:  
 drug dosing, 
 exclusion criteria, 
 general protocol issues, 
 informed consent form issues, 
 inclusion criteria, 
 missed study procedure, 
 SAE issues, 
 visit windows, 
 other, and 
 unknown. 
 
Impacts of the above protocol deviations on the analysis population will be determined by 
study team before study closure and documented in the SAP. 
The frequency and percentage of patients with each protocol deviation along with the impact 
on the analysis population will be presented by treatment group and overall for each study 
part using the ITT Population.  A listing of patients with protocol deviation(s) will also be 
provided. 


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9 
EFFICACY ANALYSIS 
Unless otherwise stated, efficacy analyses will be performed on both the mITT and PP 
populations (see Section 5 of this SAP). 
Tumor measurements based on physical examination will occur at baseline and on the first 
day of each treatment cycle. Tumor assessments will be made by CT/MRI/Physical Exam 
prior to dose initiation, at the first protocol-specified tumor measurement evaluation at the 
end of Cycle 2 and then every 2-3 cycles, and at End of Treatment.    
 
In Part 1, FDG-PET scans were performed at investigator discretion based on totality of 
additional available data for the subject. 
 
RECIST 
Imaging will be performed on the abdomen, chest, pelvis and the site of the primary tumor if 
elsewhere. The same imaging modality used for an individual patient (i.e., CT or MRI) at 
Screening should be maintained throughout the study. The findings will be assessed according to 
the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).  
 
The response criteria in evaluation of target lesions are defined as follows: 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
1 or more new lesions is also considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
The number and percent of patients with each tumor response will be tabulated using the PP 
Population by study part, dose level/treatment group, and study visit.  Bar graphs of genetic 
information (BRAF, FGFR3, etc.) leading to target lesion response and best overall response 
will also be presented. 
10 SAFETY 
Safety analyses will be performed using the Safety Population. Safety will be assessed by 
examining all adverse events reported during the study including the incidence, and 
relationship to BVD-523.  In addition, safety evaluations will be conducted at Screening, 
Baseline, Days 8, 15, 22, 29, 36, 43, and, in patients who continue treatment, every 3 weeks 
or if clinically indicated thereafter.  These evaluations will include a physical examination, 
ECOG performance status, vital signs, and clinical laboratory evaluations (hematology, 


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chemistry, urinalysis and pregnancy test).  Electrocardiography measurements will be 
collected in Cycle 1 (determined by ECG at Screening and Day 8 and 12±2 hours Holter 
monitoring during PK sampling days).  Patients with a normal ECG in Cycle 1 need not have 
repeat ECGs in subsequent cycles.  An ophthalmologic assessment will also be conducted at 
screening, at the end of study and at other visits by an ophthalmologist if clinically indicated. 
Additionally, subjects will be asked to return for a 30 day safety visit (or earlier if subsequent 
therapy is initiated prior to 30 days) or contacted by phone after the last dose of study 
medication is taken. 
10.1 EXPOSURE TO STUDY DRUG  
Descriptive statistics will be provided for the total (cumulative) doses taken and total 
duration of treatment by treatment group for each study part.  The total duration of treatment 
is calculated as (treatment stop date – treatment start date) + 1.  If treatment stop date is 
missing, the date of final clinic visit will be used.  By subject listing of study drug exposure 
will also be presented by study part and treatment group for each treatment cycle and all 
cycles combined. 
10.2 ADVERSE EVENTS 
An adverse event is defined as any untoward medical occurrence in a patient administered a 
medicinal product that does not necessarily have a causal relationship with this treatment.  
This includes an exacerbation of pre-existing conditions or events, inter-current illnesses, 
drug interaction, or the significant worsening of the indication under investigation that is not 
recorded elsewhere in the eCRF under specific efficacy assessments.  The reporting period of 
an AE begins from the time that the patient provides informed consent through and including 
30 calendar days after the last administration of BVD-523 (or at the time when a patient 
begins a new anti-cancer therapy).  Anticipated fluctuations of pre-existing conditions, 
including the disease under study that does not represent a clinically significant exacerbation 
or worsening, need not be considered AEs. 
The severity of an AE will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 4 with values of Grade 
1 to Grade 5 (increased in severity). For AEs not covered by NCI CTCAE, the severity will 
be characterized as “mild,” “moderate,” or “severe” according to the following definitions: 
• Mild (equivalent to Grade 1) events are usually transient and do not interfere with the 
patient’s daily activities. 
• Moderate (equivalent to Grade 2) events introduce a low level of inconvenience or 
concern to the patient and may interfere with daily activities. 
• Severe (equivalent to Grade 3) events interrupt the patient’s usual daily activities.  
All AE relationship to the study drug, BVD-523, are classified as “unrelated,” “possibly 
related,” or “related.” 
AE Coding 
Any AE including SAE in verbatim term will be coded in accordance with the Medical 
Dictionary for Regulatory Activities (MedDRA®) dictionary version 16.0 to a system organ 
class (SOC) and preferred term (PT) within each SOC.  Analysis of AEs will then be 
performed using SOCs and PTs. 


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Dose Limiting Toxicities, Maximum Tolerated Dose, and Recommended Phase 2 Dose 
As specified in Section 2.1.1, a DLT for Part 2 is defined (per definition in protocol 
amendment 7) as a BVD-523 related toxicity in the first 21 days of treatment that results in:  
 
• ≥ Grade 4 hematologic toxicity for > 1 day; 
• Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding; 
• ≥ Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, 
pain, and rash (these become DLTs if the AE persists despite adequate treatment), a 
doubling of AST/ALT in patients with grade 2 ALT/AST at baseline; 
• A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, 
despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for > 7 days) due to 
BVD-523-related toxicity3. 
 
As specified in Section 2.1.1, the MTD is defined as the highest dose level at which ≤33% of 
patients experience BVD-523 related DLTs in the first 21 days of treatment.  The RP2D may 
be as high as the MTD and will be determined in discussion with the Clinical Investigators, 
the Medical Monitor, and the Sponsor.  Observations related to pharmacokinetics (PK), 
pharmacodynamics (PD), and any cumulative toxicity observed after multiple cycles may be 
included in the rationale supporting the RP2D.  Pharmacokinetic, pharmacodynamics, and/or 
Holter measurements may be suspended pending review of accumulated patient experience. 
 
Treatment Emergent Adverse Event 
A treatment emergent adverse event (TEAE) is any AE temporally associated with the use of 
BVD-523 (from BVD-523 initiation until 30 calendar days after the last administration of 
BVD-523), whether or not considered related to the study drug.  If the onset of an AE is 
missing and the AE resolution date is either after the initial BVD-523 dose date or missing, 
then the AE will be considered treatment emergent. 
 
AE Summaries   
A subject who reported multiple AEs that map to a common PT or SOC is counted only once 
for that PT or SOC at the highest severity reported and at the greatest relationship to study 
drug. 
The number and percentage of subjects who experienced at least one AE will be tabulated by 
SOC and PT with respect to dose level/treatment group for each study part.  The same 
tabulation will also be applied to any SAE, any AE leading to premature discontinuation 
from the study, treatment emergent AEs and treatment-emergent SAEs. 
                                                 
3 For Amendments 1 and 2: A treatment interruption exceeding 3 days in Cycle 1 due to drug-related toxicity (or inability to begin Cycle 2 
for > 7 days) due to drug-related toxicity. 
For Amendment 3: A treatment interruption exceeding 5 days in Cycle 1 due to drug-related toxicity (or inability to begin Cycle 2 for > 7 
days due to drug-related AE) 
For Amendments 4, 5, and 6: A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite adequate 
treatment) in Cycle 1 (or inability to begin Cycle 2 for > 7 days) due to BVD-523-related toxicity. 
 


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The number and percentage of subjects who experienced at least one AE will also be 
tabulated by SOC and PT within each dose level/treatment group with respect to relationship 
to study drug (unrelated, possibly related, and related) and severity (Grade 1 to Grade 5).   
Subject listings will also be provided for all AEs, all SAEs, all AEs leading to early 
discontinuation from the study and all AEs leading to study drug interruptions and length of 
interruptions. 
 
Bar graphs of AEs in CTCAE Term will be displayed in decreasing order of incidence from 
most common to least common.  Each bar in the plot will represent an AE in CTCAE Term.  
Severity of AE (grades) will be embedded in each bar using the percentages of patients in 
each AE grade.  These plots will be provided for all AE tables produced. 
10.3 SERIOUS ADVERSE EVENTS AND DEATH 
Separate data listings and summaries will be presented for all SAEs and deaths.   
10.4 LABORATORY EVALUATIONS 
Laboratory evaluations obtained from the following clinical laboratory tests will be collected 
at Screening, Baseline, Days 8, 15, 22, 29, 36, 43, and, in patients who continue treatment, 
every 3 weeks or if clinically indicated thereafter: 
• Hematology – hemoglobin, hematocrit, white blood cells (WBC) count with 
differential, red blood cells (RBC) count, erythrocyte sedimentation rate (ESR), and 
platelet count. 
• Blood Chemistry – albumin, alkaline phosphatase (ALP), total bilirubin, calcium, 
chloride, creatinine, creatinine clearance, glucose, inorganic phosphorus, potassium, 
total protein, alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-
reactive protein (CRP), Lactic dehydrogenase (LDH), sodium, blood urea nitrogen 
(BUN), and uric acid. 
• If the total bilirubin concentration is increased above 1.5 times the upper normal 
limit, total bilirubin should be differentiated into the direct and indirect reacting 
bilirubin. 
• Cholesterol, HDL, LDL, and triglycerides levels will be measured at Screening 
and first day of each cycle only. 
• Urinalysis – specific gravity, pH, semi-quantitative “dipstick” evaluation of glucose, 
protein, bilirubin, ketones, leukocytes, and blood.  Abnormal findings by dipstick will 
trigger a full microscopic examination including RBC, WBC, and casts.   
 
Results of all evaluations (normal, abnormal clinically significant, abnormal not clinically 
significant, not done) from each laboratory test will be tabulated by study visit and treatment 
group for each study part.  A listing of all laboratory evaluations and abnormal clinically 
significant laboratory evaluations will also be provided. 


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10.5 VITAL SIGNS 
Descriptive statistics for systolic blood pressure (mm Hg) diastolic blood pressure (mm Hg), 
pulse rate (bpm), temperature (°C), height (cm), and weight (kg) will be presented by study 
visit and treatment group visit for each study part.  Also, changes in these vital signs from 
baseline to each subsequent visit will be tabulated by dose level/treatment group for each 
study part.  Note that height is only collected at Screening and weight is only collected at 
Screening and at the beginning of each cycle of treatment.  
A listing of vital signs will also be provided. 
10.6 ELECTROCARDIOGRAMS AND HOLTER MONITORING 
Electrocardiogram (ECG) readings and Holter Monitoring are assessed by BioClinica 
(Princeton, NJ).  All patients will have Screening and Cycle 1 (at Day 8) ECG evaluated to 
have  ECG parameters (Heart Rate (bpm), RR (msec), PR (msec), QRS (msec), QT (msec), 
and QTcF (msec)) collected.  The QT data will be corrected using Fridericia correction and 
calculated as QTcF = QT/[RR(1/3)].  Furthermore, an overall assessment of the ECG results 
on a subject-visit level will be classified as ‘Normal’, ‘Abnormal, Not Clinically Significant’, 
or ‘Abnormal, Clinically Significant’.   
 
During PK sampling days (Cycle 1, Day 1 and 15), a subset of patients will have Holter 
monitoring (12± 2 hours) performed. 
 
For subjects with a clinically significant abnormal ECG in Cycle 1, their ECGs will be 
conducted at Days 22, 29, 36, 43, and, in patients who continue treatment, every 3 weeks or 
if clinically indicated thereafter. 
 
Holter ECG analyses will be conducted by BioClinica and are detailed in the Clinipace 
Worldwide/BioClinica work order.  All ECG parameters will be summarized as actual values 
and as changes from screening/baseline by study visit AND treatment group for each study 
part; assessments by cohort will only be performed for cohorts of at least 3 subjects. 
 
The primary analysis will be a concentration-response (PK:PD) analysis of QTcF, assuming 
no hysteresis and a linear relationship between PK and QTc.  Secondary analyses will 
provide summary statistics by time-point and dose for: HR, PR, QRS, QT, and QTcF. 
 
A listing of ECG findings will also be provided. 
10.7 OPHTHALMOLOGY EXAMINATIONS 
Ophthalmologic examinations findings include best-corrected visual acuity, visual field 
examination, intraocular pressure, external eye examination, and dilated fundoscopy will be 
collected at Screening, at study termination, and if clinically indicated.  
 
Descriptive statistics will be used to summarize these ophthalmologic examinations findings. 
A listing of all ophthalmologic examinations findings will also be provided 


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10.8 PHYSICAL EXAMINATIONS 
Physical examinations will include examination of general appearance; skin; eyes; ears, nose, 
& throat; head & neck; heart; chest & lungs; abdomen; extremities; back; lymph nodes; 
musculoskeletal; and neurological.  These examinations will be conducted at Screening, 
Baseline, Days 8, 15, 22, 29, 36, 43, and, in patients who continue treatment, every 3 weeks 
or if clinically indicated thereafter. 
 
The frequency and percentage of patients with each examination finding (‘Normal’, 
‘Abnormal Clinically Significant’, ‘Abnormal Not Clinically Significant’, and ‘Not Done’) 
will be tabulated for each body system by study visit and dose level/treatment group for each 
study part.   
 
A listing of physical examination findings will be presented. 
11 ADDITIONAL ANALYSES 
11.1 PHARMACOKINETIC ANALYSES 
Samples for PK analysis of BVD-523 and selected metabolites will be obtained from all Part 
1 patients during their first cycle of treatment (Cycle 1).  PK samples may also be obtained 
from additional patients in Part 2 depending on the outcome of initial PK analysis. 
At Visit 2 (Baseline) blood samples (3 mL) will be collected prior to dosing, and then at 0.5, 
1 (±5 minutes), 2, 4, 6, 8 (±10 minutes), and 12 (± 2 hours) post-dose after the administration 
of the first dose of the first cycle.  At Day 15 (Visit 4; at steady-state) blood samples will be 
collected prior to dosing and then, 0.5, 1, 2, 4, 6, 8, and 12 ± 2 hours post-dose.  A single 
sample will be collected on Day 22 prior to dosing on that day.   
For Part 1 subjects, at Visit 2 (Baseline) urine samples will be collected pre-dose.  Total urine 
for the 1–6-hour and 6–12 ±2-hour time periods post-dose after the administration of the first 
dose of the first cycle will also be collected.  At Day 15 (Visit 4; at steady-state) urine 
samples will be collected pre-dose and then for the 1–6-hour and 6–12 ±2-hour time periods 
post-dose.  No urine PK samples will be collected for Part 2 subjects. 
Below is the list of various PK parameters that will be calculated after Dose 1 (Day 1) and at 
Steady State (Day 15) using both blood and urine samples: 
PK  
Parameter 
(plasma) 
Description 
Cmax 
Peak plasma concentration determined manually by visual inspection of plasma concentration vs. 
time figures on the untransformed (linear) scale of measurement 
tmax 
Time to reach the peak plasma concentration determined manually by visual inspection of plasma 
concentration vs. time figures on the untransformed (linear) scale of measurement 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours postdose, calculated by linear/log 
trapezoidal method 
AUC1-12 
Area under the plasma concentration-time curve from 1 to 12 hours postdose, calculated by linear/log 
trapezoidal method (for use in calculating CLr) 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to time of last observation after dosing 
calculated by linear/log trapezoidal method 


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λz 
Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal 
phase of the log-linear plasma concentration-time curve.  The correlation coefficient (r2) for the 
goodness of the fit of the regression line through the data points has to be 0.85 or higher for the value 
to be considered reliable.  If the WinNonlin data points are not on the linear portion of the terminal 
slope, the data points will be selected manually prior to calculation of λz 
t1/2 
Terminal half-life, defined as 0.693 (ln 2) divided by λz 
 
PK 
Parameter 
(urine) 
Description 
U1-6 
Amount excreted in urine calculated from Time 1 to 6 hours 
U1-12 
Cumulative amount excreted in urine calculated from Time 1 to 12 hours 
CLr 
Renal clearance, U1-12 divided by AUC1-12 
Ae% 
Percentage of the dose excreted in the urine, U1-12 divided by the dose and multiplied by 100. 
 
Only AUC0-last will be calculated from the single sample collected at prior to dosing on Day 
22. 
PK concentration and PK parameters calculated from both blood and urine samples will be 
provided by Covance.  Descriptive statistics [n, arithmetic mean, standard deviation, 
coefficient of variation (CV), median, minimum, maximum, geometric mean, geometric 
standard deviation geometric CV]will be used to summarize PK parameters by treatment.  
For t1/2 and tmax, regular descriptive statistics and 95% confidence intervals about the 
arithmetic mean will be calculated, if possible, for each dose, but not geometric mean, 
geometric standard deviation, and geometric CV.  Refer to Pharmacokinetic Analysis Outline 
(PKAO) for additional details re. the PK analyses.  
 
Listings of PK concentrations (blood and urine) and PK parameters will also be provided. 
11.2 PHARMACODYNAMICS ANALYSES 
Multiple biomarkers intended to demonstrate inhibition of the molecular target, and 
mechanism of action will be investigated (pRSK, pERK, Ki67, Caspase-3, and circulating 
tumor DNA) from fluid and tissue samples.  Additional biomarkers may be identified and 
measured as appropriate.  Pharmacodynamic sampling should only be completed in those 
patients that consent to optional biopsy. Those patients that do not consent to this collection 
do not need to have pharmacodynamics sample taken. Descriptive statistics will be provided 
for pharmacodynamics data collected from fluid samples.  Listings of pharmacodynamics 
data will be provided from both fluid and tissue samples. 
11.3 TUMOR GENOTYPING 
Tumor genotyping by DNA analysis may be performed in patients in Part 1.  For patients 
enrolled in Part 2 tumor genetic information (detected mutation) will be required to confirm 
eligibility.  When available the predicted mutation and/or protein change will also be 
collected. 


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 Descriptive statistics and listing of tumor genotyping data will be provided. 
12 INTERIM ANALYSIS 
Once all subjects enrolled into Part 1 of the study have been assessed for at least one full 
treatment cycle, an analysis of Part 1 safety and efficacy will be conducted in order to 
facilitate the discussions regarding MTD and RP2D; however, no formal interim analysis is 
planned for the study. 
13 END-OF-STUDY-ANALYSIS 
A final analysis will be conducted after the last subject completes or discontinues the study 
and the resulting clinical database has been cleaned, quality checked, and locked. 
14 TABLE OF CONTENTS FOR DATA DISPLAYS 
TFL Shells are included as stand-alone documents. 
 
 


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Tables/Figures 
Part I 
Part I: Study Population 
 
Part I - Table 14.1.1.1 
Subject Disposition 
ITT Population 
Part I - Table 14.1.1.2 
Analysis Population 
ITT Population 
Part I - Table 14.1.2 
Protocol Deviations 
ITT Population 
Part I - Table 14.1.3.1 
Demographic and Baseline Characteristics 
Safety Population 
Part I - Table 14.1.3.2 
Demographic and Baseline Characteristics 
ITT Population 
Part I - Table 14.1.4.1 
Prior Medications 
Safety Population 
Part I - Table 14.1.4.2 
Concomitant Medications 
Safety Population 
Part I - Table 14.1.4.3 
Concomitant Medication Taken for Adverse Events 
Safety Population 
Part I - Table 14.1.5.1 
Treatment Compliance 
Safety Population 
Part I - Table 14.1.5.2 
Exposure to Study Drug 
Safety Population 
Part I - Table 14.1.6 
Pregnancy Test Results 
Safety Population 
Part I: Efficacy  
Part I - Table 14.2.1 
Target Lesion Response per RECIST 1.1 
PP Population 
Part I - Table 14.2.2 
Non-Target Lesion Response per RECIST 1.1 
PP Population 
Part I - Table 14.2.3 
New Lesion  
PP Population 
Part I - Table 14.2.4 
Overall Response per RECIST 1.1 
PP Population 
Part I - Table 14.2.5 
Best Overall Response per RECIST 1.1 
PP Population 
Part I - Table 14.2.6 
Best Overall Response by Disease and Mutation Status 
PP Population 
Part I - Table 14.2.7 
Duration of Best Overall Response by Disease and Mutation Status 
PP Population 
Part I: Safety  
Part I - Table 14.3.1.1 
Dose Limiting Toxicities                                         Safety Population 
Part I - Table 14.3.1.2 
Details of Dose Limiting Toxicities                              Safety Population 
Part I - Table 14.3.1.3 
Doses Selected as MTD and RP2D                               Safety Population 
Part I - Table 14.3.1.4.1 
Frequency and Reasons for Dose Delays/Interruptions           Safety Population 
Part I - Table 14.3.1.4.2 
Duration of Dose Delays/Interruptions                           Safety Population 
Part I - Table 14.3.1.5 
Adverse Events                                                  Safety Population 
Part I - Figure 14.3.1.5 
Bar Graph of Adverse Events                                     Safety Population 
Part I - Table 14.3.1.6 
Serious Adverse Events                                           Safety Population 
Part I - Figure 14.3.1.6 
Bar Graph of Serious Adverse Events                            Safety Population 
Part I - Table 14.3.1.7 
Adverse Events Leading to Premature Discontinuation from 
the Study                                                  
Safety Population 
Part I - Figure 14.3.1.7 
Bar Graph of Adverse Events Leading to Premature 
Discontinuation from the Study                                   
Safety Population 
Part I - Table 14.3.1.8 
Adverse Events by Relationship to Study Drug                   Safety Population 


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Part I - Table 14.3.1.9 
Adverse Events by Severity                                       Safety Population 
Part I - Table 14.3.2.1 
Treatment Emergent Adverse Events                             Safety Population 
Part I - Figure 14.3.2.1 
Bar Graph of Treatment Emergent Adverse Events              Safety Population 
Part I - Table 14.3.2.2 
Serious Treatment Emergent Adverse Events                    Safety Population 
Part I: Death Narratives 
Part I: Laboratory Results 
Part I - Table 14.3.4.1 
Laboratory Evaluations – Hematology         Safety Population 
Part I - Table 14.3.4.2 
Laboratory Evaluations – Clinical Chemistry 
Safety Population 
Part I - Table 14.3.4.3 
Laboratory Evaluations – Urinalysis          Safety Population 
Part I: Physical Examination Results 
Part I - Table 14.3.5.1 
Physical Examinations               Safety Population 
Part I - Table 14.3.5.2 
ECOG Performance Status             Safety Population 
Part I - Table 14.3.5.3 
Electrocardiograms                  Safety Population 
Part I - Table 14.3.5.4 
Categorized Electrocardiograms         Safety Population 
Part I - Table 14.3.5.5 
Ophthalmology Examinations           Safety Population 
Part I - Table 14.3.5.6 
Vital Signs                       Safety Population 
Part I: Pharmacokinetics 
Part I - Table 14.4.1 
Pharmacokinetic Parameters Calculated from Blood Samples 
PK Population 
Part I - Table 14.4.2 
Pharmacokinetic Parameters Calculated from Urine Samples 
PK Population 
Part I: Pharmacodynamics 
Part I - Table 14.5.1 
Fluid Pharmacodynamics 
Pharmacokinetics Population 
Part I: Tumor Genotyping 
Part I - Table 14.6.1 
Tumor Genetic Information 
PP Population 
 
Part II 
Part II: Study Population 
 
Part II - Table 14.1.1.1 
Subject Disposition 
mITT Population 
Part II - Table 14.1.1.2 
Analysis Population 
mITT Population 
Part II - Table 14.1.2 
Protocol Deviations 
mITT Population 
Part II - Table 14.1.3.1 
Demographic and Baseline Characteristics 
Safety Population 
Part II - Table 14.1.3.2 
Demographic and Baseline Characteristics 
mITT Population 
Part II - Table 14.1.4.1 
Prior Medications 
Safety Population 
Part II - Table 14.1.4.2 
Concomitant Medications 
Safety Population 


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Part II - Table 14.1.4.3 
Concomitant Medication Taken for Adverse Events 
Safety Population 
Part II - Table 14.1.5.1 
Treatment Compliance 
Safety Population 
Part II - Table 14.1.5.2 
Exposure to Study Drug 
Safety Population 
Part II - Table 14.1.6 
Pregnancy Test Results 
Safety Population 
Part II: Efficacy  
Part II - Table 14.2.1 
Target Lesion Response per RECIST 1.1 
PP Population 
Part II - Figure 14.2.1 
Genetic Information Leading to Target Lesion Response 
PP Population 
Part II - Table 14.2.2 
Non-Target Lesion Response per RECIST 1.1 
PP Population 
Part II - Table 14.2.3 
New Lesion 
PP Population 
Part II - Table 14.2.4 
Overall Response per RECIST 1.1 
PP Population 
Part II - Table 14.2.5 
Best Overall Response per RECIST 1.1 
PP Population 
Part II - Figure 14.2.6 
Genetic Information Leading to Best Overall Response 
PP Population 
Part II - Table 14.2.7 
Best Overall Response by Disease and Mutation Status 
PP Population 
Part II - Table 14.2.8 
Duration of Best Overall Response by Disease and Mutation Status PP Population
Part II: Safety 
 
Part II - Table 14.3.1.1 
Dose Limiting Toxicities                                   Safety Population 
Part II - Table 14.3.1.2 
Details of Dose Limiting Toxicities                        Safety Population 
Part II - Table 14.3.1.3 
Duration of Dose Interruptions                             Safety Population 
Part II - Table 14.3.1.3 
Adverse Events                                             Safety Population 
Part II - Figure 14.3.1.4.1 
Bar Graph of Adverse Events by PT                       Safety Population 
Part II - Figure 14.3.1.4.2 
Bar Graph of Adverse Events by SOC and PT              Safety Population 
Part II - Table 14.3.1.5 
Serious Adverse Events                                     Safety Population 
Part II - Figure 14.3.1.5.1 
Bar Graph of Serious Adverse Events by PT               Safety Population 
Part II - Figure 14.3.1.5.2 
Bar Graph of Serious Adverse Events by SOC and PT     Safety Population 
Part II - Table 14.3.1.6 
Adverse Events Leading to Premature Discontinuation 
from the Study                                              
Safety Population 
Part II - Figure 14.3.1.6.1 
Bar Graph of Adverse Events Leading to Premature 
Discontinuation from the Study by PT                      
Safety Population 
Part II - Figure 14.3.1.6.2 
Bar Graph of Adverse Events Leading to Premature 
Discontinuation from the Study by SOC and PT           
Safety Population 
Part II - Table 14.3.1.7 
Adverse Events by Relationship to Study Drug             Safety Population 
Part II - Figure 14.3.1.8.1-1 Bar Graph of Probably Related Adverse Events by PT     Safety Population 
Part II - Figure 14.3.1.8.1-2 Bar Graph of Possibly Related Adverse Events by PT      Safety Population 
Part II - Figure 14.3.1.8.1-3 Bar Graph of Unrelated Adverse Events by PT             Safety Population 
Part II - Figure 14.3.1.8.2-1 Bar Graph of Probably Related Serious Adverse Events 
by PT                                                    
Safety Population 
Part II - Figure 14.3.1.8.2-2 Bar Graph of Possibly Related Serious Adverse Events 
by PT                                                    
Safety Population 
Part II - Figure 14.3.1.8.2-3 Bar Graph of Unrelated Serious Adverse Events by PT    Safety Population 


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Part II - Table 14.3.1.8 
Adverse Events by Severity                                 Safety Population 
Part II - Table 14.3.2.1 
Treatment Emergent Adverse Events by PT               Safety Population 
Part II - Table 14.3.2.1 
Treatment Emergent Adverse Events by PT                Safety Population 
Part II - Figure 14.3.2.1 
Bar Graph of Treatment Emergent Adverse Events         Safety Population 
Part II - Table 14.3.2.2 
Treatment Emergent Serious Adverse Events              Safety Population 
 
Part II: Laboratory Results 
Part II - Table 14.3.4.1 
Laboratory Evaluations – Hematology       Safety Population 
Part II - Table 14.3.4.2 
Laboratory Evaluations – Clinical Chemistry 
Safety Population 
Part II - Table 14.3.4.3 
Laboratory Evaluations – Urinalysis        Safety Population 
Part II: Physical Examination Results 
Part II - Table 14.3.5.1 
Physical Examinations               Safety Population 
Part II - Table 14.3.5.2 
ECOG Performance Status             Safety Population 
Part II - Table 14.3.5.3 
Electrocardiograms                  Safety Population 
Part II - Table 14.3.5.4 
Categorized Electrocardiograms         Safety Population 
Part II - Table 14.3.5.5 
Ophthalmology Examinations           Safety Population 
Part II - Table 14.3.5.6 
Vital Signs                       Safety Population 
Part II: Pharmacokinetics 
Part II - Table 14.4.1 
Pharmacokinetic Parameters Calculated from Blood 
Samples 
PK Population 
Part II: Pharmacodynamics 
Part II - Table 14.5.1 
Fluid Pharmacodynamics 
Pharmacokinetics Population 
Part II: Tumor Genotyping 
Part II - Table 14.6.1 
Tumor Genetic Information 
PP Population 
 


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Listings 
Part I 
Study Population 
Part I – Listing 16.2.1.1 Subject Disposition 
Part I – Listing 16.2.1.2.1 Protocol Deviations 
Part I – Listing 16.2.1.2.2 Inclusion/Exclusion Criteria Deviations - Inclusion 
Part I – Listing 16.2.1.2.3 Inclusion/Exclusion Criteria Deviations - Exclusion 
Part I – Listing 16.2.1.3.1 Demographics, Height, Weight, and Body Mass Index 
Part I – Listing 16.2.1.3.2 Baseline Characteristics 
Part I – Listing 16.2.1.4  Medical History 
Part I – Listing 16.2.1.5  Prior Treatments 
Part I – Listing 16.2.1.6  Previous Chemotherapy 
Part I – Listing 16.2.1.7  Previous Immunotherapy 
Part I – Listing 16.2.1.8.1 Relationship of WHO Drug ATC Classification and Preferred Term with Verbatim  
Part I – Listing 16.2.1.8.2 Prior Medications 
Part I – Listing 16.2.1.8.3 Concomitant Medications 
Part I – Listing 16.2.1.8.4 Concomitant Medication Taken for Adverse Events 
Part I – Listing 16.2.1.9  On Study Procedures  
Part I – Listing 16.2.1.10.1 Treatment Compliance  
Part I – Listing 16.2.1.10.2 Exposure to Study Drug 
Part I – Listing 16.2.1.10.3 BVD-523 Dose History 
Efficacy 
Part I – Listing 16.2.2.1 Target Lesions 
Part I – Listing 16.2.2.2 Non-Target Lesions 
Part I – Listing 16.2.2.3 New Lesions 
Part I – Listing 16.2.2.4 Tumor Response per RECIST 1.1 
Part I – Listing 16.2.2.5 Tumor Measurements over Time 
Safety 
Part I – Listing 16.2.3.1 DLTs, MTD, and RP2D 
Part I – Listing 16.2.3.2  Relationship of MedDRA System Organ Class and Preferred Term with Verbatim 
Part I – Listing 16.2.3.3.1 Adverse Events 
Part I – Listing 16.2.3.3.2 Adverse Events Leading to Early Discontinuation from the Study 
Part I – Listing 16.2.3.3.3 Adverse Events Leading to Study Drug Interruptions and Length of Interruptions 
Part I – Listing 16.2.3.3.4 Adverse Events Leading to Study Drug Dose De-escalations 
Part I – Listing 16.2.3.4  Serious Adverse Events 
 


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Laboratory Results 
Part I – Listing 16.2.4.1.1 Laboratory Evaluations – Hematology 
Part I – Listing 16.2.4.1.2 Laboratory Evaluations – Hematology, Abnormal and Clinically Significant 
Part I – Listing 16.2.4.2.1 Laboratory Evaluations – Clinical Chemistry 
Part I – Listing 16.2.4.2.2 Laboratory Evaluations – Clinical Chemistry, Abnormal and Clinically Significant 
Part I – Listing 16.2.4.3.1 Laboratory Evaluations – Urinalysis 
Part I – Listing 16.2.4.3.2 Laboratory Evaluations – Urinalysis, Abnormal and Clinically Significant 
 
Physical Examinations Results 
Part I – Listing 16.2.5.1  Physical Examinations 
Part I – Listing 16.2.5.2  ECOG Performance Status 
Part I – Listing 16.2.5.3  Electrocardiograms 
Part I – Listing 16.2.5.4  Holter Monitoring 
Part I – Listing 16.2.5.5  Holter Monitoring Finding 
Part I – Listing 16.2.5.6  Ophthalmology Examinations 
Part I – Listing 16.2.5.7  Vital Signs 
Part I – Listing 16.2.5.8  Pregnancy Results 
Pharmacokinetics 
Part I – Listing 16.2.6.1 Pharmacokinetic Concentration Measured from Blood Samples 
Part I – Listing 16.2.6.2 Pharmacokinetic Concentration Measured from Urine Samples 
Part I – Listing 16.2.6.3 Pharmacokinetic Parameters  
Pharmacodynamics 
Part I – Listing 16.2.7.1 Fluid/Blood Pharmacodynamics 
Part I – Listing 16.2.7.2 Tissue Pharmacodynamics 
 
Tumor Genotyping 
Part I – Listing 16.2.8 Tumor Genetic or  Genotyping Information / Result 
 
Part II 
Study Population 
Part II – Listing 16.2.1.1 Subject Disposition 
Part II – Listing 16.2.1.2.1 Protocol Deviations 
Part II – Listing 16.2.1.2.2 Inclusion/Exclusion Criteria Deviations - Inclusion 
Part II – Listing 16.2.1.2.3 Inclusion/Exclusion Criteria Deviations - Exclusion 


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Part II – Listing 16.2.1.3.1 Demographics, Height, Weight, and Body Mass Index 
Part II – Listing 16.2.1.3.2 Baseline Characteristics 
Part II – Listing 16.2.1.4 Medical History 
Part II – Listing 16.2.1.5 Prior Treatments 
Part II – Listing 16.2.1.6 Previous Chemotherapy 
Part II – Listing 16.2.1.7 Previous Immunotherapy 
Part II – Listing 16.2.1.8.1 Relationship of WHO Drug ATC Classification and Preferred Term with Verbatim  
Part II – Listing 16.2.1.8.2 Prior Medications 
Part II – Listing 16.2.1.8.3 Concomitant Medications 
Part II – Listing 16.2.1.8.4 Concomitant Medication Taken for Adverse Events 
Part II – Listing 16.2.1.9 On Study Procedures  
Part II – Listing 16.2.1.10.1 Treatment Compliance  
Part II – Listing 16.2.1.10.2 Exposure to Study Drug 
Part II – Listing 16.2.1.10.3 BVD-523 Dose History 
Efficacy 
Part II – Listing 16.2.2.1 Target Lesions 
Part II – Listing 16.2.2.2 Non-Target Lesions 
Part II – Listing 16.2.2.3 New Lesions 
Part II – Listing 16.2.2.4 Tumor Response per RECIST 1.1 
Part II – Listing 16.2.2.5 Tumor Measurements over Time 
Safety 
Part II – Listing 16.2.3.1 RP2D from Part I 
Part II – Listing 16.2.3.2 Relationship of MedDRA System Organ Class and Preferred Term with Verbatim 
Part II – Listing 16.2.3.3.1 Adverse Events 
Part II – Listing 16.2.3.3.2 Adverse Events Leading to Early Discontinuation from the Study 
Part II – Listing 16.2.3.3.3 Adverse Events Leading to Study Drug Interruptions and Length of Interruptions 
Part II – Listing 16.2.3.4 Serious Adverse Events 
 
Laboratory Results 
Part II – Listing 16.2.4.1.1 Laboratory Evaluations – Hematology 
Part II – Listing 16.2.4.1.2 Laboratory Evaluations – Hematology, Abnormal and Clinically Significant 
Part II – Listing 16.2.4.2.1 Laboratory Evaluations – Clinical Chemistry 
Part II – Listing 16.2.4.2.2 Laboratory Evaluations – Clinical Chemistry, Abnormal and Clinically Significant 
Part II – Listing 16.2.4.3.1 Laboratory Evaluations – Urinalysis 
Part II – Listing 16.2.4.3.2 Laboratory Evaluations – Urinalysis, Abnormal and Clinically Significant 
 


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Physical Examinations Results 
Part II – Listing 16.2.5.1 
Physical Examinations 
Part II – Listing 16.2.5.2 
ECOG Performance Status 
Part II – Listing 16.2.5.3 
Electrocardiograms 
Part II – Listing 16.2.5.4 
Holter Monitoring 
Part II – Listing 16.2.5.5 
Holter Monitoring Finding 
Part II – Listing 16.2.5.6 
Ophthalmology Examinations 
Part II – Listing 16.2.5.7 
Vital Signs 
Part II – Listing 16.2.5.8 
Pregnancy Results 
Pharmacokinetics 
Part II – Listing 16.2.6.1 Pharmacokinetic Concentration Measured from Blood Samples 
Part II – Listing 16.2.6.2 Pharmacokinetic Parameters 
Pharmacodynamics 
Part II – Listing 16.2.7.1 Fluid/Blood Pharmacodynamics 
Part II – Listing 16.2.7.2 Tissue Pharmacodynamics 
 
Tumor Genotyping 
Part II – Listing 16.2.8 Tumor Genetic Information 
 
 
 


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15 REVISIONS TO SAP 
The SAP dated 10MAR2015 was finalized/signed for Part 1, under protocol amendment 4.  
This version of the SAP has been revised to reflect changes to the protocol in amendments 5, 
6, and 7; and to update the list of TFL shells for Part 2. 
The definition of mITT used in the SAP (see Section 5.2) is slightly different from the 
protocol.  The protocol defined the mITT population as all subjects who sign informed 
consent, which would result in the inclusion of screen failure subjects in the mITT 
population.  To avoid this, the SAP modified the mITT definition to be all enrolled subjects, 
thereby excluding screen failures. 


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16 REFERENCES 
Guidance for Industry:  Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics:  U.S. Department of Health and Human Services, Food and Drug Administration, 
CDER, CBER, May 2007 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, et al. New Guidelines to 
Evaluate the Response to Treatment in Solid Tumors. J Natl Cancer Inst 92(3):205-216, 
2000. 
 
“Guidance for Industry and Investigators Safety Reporting Requirements for INDs and 
BA/BE Studies” of September 2010. 
 
NCI CTCAE Grading Scale Version 4 (see the NCI CTCAE web page at 
http://ctep.cancer.gov for details).