A Two-Part, Phase II, Multi-center Study of the ERK Inhibitor Ulixertinib (BVD-523) for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations
Phase: PHASE2
Conditions: Advanced Solid Tumor, BRAF Gene Mutation, BRAF Gene Alteration, MEK Mutation, MEK Alteration, MAP2K1 Gene Mutation, MAP2K1 Gene Alteration, MAP2K2 Gene Mutation, MAP2K2 Gene Alteration
Sponsor: BioMed Valley Discoveries, Inc

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CLINICAL STUDY PROTOCOL 
 
A Two-Part, Phase II, Multi-center Study of the ERK 
Inhibitor Ulixertinib (BVD-523) for Patients with Advanced 
Malignancies Harboring MEK or Atypical BRAF Alterations 
Protocol Number: BVD-523-ABC 
 
National Clinical Trial (NCT) 
Identified Number:  
NCT04488003 
IND Sponsor:  
BioMed Valley Discoveries, Inc. 
 
4435 Main Street, Suite 550 
 
Kansas City, MO 64111 
 
Medical Monitor: 
Cmed Inc. 
4000 Aerial Center Parkway 
Suite 102 
Morrisville, NC 27560 
 
Protocol Version: 
1.0 
Date:  
01 JUN 2020 
 
 
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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PROTOCOL APPROVAL SIGNATURE PAGE 
SPONSOR: BIOMED VALLEY DISCOVERIES, INC 
I have read and understand the contents of Version 1.0 of this clinical protocol for 
Study No. BVD-523-ABC dated 01 Jun 2020 and I agree to meet all obligations of the 
sponsor as detailed in all applicable regulations and guidelines. In addition, I will inform 
the Principal Investigator and all other investigators of all relevant information that 
becomes available during the conduct of this study. 
Approved By: 
 
 
 
 
 
Brent L. Kreider, PhD. 
Chief Operations Officer, BioMed Valley Discoveries, Inc. 
 
Date 
 
 

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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of Version 1.0 of this clinical protocol for 
Study No. BVD-523-ABC dated 01 Jun 2020 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: 
Principal Investigator: 
Name:   
 
Title:   
 
Institution:    
Address:    
Address: 
 
Phone:  
 
Fax:  
 
 
 
 
 
 
 
 
  
Signature 
 Date 
 
 

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Table of Contents 
1 
STATEMENT OF COMPLIANCE ..................................................................... 11 
2 
ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 12 
3 
PROTOCOL SUMMARY .................................................................................. 16 
3.1 
Synopsis .................................................................................................. 16 
3.2 
Schema .................................................................................................... 21 
3.3 
Schedule of Activities (SoA) ..................................................................... 21 
4 
INTRODUCTION .............................................................................................. 25 
4.1 
Study Rationale ....................................................................................... 25 
4.2 
Background .............................................................................................. 25 
4.2.1 
Potential Risk .................................................................................. 27 
4.2.2 
Pharmacology Studies .................................................................... 31 
4.2.3 
Toxicity and Safety Studies ............................................................. 34 
4.2.4 
Previous Human Experience .......................................................... 35 
5 
OBJECTIVES AND ENDPOINTS ..................................................................... 42 
5.1 
Part A – Tumor Histology Agnostic .......................................................... 42 
5.1.1 
Primary Objective ............................................................................ 42 
5.1.2 
Secondary Objectives ..................................................................... 42 
5.1.3 
Exploratory Objectives .................................................................... 42 
5.2 
Part B – Tumor Histology Specific ........................................................... 43 
5.2.1 
Primary Objective ............................................................................ 43 
5.2.2 
Secondary Objectives ..................................................................... 43 
6 
STUDY DESIGN ............................................................................................... 44 
6.1 
Overall Design ......................................................................................... 44 
6.1.1 
Part A: Tumor Histology Agnostic ................................................... 44 
6.1.2 
Part B: Tumor Histology Specific .................................................... 44 
6.2 
Justification for Dose................................................................................ 44 
6.3 
Number of Patients .................................................................................. 45 
6.4 
Number of Study Sites ............................................................................. 45 
6.5 
Study Duration and End of Study Definition ............................................. 45 
7 
STUDY POPULATION ..................................................................................... 46 
7.1 
Inclusion Criteria ...................................................................................... 46 
7.2 
Exclusion Criteria ..................................................................................... 47 
7.3 
Screen Failures ........................................................................................ 48 
7.4 
Strategies for Recruitment and Retention ................................................ 48 

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STUDY DRUG .................................................................................................. 49 
8.1 
Study Drug(s) Administration ................................................................... 49 
8.1.1 
Study Drug Description ................................................................... 49 
8.1.2 
Dosing and Administration .............................................................. 49 
8.1.3 
Dose Interruptions and Adjustments ............................................... 49 
8.2 
Accountability/Appearance/Storage ......................................................... 49 
8.2.1 
Acquisition and Accountability ........................................................ 49 
8.2.2 
Formulation, Appearance, Packaging, and Labeling....................... 50 
8.2.3 
Product Storage and Stability ......................................................... 50 
8.3 
Randomization ......................................................................................... 50 
8.4 
Study Drug Compliance ........................................................................... 51 
8.5 
Concomitant Therapy and Rescue Medication ........................................ 51 
9 
STUDY DRUG DISCONTINUATION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ............................................................... 52 
9.1 
Discontinuation of Study Drug ................................................................. 52 
9.2 
Patient Discontinuation Criteria ................................................................ 52 
9.3 
Patient Withdrawal From the Study ......................................................... 52 
9.4 
Long Term Follow Up............................................................................... 53 
9.5 
Lost to Follow-up ..................................................................................... 53 
10 STUDY ASSESSMENTS AND PROCEDURES ............................................... 55 
10.1 Methods of Assessment and Criteria for Evaluation ................................ 55 
10.1.1 
Demographic Data .......................................................................... 55 
10.1.2 
Medical and Cancer History ............................................................ 55 
10.1.3 
Prior and Concomitant Medications ................................................ 55 
10.1.4 
Vital Signs and Physical Examination ............................................. 55 
10.1.5 
Ophthalmology Examination ........................................................... 56 
10.1.6 
Laboratory Assessments ................................................................ 56 
10.1.7 
Electrocardiogram (ECG) ................................................................ 57 
10.1.8 
Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) ........ 57 
10.1.9 
Disease Status ................................................................................ 57 
10.1.10 Tissue Biopsy ................................................................................. 57 
10.1.11 Blood Samples for Pharmacokinetic (PK) Analysis ......................... 58 
10.1.12 Blood Samples for Pharmacodynamic (PD) and ctDNA Analysis ... 58 
10.1.13 Adverse Events ............................................................................... 58 
10.2 Criteria for Evaluation .............................................................................. 58 
10.2.1 
Efficacy ........................................................................................... 58 

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10.2.2 
Pharmacokinetics (PK) ................................................................... 59 
10.2.3 
Circulating Tumor DNA ................................................................... 59 
10.2.4 
Pharmacodynamics (PD) ................................................................ 59 
10.3 Description of Study Visits for Patients Receiving Ulixertinib ................... 59 
10.3.1 
Description of Study Visits for Cycle 1 ............................................. 59 
10.3.2 
Description of Study Visits for Cycle 2 ............................................. 63 
10.3.3 
Cycle 3 and Subsequent Cycles Visit (Day 1 ± 3 of each cycle) ..... 63 
10.3.4 
Description of Study Visits for Patients Enrolled in Part B and 
Receiving Physician’s Choice of Treatment .................................... 64 
10.3.5 
End of Treatment Visit .................................................................... 64 
10.3.6 
Safety Follow-Up Assessment ........................................................ 65 
10.3.7 
Follow Up ........................................................................................ 65 
10.3.8 
Unscheduled Visits ......................................................................... 65 
10.4 Adverse Events and Serious Adverse Events .......................................... 66 
10.4.1 
Definition of Adverse Events (AE) ................................................... 66 
10.4.2 
Definition of Serious Adverse Events (SAE) ................................... 66 
10.4.3 
Classification of an Adverse Event .................................................. 67 
10.4.4 
Time Period and Frequency for Event Assessment and Follow-up. 68 
10.4.5 
Adverse Event Reporting ................................................................ 69 
10.4.6 
Serious Adverse Event Reporting ................................................... 69 
10.4.7 
Overdose ........................................................................................ 70 
10.4.8 
Reporting of Pregnancy .................................................................. 70 
11 STATISTICAL CONSIDERATIONS .................................................................. 72 
11.1 Statistical Analysis Plan ........................................................................... 72 
11.2 Sample Size Determination ..................................................................... 72 
11.2.1 
Part A .............................................................................................. 72 
11.2.2 
Part B .............................................................................................. 72 
11.3 Randomization ......................................................................................... 72 
11.4 Analysis Sets ........................................................................................... 73 
11.4.1 
Full Analysis Set ............................................................................. 73 
11.4.2 
Safety Analysis Set ......................................................................... 73 
11.4.3 
Per Protocol Analysis Set ............................................................... 73 
11.5 Data Presentation .................................................................................... 73 
11.5.1 
Demographic .................................................................................. 73 
11.5.2 
Baseline Characteristics ................................................................. 74 
11.5.3 
Medical History and Physical Examination ..................................... 74 

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11.5.4 
Concomitant Medications or Treatments ........................................ 74 
11.5.5 
Efficacy Analysis ............................................................................. 74 
11.5.6 
Pharmacokinetic (PK) / Pharmacodynamic (PD) Data .................... 76 
11.5.7 
Safety Analysis ............................................................................... 76 
11.6 Interim Analysis ....................................................................................... 77 
11.7 Changes in the Conduct of the Study or Planned Analysis ...................... 77 
12 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ......................................................................................... 78 
12.1 Regulatory, Ethical, and Study Oversight Considerations........................ 78 
12.1.1 
Informed Consent Process ............................................................. 78 
12.1.2 
Study Discontinuation and Closure ................................................. 78 
12.1.3 
Confidentiality and Privacy .............................................................. 79 
12.1.4 
Future Use of Stored Specimens and Data .................................... 80 
12.1.5 
Key Roles and Study Governance .................................................. 81 
12.1.6 
Auditing Procedure ......................................................................... 82 
12.1.7 
Data Handling and Record Keeping ................................................ 83 
12.1.8 
Protocol Deviations ......................................................................... 84 
12.1.9 
Publication and Data Sharing Policy ............................................... 84 
12.1.10 Conflict of Interest Policy ................................................................ 84 
12.1.11 Insurance ........................................................................................ 84 
12.2 Protocol Amendment History ................................................................... 85 
13 REFERENCES ................................................................................................. 86 
 

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List of In-Text Tables 
Table 3.1 
Part A and B: Schedule of Activities ..................................................... 22 
Table 4.1 
Previous Human Experience with Ulixertinib ........................................ 36 

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List of In-Text Figures 
Figure 4.1 BVD-523 Displays Dose Dependent Efficacy in the Murine 
Xenograft Model of Human BRAF-Mutant Melanoma Cell Line 
A375 ...................................................................................................... 32 
Figure 4.2 Mean Tumor Volume Plot; BVD-523 and Dabrafenib Combination 
Demonstrates Superior Efficacy Compared to Either Single Agent 
Alone in the A375 BRAF Mutant Melanoma Xenograft Model .............. 33 
Figure 4.3 Kaplan-Meyer Plot; BVD-523 and Dabrafenib Combination 
Demonstrates Superior Survival Compared to Either Single Agent 
Alone in the A375 BRAF Mutant Melanoma Xenograft Model .............. 33 
Figure 4.4 Percent Target Lesion Change in Patients from BVD-523-01 with 
BRAF non-V600 mutations ................................................................... 40 
Figure 4.5 Study Durations of Patients from BVD-523-01 with BRAF non-
V600 mutations ..................................................................................... 41 
 

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List of Appendices 
Appendix 1 Non-Permitted Concomitant Medications ............................................. 88 
Appendix 2 List of Accepted Atypical BRAF Type II Alterations for Group 2 ........... 89 
Appendix 3 ECOG Performance Status ................................................................... 90 
 
 
 

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1 
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on 
Harmonization Good Clinical Practice (ICH GCP) and the applicable United States 
(US) Code of Federal Regulations (CFR). The principal investigator will assure that 
no deviation from, or changes to the protocol will take place without prior agreement 
from the Investigational New Drug (IND) or Investigational Device Exemption (IDE) 
sponsor, funding agency and document approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed 
Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval. Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study. All changes to the consent form will be IRB 
approved; a determination will be made regarding whether a new consent needs to 
be obtained from participants who provided consent, using a previously approved 
consent form. 
 

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2 
ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
%F 
Absolute bioavailability 
°F 
Degrees Fahrenheit 
µg 
Microgram 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase (SGPT) 
AML 
Acute myeloid leukemia 
AST 
Aspartate transaminase (SGOT) 
AUC 
Area under the plasma concentration-time curve 
BCVA 
Best-corrected visual acuity  
b.i.d. 
Twice daily 
BOR 
Best overall response 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
cm 
Centimeter 
Cmax 
Maximum concentration 
CMC 
Carboxymethylcellulose 
CMP 
Clinical Monitoring Plan 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete remission/complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CRp 
Complete remission with incomplete platelet recovery 
CSR 
Central serous retinopathy 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 1A2 
Cytochrome P450 isoform 1A2 
CYP 2D6 
Cytochrome P450 isoform 2D6 
CYP 3A4 
Cytochrome P450 isoform 3A4 
dL 
Deciliter 
DLT 
Dose limiting toxicity 
DOB 
Date of birth 
DOR     
Duration of response 
DSPV 
Drug Safety and Pharmacovigilance                  
DUSP 
Dual-specificity phosphatase 
EC 
Ethics Committee 

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Abbreviation 
Definition 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EOS 
End-of-study 
EOT 
End of treatment 
ERK 
Extracellular signal-regulated kinase 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
hCG 
Human chorionic gonadotropin 
HCl 
Hydrochloride 
HDPE 
high-density polyethylene 
hERG 
Human ether-a-go-go related gene  
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IST 
Investigator sponsored trial 
ITT 
Intent-to-treat 
IxRS 
Interactive Voice/Web Response System 
kg 
Kilogram 
LD 
Largest diameter 
LDH 
Lactate dehydrogenase 
LS 
Least squares 
LVEF 
Left ventricular ejection fraction 
MAPK 
Mitogen-activated protein kinase 
MDS 
Myelodysplastic syndrome 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated protein kinase/extracellular signal-related kinase 
mg 
Milligram  
mL 
Milliliter  
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition 
NCI 
National Cancer Institute 

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Abbreviation 
Definition 
ng 
Nanogram 
NOS 
Not otherwise specified 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamics 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PIC 
Powder-in-capsule 
PK 
Pharmacokinetics 
PP 
Per protocol 
PR 
Partial response 
PT 
Prothrombin time 
QC 
Quality Control 
QT 
A measure between Q and T waves in heart electrical system 
QTc 
Corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
R2PD 
Recommended Phase 2 Dose 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumors (Version 1.1) 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 dose 
RPPA 
Reverse Phase Protein Arrays 
RSK 
Ribosomal S6 kinase 
RTK 
Receptor tyrosine kinase 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Systems 
SD 
Standard deviation 
SEM 
Standard error of the mean  
SMC 
Safety Monitoring Committee 
SoA 
Schedule of Activities 
SoC 
Standard of care 
SOP 
Standard Operating Procedure 
TEAE 
Treatment emergent adverse event 
TESAE 
Treatment emergent serious adverse event 
TFS 
Tumor-free survivors 
TGD 
Tumor growth delay 
TGI 
Tumor growth inhibition 
TTE 
Time to endpoint 
ULN 
Upper limit of normal 

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Abbreviation 
Definition 
UV 
Ultraviolet 
VF 
Visual field 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 

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3 
PROTOCOL SUMMARY 
3.1 
SYNOPSIS 
Sponsor: 
BioMed Valley Discoveries, 
Inc. 
Investigational Product: 
Ulixertinib (BVD-523) 
Developmental Phase:   
Phase II 
Protocol Number: 
BVD-523-ABC 
Title of Study: 
A two-part, phase II, multi-center study of the ERK inhibitor ulixertinib (BVD-523) for patients with 
advanced malignancies harboring MEK or atypical BRAF alterations. 
Study Description: 
BVD-523-ABC is a multi-center, phase II study that will be conducted in two parts. 
Patients will receive twice daily oral doses of ulixertinib in 28-day treatment cycles until disease 
progression, unacceptable toxicity, consent is withdrawn, or another withdrawal criterion is met. 
Treatment cycles will occur consecutively without interruption except when necessary to manage 
adverse events (AEs). 
Part A (tumor histology agnostic) will be open label and enroll patients to one of six groups 
based on their tumor alteration: 
• 
Group 1: Patients with tumors, other than colorectal cancer (CRC), having a BRAF 
alteration that results in an amino acid change at positions G469, L485, or L597. 
• 
Group 2: Patients with tumors, other than CRC, having a defined Class 2 BRAF alteration 
(see Appendix 2). 
• 
Group 3: Patients with tumors, other than CRC, having an atypical BRAF alteration (non 
V600) that is not specified in Group 1 or Group 2. 
• 
Group 4: Patients with CRC having any atypical BRAF alteration. 
• 
Group 5: Patients with tumors, other than CRC, harboring alterations in MEK1/2. 
• 
Group 6: Patients with CRC harboring alterations in MEK1/2. 
Part B (tumor histology specific) will randomly enroll patients with one of up to three specified 
tumor histologies to receive either ulixertinib or the physician’s choice of treatment in a 2:1 ratio 
(physician’s choice will be restricted to two approved (not off-label) treatments for each tumor 
histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as 
physician choice)). Tumors must harbor a specified MEK or atypical BRAF alteration. If a patient 
progresses on physician’s choice of treatment, crossover to the ulixertinib arm is permitted.   
The specific histologies to be included in this part will be selected based on available data and 
discussion with the clinical investigators, the medical monitor, and the sponsor. 
 
 
 
 

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Sponsor: 
BioMed Valley Discoveries, 
Inc. 
Investigational Product: 
Ulixertinib (BVD-523) 
Developmental Phase:   
Phase II 
Objectives and Endpoints: 
Part A – Tumor histology agnostic 
• 
Primary: To assess the clinical benefit of ulixertinib as measured by the overall response 
rate (ORR) in patients receiving ulixertinib that have advanced malignancies harboring a 
MEK or atypical BRAF alteration. 
ORR will be defined as the percentage of patients achieving a Best Overall Response 
(BOR) of confirmed Complete Response (CR) and/or Partial Response (PR), according to 
RECIST 1.1. 
• 
Secondary:  
o 
To evaluate the safety profile of ulixertinib per CTCAE v5.0, including term, 
incidence, severity, and duration of AEs. 
o 
To assess the duration of response (DOR), according to RECIST 1.1. 
o 
To assess the progression free survival (PFS), according to RECIST 1.1 and 
overall survival (OS) over 18 months. 
o 
To measure the blood levels of ulixertinib and selected metabolites: 
Pharmacokinetic profile of ulixertinib (BVD-523) and selected metabolites. 
• 
Exploratory:  
o 
To evaluate the effects of ulixertinib on pharmacodynamic markers: ctDNA tissue 
biopsies, and/or blood to assess biomarkers. Assays include, but are not limited 
to, phosphorylation of RSK from whole blood, Reverse Phase Protein Arrays 
(RPPA) to assess protein levels, e.g. DUSP 4/6, plus Nanostring and/or RNA-
exome to assess mRNA expression in tissue pre- and post-ulixertinib treatment. 
Part B – Tumor histology specific 
• 
Primary: To assess PFS in patients receiving ulixertinib in defined tumor histologies (up to 
three histologies to be selected) compared to physician’s choice of treatment. Patient’s 
tumors must harbor a specified MEK or atypical BRAF alteration.  
PFS will be defined as the time from first day of trial medication to disease progression 
according to RECIST 1.1, or death. 
• 
Secondary:  
o 
To evaluate the safety profile of ulixertinib per CTCAE v5.0, including term, 
incidence, severity, and duration of AEs. 
o 
To assess OS over 18 months in patients receiving ulixertinib with a defined tumor 
histology and a MEK or atypical BRAF alteration, compared to physician’s choice 
of treatment. 
o 
To determine ORR and DOR in patients receiving ulixertinib with a defined tumor 
histology and a MEK or atypical BRAF alteration, according to RECIST 1.1, 
compared to physician’s choice of treatment. 
Study Population - Criteria for Inclusion: 
Patients must meet all of the inclusion criteria to be eligible. 
1. Patients with a locally advanced or metastatic malignancy, that has progressed following 
systemic therapy for their disease, if available, or for which the patient is not a candidate or 
refuses.  
2. Tumors harboring a MEK or atypical BRAF alteration.  

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Sponsor: 
BioMed Valley Discoveries, 
Inc. 
Investigational Product: 
Ulixertinib (BVD-523) 
Developmental Phase:   
Phase II 
3. Provide signed and dated informed consent prior to initiation of any study-related procedures 
that are not considered standard of care (SoC). 
4. Male or female patients aged ≥18 years. 
5. Patients must have measurable disease by RECIST version 1.1. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2. 
7. Adequate renal function [creatinine ≤1.5 times ULN (upper limit of normal)] or a glomerular 
filtration rate (GFR) of ≥50 mL/min (using Cockcroft-Gault). 
8. Adequate hepatic function [total bilirubin ≤1.5 times ULN; AST (aspartate transaminase) and 
ALT (alanine transaminase) ≤3 times ULN or ≤5 times ULN if the elevation is due to liver 
involvement by tumor]. 
9. Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x 109 cells/L; absolute 
neutrophil count ≥1.5 x 109 cells/L). 
10. Adequate cardiac function:  
• 
Left ventricular ejection fraction (LVEF) of >50% as assessed by multi-gated 
acquisition (MUGA) or ultrasound/echocardiography (ECHO); and  
• 
A corrected QT interval (QTc) <480ms by the Fridericia method (QTcF).  
11. 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 last administration of study drug. 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 last administration of study 
drug. 
12. Willing and able to participate in the trial and comply with all trial requirements. 
13. Patients with a prior or concurrent malignancy whose natural history or treatment does not 
have the potential to interfere with the safety or efficacy assessment of the investigational 
agent may be included after consultation with the medical monitor. 
Study Population - 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. Having received any cancer-directed therapy (chemotherapy, hormonal therapy, biologic or 
immunotherapy, etc.) within 28 days or 5 half-lives (whichever is shorter) prior to the first dose 
of study drug. Patients previously treated with radiotherapy must have recovered from the 
acute toxicities associated with such treatment. 

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Sponsor: 
BioMed Valley Discoveries, 
Inc. 
Investigational Product: 
Ulixertinib (BVD-523) 
Developmental Phase:   
Phase II 
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 study drug. A minimum of 10 days between termination of the prior 
investigational drug and administration of study drug is required. In addition, any drug-related 
toxicity except alopecia should have recovered to Grade 1 or less.  
7. Prior therapy with any ERK inhibitor (e.g. LY3214996, LTT462).   
8. Groups 1-4: Prior therapy with any BRAF and/or MEK inhibitor (e.g. encorafenib, dabrafenib, 
vemurafenib, binimetinib, trametinib, cobimetinib) is excluded. Prior BRAF and/or MEK 
inhibitor therapy is permitted for Groups 5 and 6. 
9. For Part B, agents targeting BRAF or MEK kinases and experimental agents are not permitted 
as physician’s choice  
10. Pregnant or breast-feeding women. 
11. Any evidence of serious active infections. Patients are allowed to enroll if they have been 
fever-free for at least 48 hours and are on an active treatment that is not prohibited in 
Appendix 1. 
12. Any important medical illness or abnormal laboratory finding that would increase the risk of 
participating in this study (based on the investigator’s judgment).  
13. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy 
(CSR). 
14. Concurrent therapy with any other investigational agent. 
15. Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2, CYP2D6, 
and CYP3A4. 
Concomitant Medications: 
Necessary supportive care such as antibiotics, blood product transfusions, antiemetics, 
antidiarrheals, etc., will be allowed. Drugs that are strong inhibitors or inducers of CYP1A2, 
CYP2D6, and CYP3A4 will not be allowed during the study (see Appendix 1). 
Description of Sites/Facilities Enrolling Patients: 
The study will take place at sites within the United States. Approximately, up to 25 sites will be 
utilized, however, because the patient population is relatively rare, clinical sites may need to be 
added as qualifying patients are found. Clinical trial networks may be utilized. 
Description of Study Drug: 
Ulixertinib (BVD-523), 600 mg formulated blend, taken orally, with food, twice-daily for each 28-day 
cycle. 
Study Duration: 
Approximately 38 months. 
Patient Number: 
Total enrollment for Part A is targeted at approximately 228 patients with 38 patients per group. 
Additional patients may be enrolled as appropriate. 
Total enrollment for Part B is targeted to approximately 80-100 patients per histology with up to 
three histologies included; however, additional patients may be enrolled.  

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Sponsor: 
BioMed Valley Discoveries, 
Inc. 
Investigational Product: 
Ulixertinib (BVD-523) 
Developmental Phase:   
Phase II 
Patient Duration: 
Each patient will continue on study therapy until documented disease progression, intolerable 
toxicity, study closure, or until other treatment discontinuation criteria is met. Patients who 
discontinue study therapy prior to disease progression, will continue to be followed for progression. 
It is estimated that participants will be on study for up to 30 months. 
Statistical analysis: 
The Full Analysis Set (FAS) will include all patients who received at least one dose of study 
medication. For Part B, analyses performed on the FAS will allocate patients’ treatment group as 
randomized. 
The safety analysis set will include all patients who received at least one dose of study medication. 
For Part B, analyses performed on the safety population will allocate patients’ treatment group as 
actually received. 
The per-protocol (PP) analysis set will include all patients of the FAS who completed the study 
without any major protocol deviations. 
All analyses will be performed separately for Part A and Part B, and by group/tumor histology. 
Efficacy analysis: 
The efficacy analysis will be performed on the FAS. 
ORR is defined as the percentage of patients achieving a BOR of confirmed complete response 
(CR) and/or partial response (PR) as assessed by the investigator for Part A, and both as 
assessed by the investigator and as adjudicated by the independent review committee for Part B.  
ORR will be calculated with the corresponding 95% confidence interval (CI). For Part B, ORR will 
be compared between ulixertinib and physician’s choice of treatment using a Chi square test. 
DOR is defined as the time from first response to disease progression or death. PFS is defined as 
the time from first day of trial medication to disease progression or death. OS is defined as the 
time from first day of trial medication to death. Censoring rules will be applied as appropriate. 
DOR, PFS, and OS will be analyzed using Kaplan-Meier estimates and curves, median PFS and 
respective 95% CIs. For Part B, DOR, PFS, and OS will be compared between ulixertinib and 
physician’s choice of treatment using a Log Rank test. These analyses will be performed based on 
investigator assessment for Part A, and both on adjudicated assessment by the independent 
review committee and on investigator assessment for Part B. 
Sensitivity analyses will be conducted. 
Safety analysis: 
The safety analysis will be performed on the safety analysis set. 
AEs, including treatment-emergent adverse event, AEs considered study drug-related, deaths, 
SAEs, and AEs resulting in study drug discontinuation, will be summarized (number and 
percentage of patients) by System Organ Class and Preferred Term. 
The parameters associated with the clinical laboratory tests (hematology, clinical chemistry, and 
urinalysis) will be summarized with descriptive statistics by visit and for the change from baseline 
to each planned post-baseline visit. Graded laboratory abnormalities will be defined using the 
grading scheme based on NCI CTCAE and summarized. Shift tables will also be produced. 

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Sponsor: 
BioMed Valley Discoveries, 
Inc. 
Investigational Product: 
Ulixertinib (BVD-523) 
Developmental Phase:   
Phase II 
Changes in the patient’s physical examination findings, vital sign parameters, and ECG will be 
summarized by group/tumor histology and overall, and any abnormal values will be tabulated. 
3.2 
SCHEMA 
 
 
 
3.3 
SCHEDULE OF ACTIVITIES (SOA) 
The Schedule of Activities (SoA) table (Table 3.1) provides an overview of the protocol 
visits and procedures. Refer to Section 10, Study Assessments and Procedures for 
detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in 
the SoA table in order to conduct evaluations or assessments required to protect the 
wellbeing of the patient. Every effort should be made to follow the SoA for the entire 
study. 
Group 1 (n=38)
•
Alterations at BRAF-G469, -
L485, or -L597
•
Any histology (excluding CRC)
Group 2 (n=38)
•
Defined class II BRAF 
alterations (see appendix 2)  
•
Any histology (excluding CRC)
Group 3 (n=38)
•
Any other atypical BRAF 
alteration
•
Any histology (excluding CRC)
Group 4 (n=38)
•
Any atypical BRAF alteration
•
CRC patients only
Group 5 (n=38)
•
MEK1/2 alteration
•
Any histology (excluding CRC)
Group 6 (n=38)
•
MEK1/2 alteration
•
CRC patients only
PART A
Ulixertinib 600 mg BID
PART B
Defined histology and alterations determined by Part A 
Randomized: Ulixertinib 600 mg BID or Physician's choice
1: Defined histology and alterations
Ulixertinib 600 mg BID
Physician’s choice
2: Defined histology and alterations
Ulixertinib 600 mg BID
Physician’s choice
3: Defined histology and alterations 
Ulixertinib 600 mg BID
Physician’s choice
2:1
2:1
2:1

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Table 3.1 
Part A and B: Schedule of Activities 
 
 
Cycle 1 
Day 1 through 28 
Cycle 2 
Day 29 through 56 
Cycle 3-X 
28-day cycles, visit 
on 1st day of cycle 
Post Treatment Period 
Visit 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
 -X Tx 
End of 
Treatment 
(EOT) Visit 
Safety Follow-
Upa 
Follow-
Upb 
Visit Day 
-28 to -1 
1 ± 0 
8 ± 3 
15 ± 3 
29 ± 3 
36 ± 3 
43 ± 3 
57 ± 3 
<14 ± 3 days 
after last dose 
30 ± 3 days 
after last dose 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Cancer historyd 
X 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Measure height  
X 
 
 
 
 
 
 
 
 
 
 
Measure weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examinatione 
X 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ophthalmology examf 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy testg,h 
X 
Xg 
 
 
Xh 
 
 
Xh 
Xh 
 
 
Clinical lab testsi, j 
X 
Xi 
X 
X 
X 
X 
X 
Xj 
X 
 
 
Electrocardiogram (ECG)k 
X 
 
 
 
 
 
 
 
 
 
 
ECHO cardiogram or 
MUGA 
X 
 
 
 
 
 
 
 
 
 
 
Assess current disease 
statusl 
X 
 
 
 
X 
 
 
X 
X 
 
Xm 
Study drug administrationn 
 
X 
 
X 
 
 
 
 
 
 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Table 3.1 
Part A and B: Schedule of Activities 
 
 
Cycle 1 
Day 1 through 28 
Cycle 2 
Day 29 through 56 
Cycle 3-X 
28-day cycles, visit 
on 1st day of cycle 
Post Treatment Period 
Visit 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
 -X Tx 
End of 
Treatment 
(EOT) Visit 
Safety Follow-
Upa 
Follow-
Upb 
Obtain unused drug 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance by pill count 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug dispensed 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Part A Only 
Tissue biopsy, if 
indicatedo,p 
Xo 
 
 
 
X 
 
 
 
Xp 
 
 
Pharmacodynamic blood 
samplesq 
 
X 
 
X 
 
 
 
 
 
 
 
ctDNAr 
 
X 
 
X 
X 
 
 
 
X 
 
 
Pharmacokinetic sampless 
 
 
 
Xs 
 
 
 
 
 
 
 
Part B Only 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
Table footnotes: 
a 
Patients will return to the clinic or will be contacted for a safety follow-up assessment 30 days ± 3 days after the last dose of study drug was 
taken; or earlier if subsequent therapy for advanced malignancy is initiated prior to 30 days ± 3 days.   
b 
Patients or their legally authorized representatives will be contacted every three months (± 7 days) until death, end of the study, or patient 
withdrawal of consent, whichever comes first. Survival and subsequent treatment status may be collected by public records, medical records, 
or by contacting the patient or their legally authorized representative by phone. 
c 
Full medical history at screening, only review/update of history at subsequent visits. 
d 
Oncologic history of the malignancy under study including prior regimens (duration of therapy, best response on therapy, date of 
discontinuation, and reason for discontinuation), surgery, and radiation therapy. 
e 
Physical examinations should be symptom driven after the Screening Visit. 
f 
Ophthalmological examinations will be performed by an ophthalmologist at screening, and whenever clinically indicated. In Part B, only 
patients in the ulixertinib arm need an ophthalmological exam. See section 10.1.5 for a full description of tests.  
g 
ONLY if the screening serum pregnancy test was performed more than 1 day previously. 

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h 
After screening and baseline, if urine pregnancy test is positive, confirm with serum test. 
i 
Visit 2 clinical lab samples should be collected pre-dose if not done during Screening Visit within 72 hours of start of treatment. 
j 
Chemistry, hematology, and urinalysis. After Cycle 2, clinical labs to be performed prior to starting each new cycle or more frequently when 
clinically indicated at the investigator’s discretion. See section 10.1.6 for a full description of test.  
k 
Patients with a normal ECG in Cycle 1 do not need to have repeat ECGs in subsequent cycles. Patients should be supine for 5 minutes prior 
to the ECG. 
l 
Tumor assessments will be made prior to dose initiation, at Visit 5, and then every 2 cycles. Patients who discontinue treatment for reasons 
other than progression will have assessments at the EOT visit (unless their previous assessment was performed within 28 days). The same 
imaging modality used for an individual patient (i.e. CT or MRI) at Screening should be maintained throughout the study. 
m 
Patients that discontinue study treatment for any reason other than disease progression, must continue to have disease assessments every 8 
weeks (± 7 days) until disease progression or the initiation of subsequent anticancer therapy. 
n 
Study drug to be taken twice daily. The first dose should be taken in the clinic on days when PD sampling occurs i.e., Cycle 1/Visit 2 (Day 1) 
and Cycle 1/Visit 4 (Day 15), remaining doses on all other days to be self-administered by patient. 
o 
Tissue biopsy for Part A only. If a patient has undergone a biopsy within ≤ 6 months and has not received any anticancer treatment since 
undergoing the biopsy, archival tissue from this biopsy may be used to fulfill screening tissue requirements. 
p 
Tissue biopsy at final study visit/at progression is optional, but strongly encouraged to help elucidate mechanism of resistance. 
q 
Collect pre-dose and 4 hour +/- 10 mins post-dose blood samples for PD. 
r 
Collect plasma for ctDNA.  
s 
Sample for PK should be collected pre-dose trough at steady state (patients who have received at least 5 days, or 10 consecutive doses, of 
study drug).   
 
 

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4 
INTRODUCTION 
4.1 
STUDY RATIONALE 
This BVD-523-ABC study builds on the safety and clinical activity experience of 
previous studies that have evaluated ulixertinib as a novel targeted cancer treatment 
in cohorts of patients with specific genetic alterations and tumor histologies that result 
in aberrant MAPK pathway signaling. Early clinical data have demonstrated anti-tumor 
activity with ulixertinib treatment and have identified specific groups of patients for 
whom additional development is warranted. 
4.2 
BACKGROUND 
Ulixertinib (BVD-523) is a small molecule inhibitor of extracellular signal-regulated 
kinase (ERK) family kinases (ERK1 and ERK2) that is being developed as a novel 
anti-cancer drug (Germann et al, 2017; Sullivan et al, 2018). ERK kinases are 
downstream components of the mitogen-activated protein kinase (MAPK) signaling 
cascade (RAS-RAF-MEK-ERK). Ulixertinib has demonstrated promising early efficacy 
for patients with tumors harboring alterations in the MAPK pathway, including atypical 
(non-V600) BRAF alterations, for which there are currently no approved targeted 
agents. This clinical protocol expands upon the ulixertinib Phase I signal to evaluate 
the utility of ulixertinib to treat patients with tumors harboring an atypical BRAF 
alteration. Furthermore, the potential to treat MEK1/2 mutant cancers will also be 
explored. This patient population is rare (<1% of cancers), however a strong scientific 
rationale exists to treat patients harboring putatively activating MEK1/2 alterations with 
ERK inhibition (Emery et al, 2017; Gao et al, 2018; Yaeger et al, 2019).      
The MAPK signaling cascade is among the most frequently mutated pathways in 
human cancer. Approximately 50% of melanoma patients possess a druggable 
hotspot V600E/K mutation in the BRAF protein kinase. FDA approvals of both immune 
system- (ipilimumab, nivolumab, and pembrolizumab) and signal transduction-
targeted (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib 
plus binimetinib) therapies have greatly expanded the armamentarium available for 
treating BRAF V600 mutation-dependent cancers.  
Atypical BRAF alterations (non-V600) are found in many cancers and are more 
prevalent than V600 mutations in certain tumor types. For example, between 50–80% 
of BRAF mutations in non-small cell lung cancer (NSCLC) and 22–30% in colorectal 
cancer (CRC) encode for BRAF non-V600 alterations (Danker et al, 2018). As next 
generation sequencing becomes standard clinical practice, oncologists are frequently 
identifying non-V600 BRAF alterations in their patients’ tumors. Unfortunately, there 
are no approved therapies targeting these alterations and thus there remains a lack 

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of viable therapeutic options that could be employed for optimal treatment of these 
patients.   
From recent studies, a new classification system is emerging for BRAF mutations 
based on biochemical and signaling mechanisms associated with these mutants (Yao 
et al, 2015; Yao et al, 2017; Dankner et al, 2018; Yaeger et al, 2019). Class I BRAF 
mutations affect amino acid V600 and signal as RAS-independent active monomers.  
While ulixertinib has demonstrated activity against MAPK pathway activity initiated by 
Class I BRAF mutations and thus may offer unique possibilities as single-agent or in 
combinations, these mutations are currently being addressed clinically with FDA 
approved inhibitors of BRAF plus MEK (dabrafenib plus trametinib, vemurafenib plus 
cobimetinib, and encorafenib plus binimetinib).   
Class II BRAF alterations function as RAS-independent activated dimers and are not 
addressed by available approved targeted therapies. Ulixertinib has demonstrated 
clinical activity against several of these class II BRAF alterations, across multiple 
tumor types (Sullivan et al, 2018).   
Class III BRAF alterations exhibit enhanced binding to RAS and wild-type RAF to 
signal as mutant BRAF-wild-type RAF dimers, thus amplifying the signaling 
downstream of RAS and thus require upstream activation to drive ERK signaling. For 
this reason, Class III BRAF alterations commonly co-occur in the context of other 
drivers of MAPK signaling, e.g. RAS mutation, NF1 loss, RTK activation.  
In human tumors the incidence of MEK1/2 mutations is rare (<1%). Similar to BRAF, 
a mechanism-based classification system has been proposed (Gao et al, 2018).  
Preclinical data has demonstrated activity of ulixertinib in MEK mutant models (Emery 
et al, 2017). 
In summary, ulixertinib, is a potent and selective inhibitor of the key MAPK pathway 
enzymes ERK1 and ERK2, has shown potent anti-tumor effects, including anti-cancer 
activity using in vitro cellular assays and in vivo tumor xenograft models. Our initial 
open-label, first-in-human clinical study (NCT01781429) with oral ulixertinib was 
conducted to identify the maximum tolerated dose (MTD) and the RP2D. Study aims 
also included assessment of the PK and pharmacodynamic properties of ulixertinib as 
well as preliminary efficacy in patients with genetic aberrations in BRAF (both V600 
and non-V600 amino acids), NRAS, and MEK. Consistent with current scientific 
understanding, class II BRAF mutations were demonstrated to be sensitive to single-
agent ulixertinib, largely independent of tumor type. In particular, non-V600 BRAF 
mutations, including G469A/V, L485W, and L597Q, across a variety of solid tumors, 
were shown to be clinically actionable for the first time, with durable objective 
responses.   

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The potential risk profile of ulixertinib is described in further detail in the following 
sections. 
4.2.1 
Potential Risk 
Preliminary evidence from in vitro and in vivo toxicological assessments of ulixertinib 
and data to-date from the experience in humans suggests the molecule has a safety 
profile supportive of its development as an anti-cancer therapeutic. Additionally, 
human clinical trials have been conducted using other drugs known to affect the MAPK 
pathway and findings from these studies may provide information regarding possible 
safety risks that may be mechanistically attributable to MAPK pathway inhibition.   
Thus, the risk profile for ulixertinib may potentially include the following: 
Dermatological Lesions 
Dermatological lesions have been seen in rodent GLP toxicology studies of ulixertinib.  
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 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 was observed in a subset of the patients treated 
in studies BVD-523-01 and BVD-523-02, with approximately 81% of patients in study 
BVD-523-01 and 38% in study BVD-523-02 experiencing TEAEs in the System Organ 
Class skin and subcutaneous tissue disorders, regardless of attribution. The TEAEs 
were most frequently rash (coded to various preferred terms), dermatitis acneiform, 
and pruritus; and one patient with a history of squamous cell carcinoma developed a 
keratoacanthoma while on treatment with ulixertinib. Rash has been treated with 
topical and/or oral agents (e.g., steroids), and dose reductions/interruptions as 
needed. One case of Stevens-Johnson syndrome assessed as possibly related to 
BVD-523, but confounded by concomitant medications, including an antibiotic, was 
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diagnosis was made clinically, without a biopsy. Discontinuations due to skin disorders 
have occurred but have been uncommon.  
Gastrointestinal Toxicity 
Preclinical toxicity studies of ulixertinib have provided evidence of exposure-related, 
reversible gastrointestinal toxicities, and these toxicities, including nausea, vomiting, 
and diarrhea, have also been observed at high frequency in the clinical program, in 
some cases occurring in association with dehydration and elevated creatinine/renal 
insufficiency. Nausea, vomiting, and diarrhea have been managed with ulixertinib 
dosing interruptions and supportive medications as needed and, in some cases, dose 
reduction of ulixertinib has been undertaken. Gastrointestinal hemorrhage (both upper 
and lower) has been reported in the ulixertinib program with the majority of events 
assessed as unrelated to study drug. The severity and reversibility of these non-
clinical and clinical toxicities, while not meriting a specific monitoring or treatment plan, 
warrant active routine monitoring of patients for this toxicity.  
General Disorders 
Study drug-related disorders characterized as general disorders, including fatigue, 
edema, and fever, have been observed in the ulixertinib program. In some patients, 
fatigue has been assessed as grade 3 in severity, but has not prompted study drug 
discontinuation. Events in the general disorders’ category have been managed 
variably with supportive medications and/or interruption of study drug administration 
until improvement or resolution. A Death (NOS) assessed as possibly related to 
ulixertinib and to metastatic duodenal carcinoma was reported in a 79-year-
old patient; no autopsy was performed.  
Hepatic and Renal Effects 
Study drug-related events of mild, moderate, and severe elevated AST and/or ALT 
have also been observed in the ulixertinib clinical program and were described as 
dose limiting toxicities (DLTs) in study BVD-523-01 at a dose of 900mg b.i.d. and in 
study BVD-523-02 at a dose of 750mg b.i.d. Drug-related events of elevated AST 
and/or ALT have been managed with interruptions of study drug followed in some 
instances by dose reduction. Study drug-related events of mild, moderate, and severe 
increased creatinine have also been observed, sometimes in conjunction with 
vomiting, diarrhea, and dehydration. Management has consisted of study drug 
interruption, rehydration, and, in some instances, dose reduction or discontinuation of 
study drug. 

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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). 
Hematologic effects in the ulixertinib clinical program have included, anemia, 
leukopenia, neutropenia, lymphopenia, and thrombocytopenia. One case of possibly 
related, grade 3, reversible, thrombotic thrombocytopenia purpura was reported in a 
patient with melanoma while receiving ulixertinib at a dose of 450mg b.i.d. A case of 
grade 4, life-threatening thrombocytopenia assessed as possibly related to ulixertinib 
as well as to underlying Noonan Syndrome was reported in a 23-year-old woman. 
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 
Ulixertinib exhibits an absorbance peak in the range of UV-A/UV-B light, specifically 
at ~320 nm. In clinical studies with ulixertinib to date, 5 TEAEs of photosensitivity 
reaction in patients on 75mg (1 patient) and 600mg b.i.d. (4 patients) have been 
reported (all in study BVD-523-01). 
Beyond dermatological monitoring (above), potential risks of direct phototoxic 
reactions induced by ulixertinib should be further minimized by advising patients to 
minimize sun exposure, use broad-spectrum sunscreens, and wear sunglasses.  
Patients will be informed that relevant sun exposure may occur even through glass, 
such as while driving. 
Ophthalmological Effects 
While the preclinical toxicology studies of ulixertinib have not revealed any exposure-
dependent ophthalmological toxicities, based on clinical studies of MEK1/2 inhibitors 
which highlighted ocular toxicities that may reflect mechanistically attributable risks 
observable in a proportion of patients, clinical studies of ulixertinib have included close 
monitoring for ocular toxicities. In the clinical trials to date, the following ocular events 
have been rarely reported (n=115): visual impairment (7%), vision blurred (4%), 
photophobia (2%), retinal vein occlusion (<1%, reversible grade 3), vitreous floaters 
(<1%), chorioretinopathy (<1%), halo vision (<1%), and retinal detachment (<1%). 
Although it is not definitively understood whether ocular toxicities reflect primary 
pharmacology associated with global inhibition of the MAPK pathway, specific 

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management and exclusion criteria will be defined in this study protocol as the 
toxicities could potentially severely and irreversibly impact patient well-being. 
Cardiac Effects 
The balance of preclinical evidence suggests ulixertinib has low, but observable, 
potential to cause QT prolongation.  In study BVD-523-01, 105 patients (24 patients 
in Part 1 and 81 patients in Part 2) were included in an analysis of QT prolongation. 
Electrocardiograms extracted from 12-lead Holter monitors, along with time matched 
pharmacokinetic blood samples, were collected over 12 hours on cycle 1, day 1 and 
cycle 1, day 15 and analyzed by a core ECG laboratory. The estimated mean changes 
from the baseline in the study-specific QTc interval, at the ulixertinib Cmax, were – 
0.529 msec (90% confidence interval [CI] – 6.621, 5.562) on day 1 and – 9.202 msec 
(90% CI – 22.505, 4.101) on day 15, well below the 20 msec threshold considered 
appropriate for oncology agents. Overall, the evaluated ECG data showed that 
ulixertinib does not prolong the corrected QT interval using the Fridericia formula 
(QTcF) interval in patients in a concentration-dependent manner; ulixertinib may 
modestly increase the heart rate to a degree not likely to be of clinical significance for 
patients without underlying significant cardiovascular conditions (Mendzelevski et al, 
2018).  
TEAEs in the System Organ Class of cardiac disorders have been reported in 
approximately 14% of the patients treated to date, with preferred terms including 
tachycardia, atrial fibrillation, and palpitations. One case of cardiac failure was 
considered at least possibly related to ulixertinib. Patients dosed with ulixertinib 
undergo assessment of cardiac status (LVEF and ECG) at baseline and subsequently 
as needed. 
Tissue Mineralization 
Dose-dependent tissue mineralization in association with an increase in serum 
phosphorus and a modest decrease in serum calcium was observed in rodent 
toxicology studies of ulixertinib. Furthermore, 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 that may indicate shifts in mineralization of the bone 
and tissues, including blood chemistry analyses for calcium and inorganic phosphate, 
are performed in the clinical program and any indication of abnormalities may result 
in further investigations. TEAEs of hypocalcemia and increased blood phosphorus 
have been reported; however, tissue mineralization has not been reported. 

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4.2.2 
Pharmacology Studies 
In this section a short summary of preclinical data is provided. Detailed information is 
presented in the current ulixertinib (BVD-523) Investigator’s Brochure and Germann 
et al, 2017.  
The observation that ulixertinib’s cellular potency is associated with MAPK pathway 
alterations, which are characterized by ERK activity and dependency, was confirmed 
and extended with the use of murine xenograft models. Ulixertinib has demonstrated 
dose-dependent efficacy in human mouse xenograft models, which harbor alterations 
within the MAPK pathway. This includes BRAF (V600E) cell line xenograft models 
A375 (melanoma) and colo205 (colon), and KRAS (G12C) mutant model MIAPaca2 
(pancreas). In addition, ulixertinib activity has also been demonstrated in a patient 
derived xenograft melanoma model established from the tumor of an individual 
relapsing off BRAF targeted therapy with vemurafenib. Furthermore, ulixertinib 
displayed impressive activity when used in combination with BRAF inhibitor 
dabrafenib (Germann et al, 2017).  
4.2.2.1 
Single Agent Ulixertinib is Efficacious in a Mouse Xenograft 
Model of BRAF Mutant Human Melanoma Cell Line (A375) 
In A375 cell line xenografts, 5, 25, 50, and 100 mg/kg twice daily doses of ulixertinib 
were compared following 18 days of treatment. For all doses, no significant body 
weight changes were observed. Ulixertinib demonstrated significant dose-dependent 
antitumor activity starting at 50 mg/kg twice daily (Figure 4.1). Doses of 50 and 100 
mg/kg twice daily significantly attenuated tumor growth, with tumor growth inhibition 
(TGI) of 71% (P = 0.004) and 99% (P < 0.001), respectively. Seven partial responses 
(PR) were noted in the 100 mg/kg twice daily group; no regression responses were 
noted in any other group. 
 
 
 
 
 
 
 
 

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Figure 4.1 
BVD-523 Displays Dose Dependent Efficacy in the Murine 
Xenograft Model of Human BRAF-Mutant Melanoma Cell Line 
A375 
 
4.2.2.2 
Ulixertinib Demonstrates Profound Anti-Tumor Activity when 
Combined with Dabrafenib in Mouse Xenograft Model of 
BRAF Mutant Human Melanoma Cell Line (A375) 
To evaluate the benefit of the combination, efficacy was assessed in vivo utilizing 
xenografts of the BRAF (V600E) mutant human melanoma cell line A375. Because of 
the response of combined dabrafenib and ulixertinib treatment, dosing in the 
combination groups was stopped on day 20 to monitor for tumor regrowth and was 
reinitiated on day 42 (Figure 4.2). Tumors were measured twice weekly until the study 
was terminated on day 45. The median time to endpoint (TTE) for controls was 9.2 
days, and the maximum possible tumor growth delay (TGD) of 35.8 days (end of 
study) was defined as 100%. Temozolomide treatment resulted in a TGD of 1.3 days 
(4%) and no regressions. The 50- and 100-mg/kg dabrafenib monotherapies produced 
TGDs of 6.9 days (19%) and 19.3 days (54%), respectively, a significant survival 
benefit (P < 0.001), and 1 PR in the 100 mg/kg group. The 100-mg/kg ulixertinib 
monotherapy resulted in a TGD of 9.3 days (26%), a significant survival benefit (P 
< 0.001), and 2 durable complete responses (CRs). The combinations of dabrafenib 
with ulixertinib each produced the maximum possible 100% TGD with statistically 
superior OS compared with their corresponding monotherapies (P < 0.001). The 
lowest dose combination produced a noteworthy 7/15 tumor-free survivors (TFS), and 
the 3 higher dosage combinations produced a total of 43/44 TFS, consistent with 
curative or near-curative activity observed in the Kaplan-Meyer plot ( 
Figure 4.3).  
0
4
8
12
16
20
0
500
1000
1500
2000
2500
3000
3500
Time (Day)
Tumor Volume (mm3) 
Vehicle
BVD-523 (5 mg/kg, po, BID)
BVD-523 (25 mg/kg, po, BID)
BVD-523 (50 mg/kg, po, BID)
BVD-523 (100 mg/kg, po, BID)

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Figure 4.2 
Mean Tumor Volume Plot; BVD-523 and Dabrafenib Combination 
Demonstrates Superior Efficacy Compared to Either Single Agent 
Alone in the A375 BRAF Mutant Melanoma Xenograft Model 
 
 
Figure 4.3 
Kaplan-Meyer Plot; BVD-523 and Dabrafenib Combination 
Demonstrates Superior Survival Compared to Either Single Agent 
Alone in the A375 BRAF Mutant Melanoma Xenograft Model 
 
 
 

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4.2.3 
Toxicity and Safety Studies 
When ulixertinib was characterized using in vitro screens against 66 receptors and ion 
channels, no toxicologically significant interactions were identified. Additionally, 
ulixertinib was negative in bacterial mutation and in vivo micronucleus screening 
assays; therefore, ulixertinib is not considered to have a significant genetic toxicology 
risk. 
While ulixertinib modestly inhibits the human ether-a-go-go related gene (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, ulixertinib is considered to have a low 
potential to cause QT prolongation in patients, but, as stated, patients dosed with 
ulixertinib in the first-in-human study, BVD-523-01, were monitored for potential QTc 
prolongation and related cardiotoxicities via Holter monitoring. No clinically significant 
cardiac abnormalities have been seen in the ulixertinib clinical program to date.  
In vitro studies suggest that the compound is metabolized primarily via oxidation by 
multiple CYPs including 3A4, 2D6, and 1A2. No significant CYP induction was 
observed after up to 14 days drug treatment in rats. In vitro human liver microsome 
studies do demonstrate ulixertinib to induce CYP1A2, CYP2B6, and CYP3A4 mRNA 
expression, whist also directly inhibiting CYP2C8 and CYP3A4/5. These data suggest 
a limited potential for drug-drug interactions. 
Ulixertinib 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% carboxymethyl-cellulose (CMC) and has a half-life of 2-4 hours across all species. 
Ulixertinib was administered to male and female Sprague-Dawley rats in several 
toxicology studies: (1) a GLP study for up to 28 days at dose levels up to 50 mg/kg/day 
twice daily; (2) for up to 14 days at dose levels up to 100 mg/kg twice daily; and (3) 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 one or more tissues at toxic doses. In animals in which mineralization 
occurred after treatment with ulixertinib, 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. 

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When ulixertinib 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, ulixertinib 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. 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 (1) swelling in the neck, 
(2) decreased forelimb strength, (3) multiple clinical pathology findings, and (4) 
enlarged lymph nodes, spleen, and mammary gland. Based on these observations, 
the severely toxic dose in 10% of the animals (STD10) for ulixertinib 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. 
Ulixertinib 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 ulixertinib 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. 
Based on the data accumulated to date, ulixertinib possesses a toxicology profile 
which presents no impediment to its development as an anti-cancer agent. 
4.2.4 
Previous Human Experience 
Ulixertinib has been administered to humans in 5 commercially sponsored clinical 
studies, 4 investigator sponsored trials (IST), and 3 NCI sponsored trials to date: 

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Table 4.1 
Previous Human Experience with Ulixertinib 
Study Type 
Study Identifiers 
Status/Results 
Commercial 
sponsored 
NCT01781429  
BVD-523-01 
Phase 1 Dose-
Escalation, Safety, 
Pharmacokinetic and 
Pharmacodynamic 
Study of BVD-523 in 
Patients with Advanced 
Malignancies.  
In the first in human, phase I study of ulixertinib a total of 135 patients 
were enrolled in the dose escalation and dose expansion phases of 
the study. Twenty-seven patients were enrolled in the dose escalation 
phase (10-900 mg b.i.d.). The maximum tolerated dose (MTD) and 
recommended phase 2 dose (RP2D) was determined to be 600 mg 
twice daily given continuously. Dose-limiting toxicities (DLT) included 
rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure 
was dose proportional up to the RP2D, which provided near-complete 
inhibition of ERK activity in whole blood. In the expansion cohort (108 
patients), there were no drug related deaths; however, 32% of patients 
required a dose reduction. The most common AEs at RP2D, 
regardless of attribution, were diarrhea (50%), fatigue (50%), nausea 
(45%), decreased appetite (31%), and dermatitis acneiform (31%). In 
addition to 3 patients with partial responses during escalation (11%), 
an additional 11 of 81 (14%) evaluable patients at expansion had a 
partial response: 1 BRAFV600E mutant melanoma patient refractory to 
prior BRAF/MEK inhibitor treatment, 3 NRAS mutant melanoma 
patients, 3 patients with BRAF mutant lung cancers including response 
in brain metastases, 1 with BRAFV600E mutant glioblastoma multiforme, 
1 with BRAFG469A head & neck cancer, 1 with BRAFG469A small-bowel 
cancer, and 1 with BRAFL485W gallbladder cancer. The duration of 
response ranged from 2 to 24+ months (82, 98). A total of 28 
evaluable patients whose BRAF mutations were not at amino acid 
V600 were included in the BVD-523-01 solid tumor study of ulixertinib.  
Figure 4.4 and 4.5 provide the percent target lesion change and study 
duration for patients with atypical BRAF alterations, respectively. 

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Study Type 
Study Identifiers 
Status/Results 
Commercial 
sponsored 
NCT02296242 
BVD-523-02  
Phase 1/2 Dose-
Escalation, Safety, 
Clinical Activity, 
Pharmacokinetic and 
Pharmacodynamic 
Study of the ERK 1/2 
Inhibitor BVD-523 in 
Patients with Acute 
Myelogenous 
Leukemia or 
Myelodysplastic 
Syndromes 
An open-label, multi-center Phase I/II study to determine the safety, 
tolerability, and pharmacokinetic profile of ulixertinib in patients with 
AML or MDS, as well as to assess clinical response, PFS, and 
duration of response in those patients. The study consisted of 2 parts: 
Part 1 was a dose-escalation phase to investigate safety and 
determine the MTD and the RP2D, and Part 2 was a cohort-expansion 
phase using the RP2D to examine safety, and to identify early 
indications of clinical effects. Patients received continuous twice-daily 
oral dosing with ulixertinib in 21-day cycles. A total of 18 patients 
received at least one dose of ulixertinib in the dose-escalation phase 
(300-750mg b.i.d.). In Part 1, the MTD and RP2D were determined to 
be 600 mg b.i.d., and this is the dose that was tested in the cohort-
expansion phase (Part 2) of the study. A total of 35 patients received 
at least one dose of ulixertinib in the cohort-expansion phase of the 
study. Of the 35 patients in Part 2, 14 patients (40%) were RAS 
mutant positive and 21 patients (60%) were RAS mutant negative. The 
most frequently reported study drug-related events at RP2D were 
diarrhea (31%), nausea (20%), increased creatinine (17%), vomiting 
(9%), and rash (5%). All bone marrow biopsies in Part 1 showed less 
than partial response. In Part 2, one patient with RAS (+) AML, had 
CRp at two sequential visits. A second patient with RAS (-) AML, had 
a CR on Cycle 2, Day 1. All other evaluations in Part 2 AML patients 
showed less than PR. A third patient with RAS (+) MDS had a PR on 
Cycle 2, Day 1. All other bone marrow evaluations in Part 2 MDS 
patients showed less than PR. 
Commercial 
sponsored 
NCT02994732 
BVD-523HV001: 
A Phase 1 Study to 
Investigate the 
Absorption, 
Metabolism, and 
Excretion of [14C]BVD-
523 Following Single 
Oral Dose 
Administration in 
Healthy Male Subjects 
The purpose of study BVD-523HV001 was to evaluate the absorption 
and excretion characteristics as well as relevant pharmacokinetic 
properties of ulixertinib; and to characterize and, where possible, 
identify the metabolites present in plasma, urine, and feces in healthy 
male subjects following a single dose of 600mg (approximately 200 
μCi) of [14C]-ulixertinib. The secondary objective of this study was to 
evaluate the safety and tolerability of a single oral dose of [14C]-
labeled ulixertinib in healthy male subjects. A total of 6 subjects were 
enrolled. The absorption of ulixertinib (BVD-523) was moderate and 
after reaching Cmax, concentrations of ulixertinib (BVD-523) in plasma 
appeared to decline in a generally biphasic manner. Ulixertinib (BVD-
523) undergoes moderate metabolism to produce 13 
identified/characterized metabolites in plasma and excreta. The 
metabolites BVD-502+BVD503 and BVD-513 were formed moderately 
rapidly and their plasma concentration-time profiles generally mirrored 
that of parent drug, suggesting formation rate limited elimination. The 
metabolite BVD-506 was found to be present and disproportionate 
levels compared to levels measured in pre-clinical in vivo studies. The 
primary route of elimination was through fecal excretion. No clinically 
significant findings with respect to clinical laboratory, vital signs, ECG, 
or physical examinations. Fatigue and diarrhea were reported for 2 
subjects (33%) and were possibly related to study drug. All TEAEs 
were of mild severity and there were no moderate or severe events 
reported. 

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Study Type 
Study Identifiers 
Status/Results 
Commercial 
sponsored 
BVD-523A-FE 
A Randomized, Open-
Label, Single-Dose, 2-
Way Crossover Study 
to Evaluate the Effect 
of Food on the 
Pharmacokinetics, 
Safety and Tolerability 
of Orally Administered 
BVD-523 in Healthy 
Volunteers 
A Phase I, randomized, open-label, single-dose, 2-way crossover 
study to assess the safety and PK in 14 healthy male and female 
subjects. Subjects received a single oral dose of BVD-523A (an 
investigational formulated blend of ulixertinib) in 2 different treatment 
periods; once after an overnight fast of at least 10 hours and once 
after consumption of a FDA-defined high-fat breakfast. There was a 
washout period of 5 days between dosing in one period and dosing in 
the next period. Subjects were randomized equally to receive 1 of 2 
treatments sequences (fasted/fed or fed/fasted), with 7 subjects 
assigned to each sequence. Each subject received both treatments. 
PK concentrations achieved in the fed group were considerably higher 
than observed in the fasted group. However, fasting and fed conditions 
were extreme. Collective experience in patients and healthy volunteers 
shows that best exposure and variability is achieved when ulixertinib is 
taken with food. There were no clinically significant findings with 
respect to clinical laboratory, vital signs, ECG, or physical 
examination. Headache in 2 subjects (14%) under fed conditions and 
diarrhea in 1 subject (7%) under fasted conditions were considered by 
the investigators to be possibly related to the study drug. All TEAEs 
were of mild severity, and there were no moderate or severe events 
reported. 
Commercial 
sponsored 
BVD-523-FC 
A Randomized, Open-
Label, Single-Dose, 2-
Way Crossover Study 
Evaluating the 
Pharmacokinetics, 
Safety, and Tolerability 
of two oral formulations 
of Ulixertinib (BVD-523) 
in Healthy Volunteers 
A Phase I, randomized, open-label, single-dose, 2-way crossover 
study to assess the effect of two oral formulations of ulixertinib on the 
PK, safety, and tolerability of a single oral dose of 600mg ulixertinib in 
14 healthy male and female subjects. The oral formulations included a 
single dose of 600mg powder in capsule (PIC) formulation and a 
single oral dose of 600mg formulated blend formulation of ulixertinib. 
Subjects were randomized equally to receive 1 of the 2 treatment 
sequences with 7 subjects assigned to each sequence and a washout 
period of 5 days separated the treatments. The formulated blend 
formulation produced peak and total systemic exposures which were 
slightly lower than PIC formulation. Additionally, the AUClast and AUCinf 
of the formulated blend formulation were approximately 25% lower 
than compared to PIC formulation. No clinically significant findings with 
respect to clinical laboratory, vital signs, ECGs, or physical 
examinations. Headaches were reported in 4 subjects (29%) and were 
possibly related to study drug. All other possibly related TEAEs were 
only reported by 1 subject (7%). All events were of mild severity, 
except for 1 event of urticaria, which was of moderate severity. 
Investigator 
sponsored 
NCT02608229 
Phase Ib Study of 
BVD-523 Plus Nab-
Paclitaxel and 
Gemcitabine in 
Patients with 
Metastatic Pancreatic 
Cancer 
Study was stopped after part 1 (dose escalation) due to tolerability 
issues experienced from the triple combination treatment. 

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Study Type 
Study Identifiers 
Status/Results 
Investigator 
sponsored 
NCT03454035 
A Phase I Trial of 
Ulixertinib (BVD-523) 
in Combination with 
Palbociclib in Patients 
with Advanced Solid 
Tumors with 
Expansion Cohort in 
Previously Treated 
Metastatic Pancreatic 
Cancer 
Ongoing 
Investigator 
sponsored 
NCT04145297 
Phase 1 study of 
ulixertinib and 
hydroxychloroquine in 
patients with 
advanced MAPK-
mutated 
gastrointestinal 
adenocarcinomas 
Ongoing 
Investigator 
sponsored 
NCT03417739 
A Phase II Study of 
BVD-523 in Metastatic 
Uveal Melanoma 
In interim analysis of 13 patients, four patients had best response of 
SD (31%), seven had best response of progressive disease (54%), 
and two were unevaluable for response (15%). According to the Simon 
design, the trial stopped recruitment at this point due to lack of 
responders in the first stage. 
NCI 
sponsored 
NCT03155620 
Targeted Therapy 
Directed by Genetic 
Testing in Treating 
Pediatric Patients with 
Relapsed or 
Refractory Advanced 
Solid Tumors, Non-
Hodgkin Lymphomas, 
or Histiocytic 
Disorders (The 
Pediatric MATCH 
Screening Trial) 
Ongoing 
 
NCI 
sponsored 
NCT02465060 
Targeted Therapy 
Directed by Genetic 
Testing in Treating 
Patients with 
Advanced Refractory 
Solid Tumors, 
Lymphomas, or 
Multiple Myeloma (The 
MATCH Screening 
Trial) 
Ongoing 

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Study Type 
Study Identifiers 
Status/Results 
NCI 
sponsored 
NCT03698994 
Ulixertinib in Treating 
Patients with 
Advanced Solid 
Tumors, Non-Hodgkin 
Lymphoma, or 
Histiocytic Disorders 
With MAPK Pathway 
Mutations (A Pediatric 
MATCH Treatment 
Trial) 
Ongoing 
 
Figure 4.4 
Percent Target Lesion Change in Patients from BVD-523-01 with 
BRAF non-V600 mutations 
 
 
 
 

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Figure 4.5 
Study Durations of Patients from BVD-523-01 with BRAF non-
V600 mutations 
 
 
Based on these data it was concluded that ulixertinib at 600mg twice a day has an 
acceptable safety profile and has produced durable responses in patients with NRAS 
mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including 
melanoma, glioblastoma multiforme, gallbladder, head and neck cancers, and lung 
cancers and exhibits clear CNS activity. Ulixertinib also resulted in durable responses 
in patients who progressed on prior BRAF +/- MEK inhibitor treatment or who were 
treatment naïve.  
 

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5 
OBJECTIVES AND ENDPOINTS 
5.1 
PART A – TUMOR HISTOLOGY AGNOSTIC 
5.1.1 
Primary Objective 
To assess the clinical benefit of ulixertinib as measured by the ORR in patients 
receiving ulixertinib that have advanced malignancies harboring a MEK or atypical 
BRAF alteration. 
Primary Endpoint(s): ORR will be defined as the percentage of patients achieving a 
Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial 
Response (PR), according to RECIST 1.1. 
5.1.2 
Secondary Objectives 
The secondary objectives are: 
• To evaluate the safety profile of ulixertinib 
• To assess the DOR 
• To assess the PFS and OS over 18 months 
• To measure the blood levels of ulixertinib and selected metabolites 
 
Secondary Endpoint(s):  
• Safety profile, including term, incidence, severity, and duration of AEs, as per 
CTCAE v5.0 
• DOR according to RECIST 1.1 
• PFS time according to RECIST 1.1 
• OS time 
• Pharmacokinetic profile of ulixertinib (BVD-523) and selected metabolites 
5.1.3 
Exploratory Objectives 
To evaluate the effects of ulixertinib on pharmacodynamic markers. 
 
Exploratory Endpoint(s):  
• ctDNA, tissue biopsies, and/or blood to access biomarkers. Assays include, 
but are not limited to, phosphorylation of RSK from whole blood, RPPA to 
assess protein levels, e.g. DUSP 4/6, plus Nanostring and/or RNA-exome to 
asses mRNA expression in tissue pre- and post-ulixertinib treatment. 
 

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5.2 
PART B – TUMOR HISTOLOGY SPECIFIC 
5.2.1 
Primary Objective 
To assess PFS in patients receiving ulixertinib in defined tumor histologies (up to three 
histologies to be selected) compared to physician’s choice of treatment. Patient’s 
tumors must harbor a specified MEK or atypical BRAF alteration. 
Primary Endpoint(s): PFS will be defined as the time from first day of trial medication 
to disease progression according to RECIST 1.1, or death. 
5.2.2 
Secondary Objectives 
The secondary objectives are: 
• To evaluate the safety profile of ulixertinib 
• To assess OS over 18 months in patients receiving ulixertinib with a defined 
tumor histology and specified MEK or atypical BRAF alteration, compared to 
physician’s choice of treatment 
• To determine the ORR and DOR in patients receiving ulixertinib with a defined 
tumor histology and a MEK or atypical BRAF alteration, according to RECIST 
1.1, compared to physician’s choice of treatment 
 
Secondary Endpoint(s):  
• Safety profile, including term, incidence, severity, and duration of AEs, as per 
CTCAE v5.0 
• OS time 
• ORR and DOR according to RECIST 1.1 

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6 
STUDY DESIGN 
6.1 
OVERALL DESIGN 
BVD-523-ABC is a two-part, phase II, multicenter study of the ERK inhibitor ulixertinib 
(BVD-523) with an open-label, tumor histology agnostic part (Part A) and a tumor 
histology specific part (Part B). 
6.1.1 
Part A: Tumor Histology Agnostic 
Part A will include six groups of patients with advanced malignancies. Group 1 will 
include patients with advanced malignancies, other than CRC, having a BRAF 
alteration that results in an amino acid change at position G469, L485, or L597. Group 
2 will include patients with advanced malignancies, other than CRC, having a specified 
Class 2 BRAF alteration (see Appendix 2). Group 3 will include patients with advanced 
malignancies, other than CRC, having any atypical BRAF alteration that is not 
specified in Group 1 or 2. Group 4 will include patients with CRC having any activating 
atypical BRAF alteration. Group 5 will include patients with tumors, other than CRC, 
harboring alterations in MEK1/2. Group 6 will include patients with CRC harboring 
alterations in MEK1/2. 
Ongoing data from Part A will be used, in part, to prioritize one or more tumor 
histologies that warrant study in Part B.  
6.1.2 
Part B: Tumor Histology Specific 
Part B will randomly enroll patients with one of up to three specified tumor histologies 
to receive either ulixertinib or the physician’s choice of treatment in a 2:1 ratio. 
Physician’s choice will be restricted to two approved (not off-label) treatments for each 
tumor histology (agents targeting BRAF or MEK kinases and experimental agents are 
not permitted as physician’s choice). Tumors must harbor either a MEK or atypical 
BRAF alteration. The specific histology/histologies and alterations to be included in 
this part will be selected based on available data from Part A and discussion with the 
clinical investigators, the medical monitor, and the sponsor. 
The randomization information can be found in Section 8.3. In Part B, if a patient 
progresses on the physician’s choice of treatment, then they may crossover to the 
ulixertinib arm. 
6.2 
JUSTIFICATION FOR DOSE 
Based on the experience of the studies BVD-523-01 and BVD-523-02, 600 mg b.i.d. 
taken orally will be the starting dose for all patients initiating therapy with ulixertinib as 
a single agent. 

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6.3 
NUMBER OF PATIENTS 
Total enrollment for Part A is targeted at approximately 228 patients with 38 patients 
per group. Additional patients may be enrolled as appropriate. 
Total enrollment for Part B is targeted to approximately 80-100 patients per histology 
with up to three histologies included, however, additional patients may be enrolled.  
6.4 
NUMBER OF STUDY SITES 
The study will take place at sites within the United States. Approximately, up to 25 
sites will be utilized, however, because the patient population is relatively rare, clinical 
sites may need to be added as qualifying patients are found. Clinical trial networks 
may be utilized. Each study site may enroll as many eligible patients as possible due 
to the relatively rare patient population. 
6.5 
STUDY DURATION AND END OF STUDY DEFINITION 
The estimated duration of accrual is 21 months. The total duration of the study will be 
approximately 38 months. 
A patient is considered to have completed the study if they have completed all phases 
of the study including the last visit or the last scheduled procedure shown in the SoA.  
The end of the study is defined as completion of the last visit or procedure shown in 
the SoA in the trial globally. 

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7 
STUDY POPULATION 
7.1 
INCLUSION CRITERIA 
Patients must meet all of the inclusion criteria to be eligible: 
1. Patients with a locally advanced or metastatic malignancy, that has progressed 
following systemic therapy for their disease, if available, or for which the patient 
is not a candidate or refuses. 
2. Tumor harboring a MEK or atypical BRAF alteration.  
3. Provided signed and dated informed consent prior to initiation of any study-related 
procedures that are not considered standard of care (SoC). 
4. Male or female patients aged ≥18 years. 
5. Patients must have measurable disease by RECIST version 1.1. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2. 
7. Adequate renal function (using Cockcroft-Gault) [creatinine ≤1.5 times ULN 
(upper limit of normal)] or a glomerular filtration rate (GFR) of ≥50 mL/min. 
8. 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]. 
9. Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x 109 
cells/L; absolute neutrophil count ≥1.5 x 109 cells/L). 
10. Adequate cardiac function:  
• Left ventricular ejection fraction (LVEF) of >50% as assessed by multi-gated 
acquisition (MUGA) or ultrasound/echocardiography (ECHO); and  
• A corrected QT interval (QTc) <480ms by the Fridericia method (QTcF). 
11. Contraception:  
a. 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.  
b. For men: Must be surgically sterile, or compliant with a medically approved 
contraceptive regimen during and for 3 months after the treatment period.  

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12. Willing and able to participate in the trial and comply with all trial requirements. 
13. Patients with a prior or concurrent malignancy whose natural history or treatment 
does not have the potential to interfere with the safety or efficacy assessment of 
the investigational agent may be included after consultation with the medical 
monitor. 
  
7.2 
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. Having received any cancer-directed therapy (chemotherapy, hormonal therapy, 
biologic or immunotherapy, etc.) within 28 days or 5 half-lives (whichever is 
shorter) prior to the first dose of study drug. 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 study drug. A minimum of 10 days between 
termination of the investigational drug and administration of study drug is 
required. In addition, any drug-related toxicity except alopecia should have 
recovered to Grade 1 or less. 
7. Prior therapy with any ERK inhibitor (e.g. LY3214996, LTT462).   
8. Groups 1-4: Prior therapy with any BRAF and/or MEK inhibitor (e.g. encorafenib, 
dabrafenib, vemurafenib, binimetinib, trametinib, cobimetinib) is excluded. Prior 
BRAF and/or MEK inhibitor therapy is permitted for Groups 5 and 6. 
9. For Part B, agents targeting BRAF or MEK kinases and experimental agents are 
not permitted as physician choice.  
10. Pregnant or breast-feeding women. 

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11. Any evidence of serious active infections. Patients are allowed to enroll if they 
have been fever-free for at least 48 hours and are on an active treatment that is 
not prohibited in Appendix 1. 
12. Any important medical illness or abnormal laboratory finding that would increase 
the risk of participating in this study (based on the investigator’s judgment).  
13. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR). 
14. Concurrent therapy with any other investigational agent. 
15. Concurrent therapy with drugs known to be strong inhibitors or inducers of 
CYP1A2, CYP2D6, and CYP3A4.  
7.3 
SCREEN FAILURES 
Screen failures are defined as patients who consent to participate in the clinical trial but 
who do not meet one or more criteria required for participation in the trial during the 
screening procedures. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) may 
be rescreened (up to a maximum of 1 time for the same individual). Rescreened patients 
will be assigned a new subject identification number. Labs can be retested within the 
screening window and not count as a rescreen. 
7.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Potential patients will be identified by investigators in the setting of their clinics. Potential 
patients may also be identified by Strata Oncology through their Strata Precision 
Oncology Network. 

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8 
STUDY DRUG 
8.1 
STUDY DRUG(S) ADMINISTRATION 
8.1.1 
Study Drug Description 
Ulixertinib (BVD-523) is a novel, reversible, ATP-competitive 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 (Germann et al, 2017).   
More information is available in the Investigator’s Brochure for ulixertinib. 
8.1.2 
Dosing and Administration 
Patients will initially receive 600 mg oral doses of the formulated blend formulation of 
ulixertinib. Ulixertinib is to be taken twice daily (b.i.d.) orally with at least 8 ounces of 
water for 28 days (a “Cycle”), at 12-hour ± 2 hour intervals. The study drug should be 
taken at approximately the same time each day with food. 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. Missed doses should 
be skipped and not taken as a double dose at the next dosing timepoint.  
Patients will be provided enough ulixertinib for a full cycle to self-administer at home. 
8.1.3 
Dose Interruptions and Adjustments 
Patients experiencing unacceptable toxicity will have their treatment interrupted until 
the toxicity returns to ≤ Grade 1 or pre-treatment baseline (whichever is more severe).  
Resumption of ulixertinib may occur at a lower dose level, aligning with capsule dose 
availability. Such dose adjustments will be done in consultation with the investigators 
and medical monitor of the study. 
If a non-treatment related AE or toxicity-related dose delay lasts for > 21 days, 
treatment will be discontinued permanently, and the patient should be removed from 
study treatment. 
8.2 
ACCOUNTABILITY/APPEARANCE/STORAGE 
8.2.1 
Acquisition and Accountability 
Dispensing instruction will be provided in the Pharmacy Manual. 
The investigator or study staff will verify the integrity of the clinical trial supplies 
(storage conditions, correct amount received, condition of shipment, kit numbers, etc.) 
according to their Standard Operating Procedures (SOP). 

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The following data will be tracked on the drug accountability log provided by the 
sponsor, and recorded in the eCRF: 
• Date received 
• Lot number 
• Date dispensed 
• Patient number 
Records of study medication (used, lost, destroyed, and returned containers, 
individual capsules) should be made at each patient visit in the eCRF. Drug 
accountability and reconciliation will be checked by the site study monitor during site 
visits and at completion of study treatment. 
Unless prohibited by investigational site’s SOP, used study medication is to be 
retained until the monitor has verified drug accountability. Once the site monitor has 
verified drug accountability at the site, any drug remaining in opened dispensing 
containers will be destroyed. Unused and unopened study medication will be returned 
to the sponsor. 
8.2.2 
Formulation, Appearance, Packaging, and Labeling 
Ulixertinib 
drug 
substance 
is 
manufactured 
according 
to 
cGMP 
as 
a 
mono-hydrochloride salt and is supplied as a formulated powder blend comprised of 
standard excipients to support the manufacturing processes that is encapsulated in a 
hard gelatin capsule. Capsules (white) contain 150 mg of ulixertinib calculated on free 
base content and are packaged in white high-density polyethylene (HDPE) bottles.  
8.2.3 
Product Storage and Stability 
Information will be provided in the study manual. 
8.3 
RANDOMIZATION 
Part A is designed as an open-label study. All patients in Part A will receive treatment 
with orally administered ulixertinib. Patients in Part B will receive either treatment with 
orally administered ulixertinib or the physician’s choice of treatment in a 2:1 ratio. In 
Part B, if a patient progresses on the physician’s choice of treatment then they may 
crossover to the ulixertinib arm. 
Part B randomization will be performed as total enrollment rather than on a site basis. 
Randomization/enrollment in both parts will be performed by using Interactive 
Voice/Web Response System (IxRS). Once written consent has been given by the 
patient, all inclusion/exclusion criteria must be checked by the investigator in order to 
confirm eligibility prior to IxRS randomization/enrollment procedures. In Part B, the 
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the physician’s choice of treatment). In both parts, the IxRS will assign the patient a 
unique patient identification number. This patient identification number will then be 
reported on all eCRF pages and in any study documents. 
8.4 
STUDY DRUG COMPLIANCE 
The investigator will dispense the study drug only for use by patients enrolled in the 
study as described in this protocol. The study drug 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 drug self-administration. Patients will be asked 
to bring their study drug container with them at 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. 
8.5 
CONCOMITANT THERAPY AND RESCUE MEDICATION 
A detailed history of medications, including prior anti-cancer therapies, and 
procedures will be documented for each patient. Concomitant medications (especially 
changes in medication, including any anti-cancer therapies) will be documented for 
each patient at each scheduled visit.   
Necessary supportive care such as anti-emetics and anti-diarrheals, etc., will be 
allowed. Medications that are known to be strong inhibitors or inducers of CYP3A4, 
CYP2D6, and CYP1A2 are not permitted during the study (for list of non-permitted 
drugs, see Appendix 1). 
If deemed necessary by the treating investigator and reviewed by the medical 
monitor, palliative radiation therapy for a single site of bone or brain metastasis is 
allowed provided that it is the only site of disease progression. The radiation field 
must not affect any of the target lesions designated for disease assessment. Protocol 
treatment will be held during radiation therapy and will be re-started after any acute 
toxicities have resolved. 
All medications administered from 30 days prior to the commencement of study 
treatment (Day 1) through the end of the treatment period will be recorded on the 
eCRF. Any changes of dosages of medication will also be noted. 

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9 
STUDY DRUG DISCONTINUATION AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
9.1 
DISCONTINUATION OF STUDY DRUG 
Discontinuation from the study drug does not mean discontinuation from the study, 
and remaining study procedures should be completed as indicated by the study 
protocol. If a clinically significant finding is identified (including, but not limited to 
changes from baseline) after enrollment, the investigator or qualified designee will 
determine if any change in patient management is needed. Any new clinically relevant 
finding will be reported as an AE. 
9.2 
PATIENT DISCONTINUATION CRITERIA 
Treatment is to be discontinued for any of the following reasons: 
• Disease progression (at the discretion of the investigator). If brain or bone 
metastases develop while on study, patients may be permitted to continue on 
study, after discussion with the medical monitor, if the overall risk/benefit is 
still favorable. 
• Unacceptable toxicity. 
• Changes in the patient's condition which render the patient unacceptable for 
further treatment (at the discretion of the investigator). 
• Investigator’s judgement. 
Patients who have been discontinued from treatment should still be followed for 
survival. 
9.3 
PATIENT WITHDRAWAL FROM THE STUDY 
Patients must be withdrawn from the study for any of the following reasons: 
• Withdrawal of informed consent. 
• Patient non-compliance (at the discretion of the investigator). 
• Patient becomes pregnant (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 will not lead to 
patient withdrawal unless they constitute a significant risk to the patient’s safety. 
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, 
became lost to follow up for any reason, or if any of the following occurs: 
• Discovery of patient ineligibility. 

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• Missed / unscheduled / off-schedule / incomplete / incorrect assessments that 
result in patients being put at risk. 
Patients who withdraw at any time preceding the last visit of Cycle 2 (Day 43) will 
constitute an early discontinuation, will not be replaced, and will be evaluated in the 
efficacy analysis. If patients withdraw due to progressive disease or AEs, replacement 
of such patients potentially introduces bias into the study. If a patient withdraws for 
other reasons, replacement of the patient will be decided by the Safety Monitoring 
Committee.  
The investigator must determine the primary reason for a patient’s withdrawal from 
the study and record this information on the eCRF. 
9.4 
LONG TERM FOLLOW UP 
Upon discontinuation of study drug, patients will be followed for survival and the 
initiation of subsequent anticancer therapy for 18 months from the date of study 
therapy initiation. Patients that discontinue study treatment for any reason other than 
disease progression, must continue to have disease assessments every 8 weeks (± 7 
days) until disease progression or the initiation of subsequent anticancer therapy. 
Patients or their legally authorized representatives will be contacted every three 
months (± 7 days) until death, end of the study, or patient withdrawal of consent, 
whichever comes first. Survival and subsequent treatment status may be collected by 
public records, medical records, or by contacting the patient or their legally authorized 
representative by phone. All efforts should be made to contact the patient at these 
time points. Refer to Section 9.5 for Lost to Follow-Up guidelines. 
9.5 
LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if they fail to return for scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions will be taken if a patient fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the patient and reschedule the missed visit 
and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the patient (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known 
mailing address). These contact attempts should be documented in the 
patient’s medical record or study file. 

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• Should the patient continue to be unreachable, they will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 

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10 STUDY ASSESSMENTS AND PROCEDURES 
10.1 METHODS OF ASSESSMENT AND CRITERIA FOR EVALUATION 
Every effort should be made to ensure that the protocol-required tests and procedures 
are completed as described. However, it is anticipated that from time to time there 
may be circumstances outside of the control of the investigator that may make it 
unfeasible to perform the test. In these cases, the investigator will take all steps 
necessary to ensure the safety and well-being of the patient. When a protocol-required 
test cannot be performed, the investigator will document the reason for this and any 
corrective and preventative actions that were taken to ensure that normal processes 
are adhered to as soon as possible. 
All trial data will be recorded on the electronic case report forms (eCRFs). Blood and 
tissue biopsy specimens will be sent to a third-party laboratory vendor for analysis. 
10.1.1 
Demographic Data 
Include date of birth (DOB), age, gender, race, and ethnicity. 
10.1.2 
Medical and Cancer History 
A complete medical history will be obtained from each patient including the specifics 
of their advanced malignancy and molecular alterations. For female patients of child-
bearing potential, the date of the last menstrual period will be noted. Smoking history 
and prior cancer therapy will be recorded. Data will be reviewed and updated at each 
visit. 
10.1.3 
Prior and Concomitant Medications 
See Section 8.5. 
10.1.4 
Vital Signs and Physical Examination 
Height should be recorded at screening only. Body weight should be recorded at each 
visit. 
Vital sign records should include body temperature, systolic/diastolic blood pressure 
(BP), and pulse rate. BP 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. 
Performance status (ECOG) should be assessed within 72 hours before start of study 
treatment and at each study visit (see Appendix 3). 

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10.1.5 
Ophthalmology Examination 
A full ophthalmic examination will be performed at the time points described in the 
SoA or when clinically indicated. They will include best-corrected visual acuity (BCVA), 
visual field examination (VF), intraocular pressure, external eye examination, and 
dilated fundoscopy. For additional details refer to study manual.  
Any patient experiencing vision changes must stop taking ulixertinib and have an 
ophthalmic evaluation. Ulixertinib may be re-started when symptoms resolve. 
10.1.6 
Laboratory Assessments 
The following clinical laboratory tests will be performed: 
• Hematology (blood sample: EDTA) – hemoglobin, hematocrit, white blood 
cells (WBC) count with differential, red blood cells (RBC) count, and platelet 
count. 
• Blood Chemistry (blood sample: serum) – albumin, alkaline phosphatase 
(ALP), total bilirubin, calcium, chloride, creatinine, glucose, inorganic 
phosphorus, potassium, total protein, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), sodium, blood urea nitrogen (BUN), uric 
acid, lactic dehydrogenase (LDH), cholesterol, and triglycerides.  
• 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. 
• Urinalysis – specific gravity, pH; semi-quantitative "dipstick" evaluation of 
glucose, protein, bilirubin, ketones, leukocytes, and blood and a microscopic 
examination including RBC, WBC, and casts will be performed if the dipstick 
is abnormal. 
• Pregnancy – Beta-hCG Qualitative Urine or Serum 
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. 
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 investigator. The investigator or 
designee will review the laboratory report after receipt of the results and assess the 
clinical significance of all abnormal values. Results must be reviewed prior to dosing 
and appropriate action taken for any clinically significant abnormal values. Values will 
be documented on the laboratory report until stabilized, or the laboratory value returns 
to a clinically acceptable range (regardless of relationship to study medication) or 
baseline.  

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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 or return to baseline. 
10.1.7 
Electrocardiogram (ECG) 
All patients require a single 12-lead ECG measurement. The parameters to be 
recorded are QT, QTc, QTC F, PR, and QRS. A standard 12-lead (with a 10-second 
rhythm strip) tracing will be used for all ECGs. Patients should be supine for 5 minutes 
prior to the ECG. 
Patients with a normal ECG in screening do not need to have repeat ECGs in 
subsequent cycles unless clinically indicated. 
10.1.8 
Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) 
LVEF will be assessed by ECHO or MUGA performed at screening and as clinically 
indicated. 
10.1.9 
Disease Status 
The decision for body areas to be scanned will depend on the extent of disease. 
Disease assessments must include all known or suspected disease sites. Imaging will 
be performed on the abdomen, chest, pelvis, and the site of the primary tumor if 
elsewhere.   
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 beginning of Cycle 2 and then every 2 cycles, and at 
End of Treatment. Patients that discontinue study treatment for any reason other than 
disease progression, must continue to have disease assessments every 8 weeks (± 7 
days) until disease progression or the initiation of subsequent anticancer therapy. The 
schedule of tumor assessments should be fixed according to the calendar, starting 
with cycle one day one, regardless of treatment delays or interruptions due to toxicity. 
The same imaging technique used to characterize each identified and reported lesion 
at baseline will be employed in the following tumor assessments. 
10.1.10 Tissue Biopsy 
Tumor biopsy during the screening period and during Visit 5 (Day 28) of treatment in 
Part A is required. If a patient has undergone a biopsy within ≤ 6 months and has not 
received any anticancer treatment since undergoing the biopsy, archival tissue from 
this biopsy may be used to fulfill screening tissue requirements. Assays to investigate 
pharmacodynamic markers of ERK inhibition in addition to exploratory analysis to 

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evaluate adaptive response in pathways in addition to MAPK will be deployed. These 
may include, but are not limited to, RPPA, Nanostring, and RNA-exome. An optional 
tumor biopsy is requested at end of treatment; this is not a mandatory collection but 
strongly encouraged in patients relapsing following robust response to ulixertinib. 
Broad molecular profiling will be applied to end of treatment/at relapse tumor samples 
to aid scientific understanding of mechanisms of resistance to ERK inhibition.   
10.1.11 Blood Samples for Pharmacokinetic (PK) Analysis 
In Part A only, plasma samples will be collected for PK analysis at Visit 4, pre-dose. 
Patients need to be at steady state for this collection, which means 10 consecutive 
doses, or 5 consecutive days. 
10.1.12 Blood Samples for Pharmacodynamic (PD) and ctDNA Analysis 
In Part A only, blood samples will be collected for PD and ctDNA analysis at Baseline 
and Visit 4. Samples for ctDNA will also be collected at Visit 5 and End of Treatment. 
Blood samples for pharmacodynamic analyses will be taken from all patients in Part 
A until the sponsor determines sampling may be discontinued based on accumulated 
patient experience. 
10.1.13 Adverse Events 
Toxicity/severity of AEs will be assessed using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grading System, Version 5.0, 
as detailed on web page: http://ctep.cancer.gov. 
Also see Section 10.6. 
10.2 CRITERIA FOR EVALUATION 
10.2.1 
Efficacy 
Overall response rate (ORR), duration of response (DOR), and progression free 
survival (PFS) are primary or secondary objectives and will be evaluated by standard 
RECIST v1.1 criterion per local investigator’s assessment and, for Part B only, 
independent, third-party review. 
The response criteria for 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. 

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• Progressive Disease: 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 Progressive Disease, taking as reference the 
smallest sum diameters while on study. 
10.2.2 
Pharmacokinetics (PK) 
• Blood samples will be collected to measure ulixertinib (BVD-523) and 
selected metabolite pharmacokinetic parameters.   
• If a patient changes doses, an additional blood sample will be collected at 
steady state (for each dose level a patient experiences). 
10.2.3 
Circulating Tumor DNA 
• Blood samples will be collected to measure circulating tumor DNA, including, 
but not limited to, BRAF and MEK alterations. 
10.2.4 
Pharmacodynamics (PD) 
• Evaluation of tissue biopsies, and/or blood to assess biomarkers such as 
dual-specificity phosphatase (DUSP), RSK, and c-Myc. 
• Additional biomarkers may be identified and measured as appropriate.  
10.3 DESCRIPTION OF STUDY VISITS FOR PATIENTS RECEIVING 
ULIXERTINIB 
10.3.1 
Description of Study Visits for Cycle 1 
Procedures performed in the first cycle are specified in the Schedule of Activities 
(SoA). Patients receiving multiple cycles of treatment will not have blood drawn for PK 
and PD measurements after Cycle 1 unless additional PK and PD data are deemed 
necessary after initial analysis or the patient changes dose. 
10.3.1.1 
Visit 1 (Day -28 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 considered Standard of Care) including optional consents (Note: 
informed consent may be obtained up to -28 days to allow flexibility in 
scheduling of the screening procedures). 

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• Evaluate all inclusion and exclusion criteria to ensure that patients meet all 
inclusion criteria and none of the exclusion criteria. 
• Record demographic data including date of birth (DOB), age, gender, race, 
and ethnicity.  Where full DOB is collected, initials will not be used. 
• Review medical history including all previous cancer treatments, best 
response to those cancer treatments, and reason for stopping them. 
• Record prior and concomitant medications including start/stop dates, 
indication, dose, toxicities, and frequency taken within 30 days of Cycle 1, 
Day 1. 
• Measure and record height and weight. 
• Record vital signs. Measure body temperature, systolic / diastolic BP, and 
pulse rate. 
• Perform and record physical examination. 
• Assess and record performance status (ECOG) within 72 hours before start 
of treatment. 
• Perform and record ophthalmology examination (ulixertinib patients only). 
• Collect blood for a serum pregnancy test for female patients who are not 
postmenopausal or surgically sterile. If positive, repeat and confirm results 
prior to Visit 2. A second positive test will result in exclusion of the patient 
from the study. 
• Collect blood samples for blood chemistries, hematology, and calculated 
creatinine clearance (using Cockcroft-Gault) within 72 hours before start of 
treatment. Analyze, review, and report any clinically significant abnormalities 
to the medical monitor before dosing. 
• Collect urine samples for urinalysis within 72 hours before start of treatment. 
• Obtain a 12-lead electrocardiogram (ECG), and echocardiogram (ECHO) or 
multi-gated acquisition (MUGA) for left ventricular ejection fraction (LVEF). 
• Assess and record current disease status within 28 days. Tumor 
assessments will be made by CT/MRI/Physical Exam. 
• PART A only: Tissue biopsy within -28 days of Visit 1 (required unless 
investigator and medical monitor deems collection inadvisable). If a patient 
has undergone a biopsy within ≤ 6 months and has not received any 
anticancer treatment since undergoing the biopsy, archival tissue from this 
biopsy may be used to fulfill screening tissue requirements. 
• Complete Screening/Enrollment Form and submit to medical monitor for 
review prior to treatment of patient. 
• For Part B only, prior to Visit 2, obtain a randomization code as outlined in 
Section 8.3. 

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10.3.1.2 
Visit 2 (Day 1 ± 0); Baseline/Drug Dispensing/Initiation of 
Treatment 
The following procedures will be performed at Visit 2 (Baseline): 
• Review Screening/Enrollment Form to confirm consent to enroll was obtained 
from medical monitor or sponsor. 
• Review all inclusion and exclusion criteria to ensure that patients meet all 
inclusion criteria and none of the exclusion criteria. 
• Review medical history for any changes since Screening Visit.  
• Record medications including start/stop dates, indication, dose, toxicities, and 
frequency for any changes since Screening Visit. 
• Measure and record weight. 
• Record vital signs. Measure body temperature, systolic / diastolic BP, and 
pulse rate. 
• Assess and record performance status (ECOG), if not done during Screening 
Visit, within 72 hours of start of treatment. 
• ONLY if the screening pregnancy test was performed more than 1 day 
previously, collect blood for a repeat serum pregnancy test for female patients 
who are not postmenopausal or surgically sterile. 
• Collect pre-dose blood samples for blood chemistries, hematology and 
creatinine clearance if not done during Screening Visit within 72 hours of start 
of treatment. 
• Collect pre-dose urine samples for urinalysis. 
• PART A only: Collect pre-dose blood samples for pharmacodynamic (PD) and 
ctDNA analyses. 
• Administer first dose of ulixertinib. 
• PART A only: Collect 4-hour (± 10 minutes) post-dose blood samples for 
pharmacodynamic analyses.  
• Assess and record AEs. 
• Dispense study drug and instruct patients how to take study drug, daily every 
12 hours ± 2 hours with at least 8 ounces of water and food.  
• Inform patients of the potential photosensitizing effects of ulixertinib and 
instruct them to avoid sunlight and wear protective clothes, sunglasses, and 
apply sunblock when outside, including when driving a car. 
10.3.1.3 
Visit 3 (Day 8 ± 3) 
The following procedures will be performed at Visit 3: 
• Review medical history. 
• Record concomitant medications including start/stop dates, indication, dose, 
toxicities, and frequency taken after Visit 2. 

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• Measure and record weight. 
• Record vital signs. Measure body temperature, systolic / diastolic BP, and 
pulse rate. 
• Assess and record performance status (ECOG). 
• 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 pill count. 
• Dispense drug supply for self-dosing and remind patients of dosing 
instructions. 
10.3.1.4 
Visit 4 (Day 15 ± 3) 
The following procedures will be performed at Visit 4: 
• Review medical history. 
• Record concomitant medications including start/stop dates, indication, dose, 
toxicities, and frequency taken after Visit 3. 
• Measure and record weight. 
• Record vital signs. Measure body temperature, systolic / diastolic BP, and 
pulse rate. 
• Assess and record performance status (ECOG). 
• Collect blood samples for blood chemistries, hematology, and creatinine 
clearance. 
• PART A only: Collect pre-dose trough blood samples for pharmacokinetic 
(PK), pharmacodynamic (PD), and ctDNA analyses. These assessments 
should be collected when the patient reaches steady state. Steady state 
refers to patients who have received at least 5 days, or 10 consecutive doses, 
of investigational product. If patients are not at steady state, these 
assessments will be rescheduled and completed at the next visit in which 
steady state is achieved. 
• Administer first daily dose of ulixertinib. 
• PART A only: Collect 4-hour (± 10 minutes) post-dose blood samples for 
pharmacodynamic analyses. 
• Collect urine samples for urinalysis. 
• Assess and record AEs. 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by pill count. 
• Dispense study drug supply for self-dosing. 

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10.3.2 
Description of Study Visits for Cycle 2 
10.3.2.1 
Visit 5 (Day 29 ± 3, first day of Cycle 2) 
The following procedures will be performed at Visit 5: 
• Review medical history. 
• Record concomitant medications including start/stop dates, indication, dose, 
toxicities, and frequency taken after Visit 4. 
• Measure and record weight. 
• Record vital signs.  Measure body temperature, systolic / diastolic BP, and 
pulse rate. 
• Assess and record performance status (ECOG). 
• PART A only: Tissue biopsy (required unless investigator and medical 
monitor deems collection inadvisable).   
• PART A only: Collect blood samples for ctDNA. 
• 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.  If serum pregnancy test is positive, withdraw patient 
from study and contact the medical monitor. 
• Assess and record AEs. 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by reviewing pill count. 
• Assess and record disease status (every 2 cycles).  
• Dispense study drug supply for self-dosing. Extra doses may be dispensed 
at the investigator’s discretion to ensure continuous dosing. 
10.3.2.2 
Visit 6 and 7 
Cycle 2 visits 6 and 7 procedures are similar to Cycle 1 visit 3, although no 
pharmacokinetic or pharmacodynamic measurements will be made unless 
specifically requested by investigator or the patient changes dose level. 
10.3.3 
Cycle 3 and Subsequent Cycles Visit (Day 1 ± 3 of each cycle) 
Cycle 3 and subsequent cycles have one scheduled visit per cycle. No 
pharmacokinetic or pharmacodynamic measurements will be made unless specifically 
requested by the investigator or the patient changes dose level. 
The following procedures will be performed at the Cycle 3 and Subsequent Cycles 
Visit: 

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• Review medical history. 
• Record concomitant medications including start/stop dates, indication, dose, 
toxicities, and frequency taken since previous visit. 
• Measure weight. 
• Record vital signs. Measure body temperature, systolic / diastolic BP, and 
pulse rate. 
• Assess and record performance status (ECOG). 
• 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 (every 2 cycles). 
• Assess and record AEs. 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by reviewing pill count. 
• Dispense study drug supply for self-dosing. Extra doses may be dispensed 
at the investigator’s discretion to ensure continuous dosing. 
10.3.4 
Description of Study Visits for Patients Enrolled in Part B and 
Receiving Physician’s Choice of Treatment 
Study procedures for patients enrolled in Part B and randomized to physician’s choice 
of treatment will be the similar to those for patients receiving ulixertinib; however, no 
pharmacokinetic or pharmacodynamic samples will be collected in Part B, and an 
ophthalmology examination will be performed only for patients receiving ulixertinib. 
Appropriate SoC monitoring can be completed at the discretion of the investigator. If 
clinical experience gained in Part A requires significant deviations in Part B from the 
procedures in Part A, these changes will be addressed in a protocol amendment.  
10.3.5 
End of Treatment Visit 
At the time of study drug discontinuation, the End of Treatment (EOT) Visit should be 
completed for all patients within 14 ± 3 days after the last dose of study drug, and 
every effort should be made to perform the procedures required. The following 
procedures will be performed at EOT Visit: 
• Review medical history. 
• Record concomitant medications including start/stop dates, indication, dose, 
toxicities, and frequency taken since previous visit. 
• Measure and record weight. 

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• Record vital signs. Measure body temperature, systolic / diastolic BP, and 
pulse rate. 
• Assess and performance status (ECOG). 
• PART A only: Collect blood samples for ctDNA. 
• PART A only: Tissue biopsy, optional, but strongly encouraged. 
• 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. 
• Assess and record disease status. 
• Assess and record AEs. 
• Obtain all unused study drug from patient. 
• Assess study drug compliance by reviewing pill count. 
• Complete end of treatment form. 
10.3.6 
Safety Follow-Up Assessment 
Patients will return to the clinic or will be contacted for a safety follow-up assessment 
30 days ± 3 days after the last dose of study drug was taken; or earlier if subsequent 
therapy for advanced malignancy is initiated prior to 30 days ± 3 days. Only 
information about AEs and SAEs will be collected at this visit. 
10.3.7 
Follow Up 
Patients will be followed for survival and the initiation of subsequent anticancer 
therapy for 18 months from the date of study therapy initiation, as outlined in 
Section 9.4. 
Patients that discontinue study treatment for any reason other than disease 
progression, must continue to have disease assessments every 8 weeks (± 7 days) 
until disease progression or the initiation of subsequent anticancer therapy. 
10.3.8 
Unscheduled Visits 
Additional visits can be performed as appropriate and at the discretion of the 
investigator. All unscheduled study visits, procedures, examinations, clinical 
laboratory evaluations etc., will be noted in the patient’s medical record and the eCRF 
including: 
• Reason for visit/procedure. 
• Follow-up. 

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• Recording of AEs and use of concomitant measures. 
10.4 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
10.4.1 
Definition of Adverse Events (AE) 
An 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 non-leading 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. 
10.4.2 
Definition of Serious Adverse Events (SAE) 
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 one 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. 

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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 or within the safety reporting period, then the event should 
be reported using the term “disease progression” with a CTCAE severity of Grade 5. 
10.4.3 
Classification of an Adverse Event 
10.4.3.1 
Severity of an Event 
The severity of the AE will be graded according to the NCI CTCAE Grading Scale 
Version 5.0 (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 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. 
• Life-threatening events require urgent intervention. 
• Fatal events result in the patient’s death. 
10.4.3.2 
Relationship to Study Drug 
The investigator will make a judgment regarding whether or not the AE was related to 
study drug, as outlined below, and in accordance with FDA guidance of 2012. 
Unrelated 
The AE is unlikely to have been caused by study drug. 
Possibly related 
It is unclear whether the AE may have been caused by study 
drug, but there is at least a reasonable possibility of a 
relationship, or a relationship cannot be ruled out. 
Related 
The AE is likely to have been caused by study drug. 
10.4.3.3 
Expectedness 
The CRO DSPV group and CRO medical monitor will be responsible for determining 
whether an AE is expected or unexpected. An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the study drug, as documented within the most recent version 
of the Investigator’s Brochure. 

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10.4.4 
Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits and interviews of a study patient presenting for medical care, or upon 
review by a study monitor. At each study visit, the investigator or their designee will 
inquire about the occurrence of AE/SAEs since the last visit. 
Any medical condition that is present at the time that the patient is screened will be 
considered as baseline and not reported as an AE. However, if the study patient’s 
condition deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
All reportable events will be recorded with start dates occurring any time after informed 
consent is obtained through and including 30 calendar days after the last 
administration of ulixertinib. Any SAE occurring after the reporting period must be 
promptly reported if a causal relationship to the study product is suspected. If the 
patient begins a new anti-cancer 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.  
All events will be followed for outcome information in accordance with good medical 
practice until they are resolved, stabilize, 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. 
10.4.4.1 
Post-Study Adverse Events and Serious Adverse Events 
All unresolved AEs will be followed by the investigator until the events are resolved 
(see Section 10.4.4), 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 designated CRO safety team (see 
Section 10.4.6) 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., or their CRO designee, 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 
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congenital anomaly in a subsequently conceived offspring of a person that has 
participated in this study. 
10.4.5 
Adverse Event Reporting 
All AEs, including local and systemic reactions, not meeting the criteria for SAEs will 
be captured on the appropriate eCRF. Information to be collected includes event 
description, time of onset, investigator’s assessment of severity, seriousness, 
relationship to the study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. 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 action taken and the outcome must also be 
recorded. All AEs occurring while on study must be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution. 
10.4.6 
Serious Adverse Event Reporting 
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 their assessment of 
relationship to study drug at the time of the initial report. Follow-up information must 
also be reported within 24 hours of first knowledge. Entry of an SAE (or updated SAE 
information) into the eCRF will trigger an automatic alert to the designated CRO safety 
team. Timely notification of an event supersedes the requirement to have all 
information at the time of the initial report.   
If the EDC system is not available, the investigator must send a completed paper 
SAE Report Form to the CRO safety team via email or fax as follows, within 24 hours.  
If no acknowledgement is received within one working day, the report should be re-
submitted. 
Safety Report Email Address: sae@cmedresearch.com  
Safety Report Fax No.: 866.240.8830 (US) or +44 1403 330459 (international) 
The SAE data must be entered into the eCRF as soon as it becomes available. 
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 

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• 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 or not 
• Outcome of the event if available 
The CRO safety team 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 Cmed Drug Safety and Pharmacovigilance via email 
sae@cmedresearch.com.  
Unexpected serious suspected adverse reactions are subject to expedited reporting 
to FDA.  The CRO safety team is responsible for submitting reports of AEs associated 
with the use of the drug that are both serious and unexpected to the FDA and to 
investigators participating in ongoing clinical studies with the study medication, 
according to 21 CFR 312.32 and the applicable guidance documents.  All investigators 
participating in ongoing clinical studies with the study medication are responsible for 
prompt submission of these reports to their Institutional Review Board (IRB) or Ethics 
Committee (EC). 
10.4.7 
Overdose 
No information on treatment of overdose of ulixertinib is currently available. In the 
event of an overdose, within 24 hours of awareness, the overdose should be reported 
as an AE and the medical monitor should be notified. All overdose cases will be 
discussed by the sponsor and medical monitor on a case-by-case basis. 
10.4.8 
Reporting of Pregnancy 
Each pregnancy in a patient or partner of a patient on ulixertinib must be reported to 
the designated CRO safety team within 24 hours of learning of its occurrence, on a 
Pregnancy Notification Form and via the contact details noted in Section 10.4.6.  If a 
patient becomes pregnant, study drug administration must be discontinued 
immediately. The pregnancy should be followed up 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. 
Pregnancy per se is not considered an AE unless there is cause to believe that the 
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Hospitalization for normal delivery of a healthy newborn should not be considered a 
SAE. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and must be 
reported as such. 
The avoidance of pregnancy or fathering a child is suggested for 3 months following 
the discontinuation of ulixertinib therapy. No information is currently available 
regarding the effects of ulixertinib on fertility, gestation or subsequent child 
development. 
Any pregnancy within 3 months after the last study drug administration should be 
reported to the study investigator and to the CRO. 

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11 STATISTICAL CONSIDERATIONS 
11.1 STATISTICAL ANALYSIS PLAN 
A formal detailed statistical analysis plan (SAP), covering statistical analyses planned 
for Part A and Part B, will be developed and finalized prior to the main analysis of 
Part A data. This section is a summary of the planned statistical analyses at the time 
of protocol development. 
A separate analysis plan will be developed specifically for the safety reviews to be 
conducted by the SMC. 
11.2 SAMPLE SIZE DETERMINATION 
11.2.1 
Part A 
Approximately 38 patients will be recruited into each group in Part A. 
With 34 patients in a group and assuming the true ORR is 40%, there is approximately 
80% power to reject the null hypothesis that the true ORR is ≤ 20% in that group, with 
a 1-sided alpha of 5%. Assuming a 10% drop out rate, up to 38 patients will be 
recruited in each group. 
11.2.2 
Part B 
It is not possible to accurately calculate the required sample size until the histologies 
of interest have been confirmed. Once the histologies of interest have been confirmed 
these calculations will be repeated and the final sample size confirmed. 
Approximately 80-100 patients will be randomized, using a 2:1 ratio, for each histology 
group in Part B.  
Using a 2-sided, log-rank test with a 5% alpha, and assuming a median PFS of 1.7 to 
8.5 months (depending on histology) in the physician’s choice arm and twice as long 
on the ulixertinib arm, approximately 80 to 100 patients will be required in each group 
to achieve 80% power to show a statistically significant difference between the arms.  
This also assumes that each group will take approximately 24 months to accrue and 
the analysis is expected to be performed 18 months following the last patient accrued. 
The anticipated loss to follow-up is estimated to be 10%. 
11.3 RANDOMIZATION 
Part A of this study is open-label, and all patients enrolled in Part A will be treated with 
ulixertinib. 
Part B of this study is open-label, patients will be randomly assigned to receive either 
ulixertinib or the physician’s choice of treatment in a 2:1 ratio. Also see Section 8.3. 

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11.4 ANALYSIS SETS 
11.4.1 
Full Analysis Set 
The full analysis set (FAS) will consist of all patients who received at least one dose 
of study medication. This analysis set will be used for all efficacy analyses. 
For Part B, analyses performed on the FAS will allocate patients’ treatment group as 
randomized. 
11.4.2 
Safety Analysis Set 
The safety analysis set will consist of all patients who received at least one dose of 
study medication. This analysis set will be used for all safety analyses. 
For Part B, analyses performed on the safety population will allocate patients’ 
treatment group as actually received. 
11.4.3 
Per Protocol Analysis Set 
The per-protocol (PP) analysis set will consist of all patients of the FAS who completed 
the study without any major protocol deviations. 
11.5 DATA PRESENTATION 
Descriptive statistics for continuous variables will include the number of patients, 
mean, standard deviation, median, minimum, maximum; frequencies and percentages 
will be displayed for categorical data. 
Summary data will be provided separately for Part A and Part B, and by group/tumor 
histology. 
Data will be analyzed using the SAS system software version 9.4 (or later). 
11.5.1 
Demographic 
Demographic characteristics of patients will be summarized in appropriate tables and 
with descriptive statistics. 
The following characteristics will be summarized in the FAS, PP, and safety analysis 
sets: 
• Age 
• Gender 
• Race 
• Ethnicity 
• Advanced malignancy information including relapsed or refractory status 
• MEK or Atypical BRAF alteration 

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11.5.2 
Baseline Characteristics 
Baseline characteristics will be summarized in appropriate tables and with descriptive 
statistics. 
The following characteristics will be summarized in the FAS, PP, and safety analysis 
sets: 
• Body weight 
• Height 
• ECOG performance status 
• Previous cancer therapies 
11.5.3 
Medical History and Physical Examination 
Medical history and physical examination assessments will be summarized in 
appropriate tables and with descriptive statistics, in the FAS, PP, and safety analysis 
sets. 
11.5.4 
Concomitant Medications or Treatments 
The number and percentage of patients taking prior and concomitant medications will 
be summarized by therapeutic class and preferred term using descriptive statistics.  
All data will be recorded as follows: 
• Prior medication: ended before first day of study drug. 
• Concomitant medication: ongoing at first day of study drug or started after 
first day of study drug. 
11.5.5 
Efficacy Analysis 
All efficacy analyses will be performed using the FAS. 
11.5.5.1 
Part A 
The primary endpoint for Part A is the overall response rate (ORR) within a group. It 
will be defined as the percentage of patients achieving a BOR of confirmed CR and/or 
PR as assessed by the investigator. The ORR will be presented with its 95% 
confidence intervals (CIs). 
All response assessments will be presented using swimmer plots and will be listed by 
patient. 
Sensitivity analyses of the primary analysis will include similar analyses using PP 
analysis set. 
Analyses of secondary efficacy endpoints will include Kaplan-Meier estimates and 
curves, median DoR and respective 95% CIs for analysis of: 

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• Duration of response (DoR): time from first response to disease progression 
or death. Patients with no event will be censored at the last available tumor 
assessment. This analysis will be based on investigator assessment. 
• Progression-free survival over 18 months (PFS): time from first day of trial 
medication to disease progression or death. Patients with no event will be 
censored at the last available tumor assessment. This analysis will be based 
on investigator assessment. 
• Overall survival over 18 months (OS): time from first day of trial medication to 
death. Patients with no event will be censored at the last date the patient is 
known to be alive. 
11.5.5.2 
Part B 
The primary endpoint for Part B is the Progression-Free Survival over 18 months 
(PFS), defined as time from first day of trial medication to disease progression as 
adjudicated by the independent review committee or death. Patients with no event will 
be censored at the last available tumor assessment. PFS will be analyzed using 
Kaplan-Meier estimates and curves, median PFS and respective 95% CIs.  
For each histology, PFS curves will be compared between ulixertinib and physician’s 
choice of treatment using Log Rank Test. The hazard ratio including 95% CI will be 
calculated by Cox’s Proportional Hazards model. 
Sensitivity analyses of the primary analysis will include similar analyses based on 
investigator response assessment and using PP analysis set. 
Analyses of secondary efficacy endpoints will include analyses similar to PFS analysis 
for: 
• Overall survival over 18 months (OS): time from first day of trial medication to 
death. Patients with no event will be censored at the last date the patient is 
known to be alive. 
• Duration of response (DoR): time from first response to disease progression 
or death. Patients with no event will be censored at the last available tumor 
assessment. This analysis will be based on assessment as adjudicated by 
the independent review committee and replicated on investigator 
assessment. 
• Overall response rate (ORR), defined as the percentage of patients achieving 
a BOR of confirmed CR and/or PR, will be presented with its 95% CIs and 
compared between ulixertinib and physician’s choice of treatment using a Chi-
square test. This analysis will be based on assessment as adjudicated by the 
independent review committee and replicated on investigator assessment. 

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11.5.6 
Pharmacokinetic (PK) / Pharmacodynamic (PD) Data 
Pharmacokinetic parameters of ulixertinib (BVD-523) and selected metabolites will be 
measured on Visit 4 (Day 15) in Part A only, this will be a single time-point collection 
prior to taking study drug on this day (trough at steady state).    
Pharmacokinetic values will be presented in by-patient listings, sorted by site, patient 
identifier, and dose. 
In Part A only, the effects of ulixertinib on pharmacodynamic markers will be 
evaluated. Collections will include ctDNA, tissue biopsies and/or blood to assess 
biomarkers. Assays include, but are not limited to, phosphorylation of RSK from whole 
blood, Reverse Phase Protein Arrays (RPPA) to assess protein levels, e.g. DUSP 4/6, 
plus Nanostring and/or RNA-exome to assess mRNA expression in tissue pre- and 
post-ulixertinib treatment. Biomarkers will be explored and listed as appropriate. 
11.5.7 
Safety Analysis 
All safety summaries will be provided for the safety analysis set. 
11.5.7.1 
Adverse Events (AE) 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
System Organ Class, High-Level Group Term, High Level Term, Preferred Term, and 
Lower-Level Term will be attached to the clinical database. 
AEs will be summarized based on the date of onset for the event. Summaries (number 
and percentage of patients) of treatment-emergent AEs will be provided by System 
Organ Class and Preferred Term, by group/tumor histology and overall. 
Treatment-emergent adverse event (TEAE) is defined as any AE that emerges during 
treatment having been absent pre-treatment or worsens relative to the pre-treatment 
state. 
Events that are considered study drug-related, deaths, SAEs, and AEs resulting in 
study drug discontinuation will also be tabulated by System Organ Class and 
Preferred Term. 
A tabulation will also be provided that summarizes treatment-emergent AEs by 
maximum severity (i.e., CTCAE grade).  
All AEs, including treatment-emergent and non-treatment-emergent AEs, will be listed 
in patient data listings. 
11.5.7.2 
Laboratory Evaluations 
The parameters associated with the clinical laboratory tests (hematology, clinical 
chemistry, and urinalysis) will be summarized with descriptive statistics by visit and 

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for the change from baseline to each planned post-baseline visit, by group/tumor 
histology and overall. Listings of all laboratory results and reference ranges will be 
provided.  
Graded laboratory abnormalities will be defined using the grading scheme based on 
NCI CTCAE (v5.0) and summarized by group/tumor histology and overall. Shift tables 
will also be produced for gradable parameters based on the baseline CTCAE grade 
and the maximum CTCAE grade. 
11.5.7.3 
Other Safety Evaluations 
Changes in the patient’s ECOG status and vital sign parameters will be summarized 
by group/tumor histology and overall, and any abnormal values will be tabulated.  
Listings of all data related to the patient’s ECOG status, physical examination findings, 
vital signs and ECG will be provided. 
11.6 INTERIM ANALYSIS 
No formal interim analyses are planned. 
The data from Part A will be analyzed at the end of Part A, and the data from Part B 
will be analyzed at the end of Part B. 
11.7 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/EC, and the Health 
Authorities.  
Changes to the statistical analyses will be documented in a SAP change log and in 
the clinical study report. 

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12 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
12.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
12.1.1 
Informed Consent Process 
12.1.1.1 
Consent and Other Informational Documents Provided to 
Patients 
Consent forms describing in detail the study drug, study procedures, and risks are 
given to the patient and written documentation of informed consent is required prior to 
performing any study-related assessment which isn’t standard of care. Consent forms 
will be reviewed and approved by the appropriate IRB/EC prior to being given to 
potential participants. 
12.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the patient agreeing to 
participate in the study and continues throughout the patient’s study participation. 
Consent forms will be approved by an Institutional Review Board (IRB) and the patient 
will be asked to read and review the document. The investigator or designee will 
explain the research study to the patient and answer any questions that may arise. A 
verbal explanation will be provided in terms suited to the patient’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as a 
research participant. The patient will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The patient should have the 
opportunity to discuss the study with their family or surrogates and think about it prior 
to agreeing to participate. The patient will sign the informed consent document prior 
to any procedures being done specifically for the study. The patient must be informed 
that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent document will be given to the patient 
for their records. The informed consent process will be conducted and documented in 
the source document (including the date), and the form signed, before the patient 
undergoes any study-specific procedures. The rights and welfare of the patient will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in the study. 
12.1.2 
Study Discontinuation and Closure 
It is agreed that for reasonable cause, either the investigator or the sponsor may 
temporarily suspend or prematurely terminate this study or the investigator’s 
participation in this study, provided a written notice is submitted at a reasonable time 

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in advance of intended suspension or termination. If discontinuation is by the 
investigator, notice is to be submitted to BioMed Valley Discoveries, Inc. If 
discontinuation is by the sponsor, notice will be provided to each investigator. If the 
study is suspended or prematurely terminated, the investigator will promptly inform 
the study patients, IRB, and the sponsor will provide the reason(s) for the suspension 
or termination. Study patients will be contacted, as applicable, and be informed of 
changes to the study visit schedule. 
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. 
If one or more patients at any dose level develop any of the following adverse events 
deemed to be possibly, probably or definitely related to ulixertinib by the investigator 
and/or medical monitor, based upon close temporal relationship or other factors, the 
study will be immediately suspended and no additional ulixertinib doses will be 
administered pending review and discussion of all appropriate study data by the SMC: 
• 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 Institutional Review Boards/Ethic Committees (IRBs/ECs) have been 
notified. 
12.1.3 
Confidentiality and Privacy 
Patient confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor and their interventions. This confidentiality 
is extended to cover testing of biological samples and genetic tests in addition to the 
clinical information relating to patients. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives 
of the IRB, or regulatory agencies may inspect all documents and records required to 
be maintained by the investigator, including but not limited to, medical records and 
pharmacy records for the patients in this study. The clinical study site will permit 
access to such records. 
The study patient’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be 

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kept in a secure location for as long a period as dictated by the reviewing IRB, 
Institutional policies, or sponsor requirements. 
Patient’s data collected on eCRFs during the trial will be documented in a deidentified 
fashion and the patient will only be identified by the patient number, and/or by the 
patient’s initials, if also required. The study data entry and study management 
systems used will be secured and password protected. 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. 
12.1.4 
Future Use of Stored Specimens and Data 
With the patient’s approval and as approved by local IRBs, de-identified biological 
samples will be stored for future analysis as warranted by the rapidly-advancing 
understanding in this field. During the conduct of the study, an individual patient can 
choose to withdraw consent to have biological specimens stored for future research. 
However, withdrawal of consent with regard to biological specimens’ storage may not 
be possible after the study is completed. 
Collected samples may be transferred for analysis to the sponsor, or to other 
laboratories working for the sponsor. 
Biological samples will be stored for the time established by regulatory requirements 
or destroyed after the final clinical study report has been finalized if storage is not 
required. There might be a new request for these samples to be used for purposes 
related to the quality assurance of the laboratory tests described in this protocol, in 
which case they will be used for this purpose. This may include the assessment of the 
quality of current tests, the maintenance or improvement of these tests, the 
development of new test methods for the markers described in this protocol, as well 
as making sure that new tests are comparable to previous methods and work reliably. 
If study results suggest that further investigations using stored biological samples are 
warranted, these tests might be carried out on an exploratory basis. In addition, 
biological samples may be used by the sponsor or their research partners for further 
research that is not related to the disease or the product under study. This testing will 
be done on anonymized samples (meaning that any identification linking the patient 
to the sample is destroyed). Patients will be asked to sign an additional, separate 

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consent form for this optional testing and refusal of consent will not affect their 
possibility of participating in the study. 
12.1.5 
Key Roles and Study Governance 
12.1.5.1 
Safety Oversight 
An internal Safety Monitoring Committee (SMC) will be set up to review the safety of 
ulixertinib as the study progresses. The SMC will consist of clinical investigators, the 
CRO medical monitor, and sponsor representatives. The SMC will review any AEs 
and SAEs that occur during the study and will examine the safety of ulixertinib, 
including toleration of the starting dose, dose interruptions, dose reductions, and 
toxicities that may occur in later cycles of treatment. 
The safety review will be performed at regular intervals, at least semi-annually to 
access safety and efficacy data. 
The entire study or treatment of individual patients may be stopped under defined 
circumstances as outlined in Section 9. 
12.1.5.2 
Independent Imaging Review  
In Part B only, a central imaging vendor selected by the sponsor will review 
radiological findings and determine response assessments (in accordance with 
RECIST 1.1). 
12.1.5.3 
Clinical Monitoring 
Site monitoring is conducted to ensure that the rights and well-being of trial patients 
are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with ICH GCP, and with applicable regulatory requirements. 
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. 
A clinical monitoring plan (CMP) will be developed by the sponsor’s CRO. 
During the course of the study, a site monitor will conduct routine site visits to review 
protocol compliance, compare eCRF entries with individual patient’s original source 
documents (accessed by the investigator), assess product accountability and ensure 
the study is conducted according to applicable regulatory requirements. The review of 

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the patient’s original medical records shall be performed in a manner which ensures 
patient confidentiality is maintained. 
The investigator shall permit the site monitor to review study data as frequently as 
deemed necessary to ensure that data are recorded in an adequate manner and that 
protocol adherence is satisfactory. 
The investigator may not enroll patients into the study until such time that an initiation 
visit, or with the agreement of the sponsor, attendance at the investigator meeting, 
has been performed by the site monitor to conduct a detailed training of the protocol 
and eCRF. 
12.1.5.4 
Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion. 
Quality control (QC) procedures will be implemented beginning with the data entry 
system and data QC checks that will be run on the database will be generated. Any 
missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted, data 
are generated, biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/sponsor’s designee, and inspection by local and regulatory authorities. Key 
trial personnel must be available to assist monitors during visits. 
12.1.6 
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 GCP. 
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. 

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12.1.7 
Data Handling and Record Keeping 
12.1.7.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the investigator. The investigator is responsible for ensuring the 
accuracy, completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data. 
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each patient enrolled in the study. Data recorded in 
the eCRF derived from source documents should be consistent with the data recorded 
on the source documents. All information on eCRFs must be traceable to 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 eCRFs, which will be 
documented as being the source data. All data requested on the eCRF must be 
entered and all missing data must be accounted for. 
Clinical data and clinical laboratory data will be entered into a 21 CFR Part 11 
compliant electronic data capture system. The data system includes password 
protection and internal quality checks to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
12.1.7.2 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the study drug. 
These documents should be retained for a longer period, however, if required by local 
regulations. No records will be destroyed without the written consent of the sponsor, 
if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained.  
Study documents include:  
• IRB/EC approvals for the study protocol and all amendments 
• All source documents and laboratory records 
• CRF copies (electronic copies on a CD-ROM) 
• Patients' informed consent forms (with study number and title of trial) 
• FDA form 1572 
• Any other pertinent study document 

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12.1.8 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or 
study manual requirements. The noncompliance may be either on the part of the 
patient, investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly. 
It is the responsibility of the investigator to use continuous vigilance to identify and 
report deviations. All deviations must be addressed in study source documents. 
Protocol deviations must be sent to the reviewing IRB per their policies. The 
investigator is responsible for knowing and adhering to the review IRB requirements. 
Further details about the handling of protocol deviations will be included in the study 
manual. 
12.1.9 
Publication and Data Sharing 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 may 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. 
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 by BioMed Valley Discoveries, Inc., or its authorized 
representatives, or in confidence to the IRB, or similar committee, except if required 
by law. 
12.1.10 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence is critical. 
Therefore, any actual conflict of interest of person who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, person who have a perceived conflict of interest will be 
required to have such conflicts managed in such a way that is appropriate to their 
participation in the design and conduct of this trial. 
12.1.11 Insurance 
The sponsor has established an insurance policy for the total anticipated duration of 
the study, covering the patients with respect to the risks involved in taking part in this 
study in accordance with this protocol. In the case of injury or disability deriving from 

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participation in the study, patients are requested to inform the investigator or their staff 
responsible for the study at the institution without delay. 
12.2 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of 
Change 
Brief Rationale 
 
 
 
 
 
 
 
 

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13 REFERENCES 
 
1. 
Dahlman et al, 2012. BRAFL597 Mutations in Melanoma Are Associated with Sensitivity to MEK 
Inhibitors. Cancer Discov September 1 2012 (2) (9) 791-797; DOI: 10.1158/2159-8290.CD-12-
0097. 
2. 
Dankner et al, 2018. Classifying BRAF alterations in cancer: new rational therapeutic strategies 
for actionable mutations. Oncogene 37, 3183–3199; DOI: 10.1038/s41388-018-0171-x. 
3. 
Dankner et al, 2018. Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of 
Class II BRAF Mutant Melanomas. Clin Cancer Res December 15 2018 (24) (24) 6483-6494; 
DOI: 10.1158/1078-0432.CCR-17-3384. 
4. 
Davies et al, 2002. Mutations of the BRAF gene in human cancer. Nature, Jun 
27;417(6892):949-54. Epub 2002 Jun 9. DOI: 10.1038/nature00766. 
5. 
Emery et al, 2017. BRAF-inhibitor Associated MEK Mutations Increase RAF-Dependent and -
Independent Enzymatic Activity. Mol Cancer Res. Oct;15(10):1431-1444. DOI: 10.1158/1541-
7786.MCR-17-0211. 
6. 
Gao et al, 2018. Allele-specific mechanisms of activation of MEK1 mutants determine their 
properties. Cancer Discov. May;8(5):648-661. Epub 2018 Feb 26. DOI 10.1158/2159-8290.CD-
17-1452.  
7. 
Germann et al, 2017. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical 
Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 
Nov;16(11):2351-2363. Epub 2017 Sep 22. DOI: 10.1158/1535-7163.MCT-17-0456. 
8. 
Houben et al, 2004. Constitutive activation of the Ras-Raf signaling pathway in metastatic 
melanoma is associated with poor prognosis. J Carcinog. 2004; 3: 6. Epub 2004 Mar 26. DOI: 
10.1186/1477-3163-3-6. 
9. 
Ikenoue et al, 2004. Different Effects of Point Mutations within the B-Raf Glycine-Rich Loop in 
Colorectal Tumors on Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase 
Kinase/Extracellular Signal-Regulated Kinase and Nuclear Factor κB Pathway and Cellular 
Transformation. Cancer Res May 15 2004 (64) (10) 3428-3435; DOI: 10.1158/0008-5472.CAN-
03-3591. 
10. Jones et al, 2017. Non-V600BRAF Mutations Define a Clinically Distinct Molecular Subtype of 
Metastatic Colorectal Cancer. JCO 35, no. 23 (August 10, 2017) 2624-2630. DOI: 
10.1200/JCO.2016.71.4394 
11. Mendzelevski et al, 2018. Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval 
in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol. 81(6):1129-
1141. 
12. Menzer et al, 2019. Targeted Therapy in Advanced Melanoma with Rare BRAF Mutations. JCO 
37, no. 33 (November 20, 2019) 3142-3151. DOI: 10.1200/JCO.19.00489. 
13. Santarpia et al, 2009. Detection and molecular characterization of a novel BRAF activated 
domain mutation in follicular variant of papillary thyroid carcinoma. Human Pathology, 40(6);827-
833. DOI: 10.1016/j.humpath.2008.11.003. 
14. Smalley et al, 2009. CRAF inhibition induces apoptosis in melanoma cells with non-V600E 
BRAF mutations. Oncogene, Jan 8;28(1):85-94. Epub 2008 Sep 15. DOI: 
10.1038/onc.2008.362. 
15. Sullivan et al, 2018. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK 
mutant advanced solid tumors: Results of a phase I dose-escalation and expansion 
study. Cancer Discov. 2018;8(2):184-195.  

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16. Wan et al, 2004.  Mechanism of activation of the RAF-ERK signaling pathway by oncogenic 
mutations of B-RAF. Cell, Mar 19;116(6):855-67. DOI: 10.1016/s0092-8674(04)00215-6. 
17. Yaeger et al, 2019.  Targeting Alterations in the RAF−MEK Pathway. Cancer Discov 
2019;9:329-341. Epub 2019 Feb 15. DOI: 10.1158/2159-8290.CD-18-1321. 
18. Yao et al, 2015. BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that 
Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell, 2015. 28(3): p. 370-83. 
19. Yao et al, 2017. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated 
RAS. Nature 548(7666): p. 234-238. 
 
 
 

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Appendix 1 
Non-Permitted Concomitant Medications 
 
1Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. 
Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of 
combination regimens on CYP3A activities. 
Strong inhibitors: ≥ 5-fold increase in AUC 
Strong inducers: ≥ 80% decrease in AUC 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers; Table 3.2 (inhibitors) and Table 3.3 (inducers), dated 12.03.19; 
Accessed 02.24.20 
 
 
INHIBITORS 
INHIBITORS 
INHIBITORS 
CYP1A2 
CYP2D6 
CYP3A 
ciprofloxacin 
bupropion 
boceprevir 
enoxacin 
fluoxetine 
clarithromycin 
fluvoxamine 
paroxetine 
cobicistat 
 
quinidine 
danoprevir/ritonavir1 
 
terbinafine 
elvitegravir/ritonavir1 
 
 
grapefruit juice 
INDUCERS 
 
idelalisib 
CYP3A 
 
indinavir/ritonavir1 
apalutamide 
 
itraconazole 
carbamazepine 
 
ketoconazole 
enzalutamide 
 
lopinavir/ritonavir1 
mitotane 
 
nefazodone 
phenytoin 
 
nelfinavir 
rifampin 
 
paritaprevir/ritonavir1 
St. John’s Wort 
 
posaconazole 
 
 
ritonavir 
 
 
saquinavir/ritonavir1 
 
 
telaprevir 
 
 
telithromycin 
 
 
tipranavir/ritonavir1 
 
 
troleandomycin 
 
 
voriconazole 

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Appendix 2 
List of Accepted Atypical BRAF Type II Alterations for 
Group 2  
BRAF Alteration 
Evidence of Pathway Activation 
(Reference Number) 
P367L/S 
17 
R462I 
2, 9, 16 
I463S 
2, 8, 15 
G464V/E/R 
2, 3, 4, 8, 9, 10, 16, 17, 18, 19 
F468C 
9 
N486_A489delinsK 
17 
N486_P490del 
17 
E586K 
2, 3, 4, 16, 17 
A598V 
2, 10, 13 
T599I/K/dup 
2, 15, 16, 17 
K601_S602delinsNT 
17 
K601E/N/T 
1, 2, 3, 10, 12, 16, 17, 18, 19  
A728V 
2, 16 
BRAF kinase duplication 
17 
BRAF fusions 
2, 3, 12, 17, 18, 19 
 
 
 
 

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Appendix 3 
ECOG Performance Status  
ECOG Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead