Clinical trial NCT02296242
Conditions: Acute Myelogenous Leukemia Myelodysplastic Syndrome
Sponsor: BioMed Valley Discoveries, Inc
Start date: 2014-11-01; Completion date: 2017-06-15
Enrollment: 53 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being performed to assess the safety, tolerability, and preliminary clinical effects of BVD-523 given orally, twice daily for 21-day cycles, in patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS).

Detailed description:
The study is being performed to assess the safety and tolerability of BVD-523 given orally, twice daily for 21-day cycles.

Part 1 of the study will establish dose limiting toxicities (DLT), maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D).

In Part 2 of the study, additional patients with particular tumor types and/or cancers harboring specific genetic mutations will be recruited for treatment at the Recommended Phase 2 Dose (RP2D). Patients may also be assessed pharmacodynamic measures in healthy or malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic measures.

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

Protocol documents:
Prot_000.pdf: 
BVD-523 
 
BioMed Valley Discoveries, Inc. 
Clinical Study Protocol: BVD-523-02 
 
Confidential 
Page 1 
 
CLINICAL STUDY PROTOCOL 
 
PHASE 1/2 DOSE-ESCALATION, SAFETY, CLINICAL 
ACTIVITY, PHARMACOKINETIC AND 
PHARMACODYNAMIC STUDY OF THE ERK1/2 INHIBITOR 
BVD-523 IN PATIENTS WITH ACUTE MYELOGENOUS 
LEUKEMIA OR MYELODYSPLASTIC SYNDROMES 
 
BVD-523-02 
 
Drug Development Phase: 
Phase 1/2 
Investigational Product: 
BVD-523 
Indication: 
Acute Myelogenous Leukemia or Myelodysplastic 
Syndrome 
Sponsor: 
BioMed Valley Discoveries, Inc. 
4520 Main St. 16th Floor 
Kansas City, MO 64111 
Protocol Version and Date: 
Version 2, 18 November 2015 
 
Conduct:  Conducted in compliance with International Conference on Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP) and in accordance with local regulatory 
requirements. 
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. 


BVD-523 
BioMed Valley Discoveries, Inc. 
Clinical Study Protocol: BVD-523-02 
PROTOCOL APPROVAL SIGNATURE PAGE 
SPONSOR: BIOMED VALLEY DISCOVERIES, INC 
I have read and understand the contents of Version 2 of this clinical protocol for Study No. 
BVD-523-02 dated 18 November 2015 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 ofthis Study. 
Brent . Kreider, Phb. 
Date 
Ch1 Operations Offi er, BioMed Valley Discoveries, Inc. 
Confidential 
Page 2 


BVD-523 
 
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Clinical Study Protocol: BVD-523-02 
 
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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of Version 2 of this clinical protocol for Study No. 
BVD-523-02 dated 18 November 2015 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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Clinical Study Protocol: BVD-523-02 
 
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PROTOCOL SYNOPSIS 
Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental Phase:   
Phase 1/2 
Title of Study: 
Phase 1/2 Dose-Escalation, Safety, Clinical Activity, Pharmacokinetic and Pharmacodynamic Study of the 
ERK1/2 Inhibitor BVD-523 in Patients with Acute Myelogenous Leukemia or Myelodysplastic Syndromes 
Protocol Number: 
BVD-523-02 
Indication: 
Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
Objectives: 
Primary objectives: 
• 
To define the safety and tolerability of BVD-523 in patients with AML or MDS by determining the 
dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the recommended Phase 2 
Dose (RP2D). 
• 
To determine the pharmacokinetic profile of BVD-523 and selected metabolites in patients with AML 
or MDS. 
Secondary objectives: 
• 
To assess clinical response in patients with AML or MDS treated with BVD-523 at the recommended 
Phase 2 Dose (RP2D). 
• 
To determine the progression-free survival (PFS) and duration of response (DOR) of AML or MDS 
patients treated with BVD-523 achieving CR (complete remission)/CRp (complete remission with 
incomplete platelet recovery). 
Exploratory objective: 
• 
To evaluate pharmacodynamic marker (biomarker) measures. 
Methodology/Study Design: 
BVD-523-02 is an open-label, multicenter, Phase 1/2 study with a dose-escalation phase (Part 1) and a cohort 
expansion phase (Part 2). 
Part 1 – Dose-escalation Phase:  A classic “3+3” design will be used to establish dose limiting toxicities (DLT), 
maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D).  Three to six patients per 
treatment cohort will be assigned to receive sequentially higher oral doses of BVD-523 on a twice daily 
schedule (b.i.d.) for 21 days (a “Cycle”), starting at a dose of 300 mg.  Patients will receive twice-daily oral 
doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another 
withdrawal criterion is noted.  Treatment cycles will occur consecutively without interruption, except when 
necessary to manage adverse events.  All dose-escalation decisions will be based on Cycle 1 safety data and 
doses will not be escalated unless the patients receiving the highest current dose have been observed for at least 
21 days (1 cycle). 
The 3 + 3 design will be conducted as follows.  Initially, 3 patients will be enrolled to a cohort; the occurrence 
of a single drug-related DLT in one of these 3 patients will prompt enrollment of up to 3 additional patients to 
that same cohort.  When more than 1 DLT occurs in ≤ 6 patients in a dosing cohort, dose escalation will be 
stopped and this dose level will be identified as the non-tolerated dose.  Doses between the non-tolerated dose 
and the preceding lower dose, where ≤ 1 DLT occurred, may be explored to more precisely define the MTD.  
This strategy allows for a rigorous determination of MTD, especially if the dose increase that resulted in 
determination of the non-tolerated dose is relatively large (i.e., > 50%). 
During the study, the Sponsor and Investigators may request that cohorts be enlarged or that evaluation of 
intermediate doses between 2 planned escalation steps be explored.  Such requests will be discussed with the 
Investigator(s), Sponsor and Medical Monitor, and should be based on all data existing at that time, including 


BVD-523 
 
BioMed Valley Discoveries, Inc. 
Clinical Study Protocol: BVD-523-02 
 
Confidential 
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Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental Phase:   
Phase 1/2 
safety and clinical activity, determinations of pharmacokinetics, pharmacodynamics, and cumulative toxicity.  
Before each escalation, investigators will be consulted to ensure that all involved agree with the escalation 
decision. 
Part 2 – Cohort-expansion Phase:  Additional patients will be recruited to one of two groups - Group 1: RAS 
mutant positive AML or MDS; Group 2: RAS mutant negative AML or MDS - to receive treatment at the 
Recommended Phase 2 Dose (RP2D).  Patients will receive twice daily oral doses of BVD-523 in 21-day 
treatment cycles until disease progression, unacceptable toxicity, or another withdrawal criterion is met.  
Treatment cycles will occur consecutively without interruption except when necessary to manage adverse 
events. 
Study Population- Criteria for Inclusion: 
Patients eligible for inclusion in this trial must fulfill all of the following criteria: 
1. Provide signed and dated informed consent prior to initiation of any study-related procedures that are not 
considered Standard of Care (SOC). 
2. Male or female patients aged ≥ 18 years. 
3. Have either of the following diagnoses: 
a. 
Morphologically confirmed AML (except acute promyelocytic leukemia (APL)) including leukemia 
secondary to prior therapy (e.g., chemotherapy, radiation therapy (XRT)) or antecedent hematologic 
disorder (e.g., MDS or myeloproliferative disorders), who have failed to achieve CR or who have 
relapsed after prior therapy and are not candidates for potentially curative therapy.   
b. Intermediate-2 or High-grade risk MDS (including chronic myelomonocytic leukemia (CMML)). 
4. Have received at least one prior therapy.  Patients who are over age 65 and have not received therapy for 
AML are also eligible, if they are not candidates for induction chemotherapy. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry out all 
pre-disease activities without restriction) to 2 (ambulatory and capable of all self-care but unable to carry 
out any work activities; up and about more than 50% of waking hours), measured within 72 hours before 
the start of treatment.   
6. Predicted life expectancy of ≥ 3 months. 
7. Adequate renal function [creatinine ≤ 1.5 times ULN (upper limit of normal)] or glomerular filtration rate 
(GFR) of ≥ 50mL/min. 
8. Adequate hepatic function [total bilirubin ≤ 1.5 x UNL; AST (aspartate transaminase) or ALT (alanine 
transaminase) ≤ 3 x UNL or ≤ 5 x UNL if due to liver involvement by tumor]. 
9. Adequate cardiac function, > institutional lower limit of normal  e.g., left ventricular ejection fraction 
(LVEF) of ≥ 50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography 
(ECHO); corrected QT interval (QTc) < 470 ms. 
10. Contraception: 
• 
For women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, 
postmenopausal (defined as no menstrual cycle for at least 12 consecutive months), or compliant with 
an acceptable contraceptive regimen (oral contraceptives, condom with spermicide, etc.) during and for 
3 months after the treatment period.  Abstinence is not considered an adequate contraceptive regimen. 
• 
For men: Must be surgically sterile, or compliant with a contraceptive regimen (as above) during and 
for a minimum of 3 months after the treatment period. 
11. Willing and able to participate in the trial and comply with all trial requirements. 
12. For Part 2 Group 1 of the Study ONLY: 
Positive for RAS mutation at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory 
prior to study entry.  


BVD-523 
 
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Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental Phase:   
Phase 1/2 
Criteria for Exclusion: 
Patients who fulfill one or more of the following criteria will not be eligible for inclusion in this trial: 
1. Concomitant malignancies except carcinoma in situ, basal or squamous cell skin carcinoma; low grade 
prostate cancer treated with prostatectomy more than 10 years ago; early stage melanoma treated with 
complete surgical excision more than 5 years ago; carcinoma in situ of cervix treated with cone procedure 
more than 8 years ago. 
2. 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.  Refractory nausea and vomiting must also be discussed with the Medical Monitor prior 
to enrolling such a patient. 
3. Uncontrolled or severe intercurrent medical condition. 
4. Patients with rapidly increasing peripheral blood blast counts (significant increase in the absolute peripheral 
blast count with white blood cell (WBC) > 30,000) or uncontrolled (absolute blast count > 30,000) while 
on hydroxyurea will be excluded. 
5. Known uncontrolled central nervous system (CNS) involvement.  (Stable asymptomatic CNS involvement 
either untreated or being treated with a stable dose (or doses) of intra-thecal therapy(ies) can be allowed if 
there is evidence that the CSF cell count is decreased and that patient is responding to IT therapy.) 
6. Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, 
etc.) within 28 days or 5 half-lives, (whichever is shorter). 
7. Any concurrent or prior use of an investigational drug (including MEK inhibitors) within 28 days or 5 half-
lives (whichever is shorter) prior to the first dose of BVD-523.  A minimum of 10 days between 
termination of the investigational drug and administration of BVD-523 is required.  In addition, any drug-
related toxicity except alopecia should have recovered to Grade 1 or less. 
8. Received chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior 
nitrosourea or mitomycin C).  Received chemotherapy regimens given continuously or on a weekly basis 
with limited potential for delayed toxicity within the last two weeks. 
9. Ongoing anticoagulant therapy that cannot be held if necessary to permit bone marrow sampling.  Patients 
who require anticoagulant therapy and cannot be maintained on low molecular weight heparin (LMWH) 
should not be considered for this study. 
10. Major surgery within 4 weeks prior to first dose. 
11. Pregnant or breast-feeding women. 
12. Any evidence of serious active infections (subjects who have been fever-free for 24 hours prior to 
enrollment and on active treatment would not be considered excluded). 
13. Any important medical illness or abnormal laboratory finding that would increase the risk of participating 
in this study (based on the investigator’s judgment). 
14. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR). 
15. Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or 
strong inducers of CYP3A4 (for list of non-permitted drugs, see Appendix 1).  
Test Product, Dose and Mode of Administration: 
Part 1: BVD-523, starting at an oral dose of 300 mg taken with at least 8 ounces of water twice-daily for each 
21 day cycle, with escalating dose levels (classic 3+3 design).  Dosing of each subject will continue until the 
subject withdraws from the study or dies.  A subject that has a Dose Limiting Toxicity (DLT) may be dose 
reduced or be withdrawn from the study depending upon the decision of the Safety Monitoring Committee 
(which includes the Sponsor, Medical Monitor and the study investigator) in Part 1. 
Part 2: BVD-523, recommended Phase 2 dose (RP2D), taken orally with at least 8 ounces of water twice-daily 


BVD-523 
 
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Clinical Study Protocol: BVD-523-02 
 
Confidential 
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Sponsor: 
BioMed Valley Discoveries, Inc. 
Investigational Product: 
BVD-523 
Developmental Phase:   
Phase 1/2 
for each 21 day cycle.  Dosing of each subject may continue until the subject is discontinued from the study.   A 
subject that has a Dose Limiting Toxicity (DLT) may be dose reduced or be withdrawn from the study 
depending upon the decision of the Safety Monitoring Committee (which includes the Sponsor, Medical 
Monitor and the study investigator). 
Concomitant Medications: 
Necessary supportive care such as antibiotics, blood product transfusions, antiemetics, antidiarrheals, etc., will 
be allowed.  Drugs that are strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of 
CYP3A4, will not be allowed during the study (see Appendix 1). 
Study Duration: 
Part 1: Approximately 6 months, Part 2: 18 to 24 months 
Criteria for Evaluation 
Safety: 
Vital signs, physical examination, ophthalmology examination, clinical chemistry, hematology, urinalysis, 
electrocardiograms (ECG).  The severity of adverse events (AEs) will be graded according to the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) Grading Scale Version 
4.03 (see the NCI CTCAE web page at http://ctep.cancer.gov for details).  
Efficacy: 
Clinical response will be assessed on results of bone marrow biopsies using International Working Group 2003 
and 2006 criteria for AML or MDS respectively (1, 2).   
Pharmacokinetics: 
Blood samples will be collected to measure BVD-523 and selected metabolite concentrations.  At Baseline 
(Visit 2, Cycle 1) and again on Day 22 (Visit 5, Cycle 1), blood samples will be collected prior to 
administration of the first daily dose and then post-dosing at the following time points: 0.5, 1, 2, 4, 6, 8, and 12 
± 2 hours. 
Pharmacodynamics: 
Blood and/or bone marrow aspirate will be used to evaluate multiple biomarkers of drug response including 
pRSK and total RSK.  Blood and/or bone marrow aspirate will be collected to measure ex vivo BVD-523 
sensitivity of leukemic cells prior to therapy on Day 1 and on Day 22 of Cycle 1.  Additional biomarkers and 
DNA sequence analysis may be identified and measured as appropriate by collection of whole blood prior to 
dosing initiation and after drug levels have reached steady-state.  
Statistical Methods: 
The sample size for Part 1 of this study was determined by clinical rather than statistical considerations.  
Approximately 20 patients will be treated in Part 1 of this study (Dose Escalation Phase) to establish dose 
limiting toxicities (DLT), maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D). 
After completion of Part 1 of this study, Part 2 will commence.  In Part 2, up to 40 additional AML or MDS 
patients will be recruited to one of two groups- Group 1: patients with positive RAS mutant AML or MDS and 
Group 2: patients with negative RAS mutant AML or MDS will be treated with the RP2D of BVD-523.  The 
purpose of the second phase of this study is to document evidence of response.  With 20 subjects in each group, 
there is an 88% probability of seeing at least one positive response in each group if the true response rate is at 
least 10%. 
The observation of DLTs in more than 33% of patients in either Part 2 cohort with at least 6 patients enrolled at 
any time during Part 2 will trigger temporary stopping of patient enrollment and revision of the definition of the 
MTD and RP2D in the specific cohort.  Subsequent patients will be treated with a dose lower than the initial 
RP2D and this dose will be determined in discussion with the Clinical Investigators, the Medical Monitor, and 
the Sponsor. 


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Clinical Study Protocol: BVD-523-02 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION ...........................................................................................................15 
1.1 
Study Drug .............................................................................................................17 
1.2 
Indication ...............................................................................................................17 
1.3 
Background to the Disease .....................................................................................17 
1.4 
Previous Human Experience ..................................................................................19 
1.5 
Preclinical Data ......................................................................................................19 
1.5.1 
Potential Risk ...............................................................................................19 
1.5.2 
Pharmacology Studies ..................................................................................21 
1.5.3 
Toxicity and Safety Studies .........................................................................22 
2 
RATIONALE FOR THE STUDY ...................................................................................24 
2.1 
Rationale for the Doses and the Dosing Regimen ..................................................24 
3 
STUDY DESIGN .............................................................................................................25 
3.1 
Study Design Overview .........................................................................................25 
3.1.1 
Study Objectives ..........................................................................................25 
3.1.1.1 
Primary Objectives .............................................................................25 
3.1.1.2 
Secondary Objectives .........................................................................25 
3.1.1.3 
Exploratory Objective ........................................................................25 
3.1.2 
Methodology / Study Design ....................................................................25 
3.1.3 
Summary of Dose Escalation .......................................................................27 
3.1.4 
Definition of MTD, DLT, and RP2D ..........................................................27 
3.1.4.1 
Definition of Maximum Tolerated Dose (MTD) ...............................27 
3.1.4.2 
Definition of Dose Limiting Toxicity (DLT) .....................................27 
3.1.4.3 
Definition of Recommended Phase 2 Dose (RP2D) ..........................28 
3.2 
Safety Monitoring Committee ...............................................................................28 
3.3 
Safety Review Meetings ........................................................................................28 
3.4 
Stopping Rules .......................................................................................................28 
3.5 
Criteria for Evaluation ...........................................................................................28 
3.5.1 
Safety ...........................................................................................................28 
3.5.2 
Efficacy ........................................................................................................29 
3.5.3 
Pharmacokinetics .........................................................................................29 
3.5.4 
Pharmacodynamics ......................................................................................29 
3.6 
Blinding and Randomization .................................................................................29 
4 
SELECTION OF PATIENTS ..........................................................................................30 
4.1 
Number of Patients .................................................................................................30 


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4.2 
Recruitment ............................................................................................................30 
4.3 
Inclusion Criteria ...................................................................................................30 
4.4 
Exclusion Criteria ..................................................................................................31 
5 
STUDY PLAN AND PROCEDURES ............................................................................33 
5.1 
Study Patient Number ............................................................................................33 
5.2 
Description of Study Visits For Part 1 ...................................................................33 
5.2.1 
Visit 1 (Day -28 to -1); Screening................................................................33 
5.2.2 
Visit 2 (Day 1 ± 0); Baseline/Drug Dispensing/Initiation of Treatment .....34 
5.2.3 
Visit 3 (Day 8 ± 1) .......................................................................................35 
5.2.4 
Visit 4 (Day 15 ± 1) .....................................................................................36 
5.2.5 
Visit 5 (Day 22 ± 1 of Cycle 1, first day of Cycle 2) ...................................36 
5.2.6 
Treatment Discontinuation Visit ..................................................................37 
5.2.7 
Unscheduled Visits ......................................................................................38 
5.3 
Study Visits for Part 1 Cycle 2 ...............................................................................38 
5.4 
Description of Study Visit for Part 1 Cycle 3 and Each Subsequent Cycle of 
Part 1 ......................................................................................................................38 
5.4.1 
Cycle 3 and Subsequent Cycles Visit (Day 1 ± 1 of each cycle) .................38 
5.5 
Description of Study Visits for Part 2 ....................................................................39 
6 
METHODS OF ASSESSMENT AND CRITERIA FOR EVALUATION .....................39 
6.1 
Demographic Data .................................................................................................39 
6.2 
Medical History ......................................................................................................39 
6.3 
Concomitant Medications ......................................................................................39 
6.4 
Physical Examination .............................................................................................39 
6.5 
Safety Assessments ................................................................................................40 
6.6 
Pharmacokinetics ...................................................................................................41 
6.7 
Pharmacodynamics ................................................................................................41 
6.8 
Efficacy ..................................................................................................................41 
6.9 
Pharmacokinetic Procedures ..................................................................................43 
6.9.1 
Blood Sampling and Processing ..................................................................43 
6.9.2 
Pharmacokinetic Endpoints .........................................................................43 
7 
DISCONTINUATION CRITERIA .................................................................................47 
7.1 
Early Discontinuation of the Study ........................................................................47 
7.2 
Discontinuation of Individual Patients ...................................................................47 
8 
TREATMENT .................................................................................................................49 
8.1 
Dosing and Administration of Study Medication ...................................................49 
8.1.1 
Dispensing Directions ..................................................................................49 
8.1.2 
Dosing Information ......................................................................................49 


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8.1.3 
Dosing Instructions for the Study Participants ............................................50 
8.2 
Rescue Medications and Concomitant Treatments .................................................50 
8.3 
Treatment Compliance ...........................................................................................50 
9 
ADVERSE EVENT MANAGEMENT ...........................................................................52 
9.1 
Definition of an Adverse Event .............................................................................52 
9.2 
Definition of a Serious Adverse Event ...................................................................52 
9.3 
Recording of Adverse Events and Serious Adverse Events ...................................53 
9.4 
Intensity of Adverse Events ...................................................................................53 
9.5 
Relationship of Adverse Events to Study Drug ......................................................54 
9.6 
Follow-Up of Adverse Events and Serious Adverse Events ..................................54 
9.7 
Post Study Adverse Events and Serious Adverse Events .......................................54 
9.8 
Regulatory Aspects of Adverse Event Reporting ...................................................54 
9.8.1 
Overdose ......................................................................................................55 
9.8.2 
Pregnancies ..................................................................................................55 
10 STATISTICAL METHODS ............................................................................................57 
10.1 
General Considerations ..........................................................................................57 
10.1.1 
Statistical and Analytical Plans....................................................................57 
10.1.2 
Determination of Sample Size .....................................................................57 
10.1.3 
Blinding and Randomization .......................................................................57 
10.2 
Analysis Datasets ...................................................................................................57 
10.2.1 
Population to be Analyzed ...........................................................................57 
10.2.2 
Modified Intent-to-treat ...............................................................................57 
10.2.3 
Per Protocol ..................................................................................................58 
10.2.4 
Definition of Study Days .............................................................................58 
10.3 
Data Presentation ...................................................................................................58 
10.3.1 
Demographic ................................................................................................58 
10.3.2 
Baseline Characteristics ...............................................................................58 
10.3.3 
Medical History and Physical Examination.................................................59 
10.3.4 
Concomitant Medications or Treatments .....................................................59 
10.3.5 
Primary Endpoints .......................................................................................59 
10.3.6 
Secondary Endpoints ...................................................................................59 
10.3.7 
Pharmacokinetic Data ..................................................................................59 
10.3.8 
Safety Data ...................................................................................................59 
10.3.9 
Adverse Events (AE) ...................................................................................60 
10.4 
Changes in the Conduct of the Study or Planned Analysis ....................................60 
11 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ........................................61 
11.1 
Declaration of Helsinki ..........................................................................................61 


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11.2 
Good Clinical Practice ...........................................................................................61 
11.3 
Institutional Review Boards/Ethics Committees ....................................................61 
11.4 
Regulatory Authority Approval .............................................................................61 
11.5 
Pre-Study Documentation Requirements ...............................................................61 
11.6 
Informed Consent ...................................................................................................61 
11.7 
Patient Confidentiality and Disclosure ..................................................................62 
11.8 
Collection, Monitoring and Auditing of Study Documentation, and Data 
Storage ...................................................................................................................62 
11.9 
Disclosure of Information ......................................................................................63 
11.10 Discontinuation of the Study ..................................................................................63 
11.11 Study Report, Publication Policy and Archiving of Study Documentation ...........63 
11.11.1 Study Report and Publication Policy ...........................................................63 
11.11.2 Study Documents .........................................................................................64 
11.11.3 Archiving of Documents ..............................................................................64 
12 REFERENCES ................................................................................................................65 
 
LIST OF IN-TEXT TABLES 
Table 3.1 
Study Medication Dosing and Pharmacokinetics/Pharmacodynamics 
Chart ................................................................................................................... 26 
Table 3.2 
Summary of Dose Escalation ............................................................................. 27 
Table 6.1 
Table 3 from IWG 2006 MDS Response Criteria ............................................. 42 
Table 6.2 
Table 4 from IWG 2003 AML Response Criteria ............................................ 42 
Table 6.3 
Part 1 and 2: Schedule of Assessments and Procedures ................................... 44 
Table 6.4 
Pharmacokinetic Parameters to be Estimated after Dose 1 and at Steady 
State .................................................................................................................... 46 
Table 10.1 Per Cycle Study Visit Definitions ..................................................................... 58 
 
LIST OF APPENDICES 
Appendix 1 Non-Permitted Concomitant Medications ......................................................... 72 
 


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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase (SGPT) 
AMS 
acute myelodysplastic syndrome 
AMP 
adenosine monophosphate 
APL 
acute promyelocytic leukemia 
AST 
aspartate transaminase (SGOT) 
AUC 
area under the plasma concentration-time curve 
b.i.d. 
twice daily 
BM 
bone marrow 
BMI 
body mass index 
BP 
blood pressure 
Bpm 
beats per minute 
BUN 
blood urea nitrogen 
CFB 
change from baseline 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
cm 
centimeter 
Cmax 
maximum concentration 
CMC 
carboxymethylcellulose 
CML 
chronic myeloid leukemia 
CMML 
chronic myelomonocytic leukemia 
CNS 
central nervious system 
CPWW 
Clinipace Worldwide 
CR 
complete remission/complete response 
CRp 
complete remission with incomplete platelet recovery 
CRF 
case report form 
CSF 
cerebrospinal fluid 
CSR 
central serous retinopathy 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
CYP 1A2 
cytochrome P450 isoform 1A2 
CYP 2D6 
cytochrome P450 isoform 2D6 
CYP 3A4 
cytochrome P450 isoform 3A4 
dL 
deciliter 
DLT 
dose limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EOS 
end-of-study 
ERK 
extracellular signal-regulated kinase 
°F 
degrees Fahrenheit 
%F 
absolute bioavailability 
FDA 
Food and Drug Administration 
FDG-PET 
18F-fluorodeoxyglucose-positron-emission tomography 
g 
gram 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HCl 
hydrochloride 
HDL 
high-density lipoprotein 
hERG 
human ether-a-go-go related gene  
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IT 
intrathecal 
ITT 
intent-to-treat 
kg 
kilogram 
LD 
largest diameter 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLOQ 
lower limit of quantification 
LMWH 
low molecular weight heparin 
LVEF 
left ventricular ejection fraction 
LS 
least squares 
µg 
microgram 
m2 
square meters 
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  
mmHg 
millimeters of mercury 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multi-gated acquisition 


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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
NCI 
National Cancer Institute 
NOEL 
no observed effect level 
ng 
nanogram 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamics 
PI 
Principal Investigator 
PI3K 
phosphatidylinositol-3-kinase 
PK 
pharmacokinetics 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
q.d. 
once daily 
QT 
a measure between Q and T waves in heart electrical system 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
RECIST 
response evaluation criteria in solid tumors (Version 1.1) 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAS 
Statistical Analysis Systems 
SCT 
stem-cell transplantation 
SD 
standard deviation 
SEER 
Surveillance, Epidemiology, and End Results 
SEM 
standard error of the mean  
SMC 
Safety Monitoring Committee 
TSH 
thyroid-stimulating hormone 
TTP 
duration of response 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WHO 
World Health Organization 
WO 
washout  
WPSS 
WHO classification–based Prognostic Scoring System 
XRT 
radiation therapy 


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1 
INTRODUCTION 
A critical hallmark of cancer is the activation of cell-growth signaling cascades independent of 
appropriate growth stimuli (3).  A canonical example of a cell growth control circuit is the 
mitogen-activated protein kinase, or MAPK, pathway.  Here, surface receptors activated by 
growth ligands signal via downstream effectors in a linear relay system: RAS family GTPases 
activate RAF family protein kinases, which in turn trigger a phosphorylation cascade involving 
mitogen-activated protein kinase/extracellular signal-related kinase (MEK) and extracellular 
signal-regulated kinase (ERK) family kinases.  ERK kinases activate an array of direct 
effectors that ultimately translate growth signaling into essential cellular functions including 
cell division and cell survival. 
Aberrant activation of the MAPK pathway is frequently observed in cancer.  Often, 
components of the MAPK pathway undergo direct genetic mutation, causing constitutive 
activation of the signaling cascade in the absence of appropriate ligands.  For example, 
members of the RAS GTPase family (KRAS, NRAS, and HRAS) were among some of the first 
endogenous oncogenes demonstrated to exhibit spontaneous, activating mutations in a variety 
of cancers, including pancreatic, colorectal and non-small cell lung malignancies (4).  
Up-regulation of the Ras>Raf>MEK>ERK and PI3K>Akt pathways and phosphorylation of the 
downstream target Bad are observed frequently in AML specimens and associated with a poorer 
prognosis than that seen in patients lacking these changes (5, 6).  Aberrant expression of a single 
pathway is associated with a poor prognosis and abnormal expression of multiple signaling 
pathways is associated with an even worse prognosis (5).  Dysregulation of the 
Ras>Raf>MEK>ERK and PI3K>Akt pathways in some AMLs may result from constitutive 
activation of Flt-3 (7, 8, 9).  Thus these two signaling pathways provide important clues 
regarding the mechanisms responsible for autonomous AML growth (10, 11, 12, 13, 14).  
Targeting these “downstream” pathways may prove effective for AML therapy, including in 
those cases where the precise mutation responsible for malignant transformation is unknown.   
AML is the most common type of acute leukemia seen in adults, with approximately 13,000 
cases diagnosed annually in the United States (US).  The median age at onset is 67 years, with 
the majority of patients being between 65 and 84 years at the time of diagnosis (15).  The 
incidence of this hematologic malignancy can be expected to increase as the US population 
ages.  AML is often fatal, with a 5-year survival rate of only 23% (16). 
The goal of treatment of AML is to achieve a complete remission by reducing the malignant 
clone(s) to allow recovery of peripheral blood production and re-population of the bone marrow 
(BM) with normal hematopoietic stem cells.  In the induction treatment of AML, complete 
remission is considered the only clinically important form of response.  The ability to achieve 
such a response has been directly correlated with survival and is a necessary first step in a 
curative treatment strategy.  In the majority of patients with AML who achieve a complete 
response (CR), the leukemia will recur within 3 years after diagnosis.  In general, the prognosis 
of patients after relapse is poor and treatment options unsatisfactory (17).   
The Ras>Raf>MEK>ERK pathway is also activated by many cytokines which are important in 
driving the proliferation and promoting the survival of myeloid cells (18).  After receptor 


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ligation, Shc, Src homology (SH)-2, a SH2-domain containing protein, becomes associated with 
the c-terminus of the cytokine receptor (19, 20, 21).  Shc recruits the GTP-exchange complex 
Grb2/Sos resulting in the loading of membrane bound Ras with GTP (22, 23).  Ras:GTP then 
recruits Raf to the membrane where it becomes activated, likely via a Src-family tyrosine kinase 
(24, 25, 26).  Raf is responsible for phosphorylation of the mitogen associated/extracellular 
regulated kinase-1 (MEK1) (27, 28, 29).  MEK1 phosphorylates extracellular regulated kinases 
1 and 2 (ERKs 1 and 2) on specific threonine and tyrosine residues (27, 28, 29). 
Activated ERK1 and ERK2 serine/threonine kinases phosphorylate and activate a variety of 
substrates including p90Rsk1 (30, 31, 32, 33, 34, 35, 36).  p90Rsk1 can activate the cyclic-AMP 
response element binding protein (CREB) transcription factor (33).  Moreover, ERK can 
translocate to the nucleus and phosphorylate additional transcription factors such as Elk1, CREB 
and Fos which bind promoters of many genes, including IL-3, a cytokine important in 
stimulating the growth and survival of early myeloid progenitor cells (32, 37, 38, 39, 40, 41, 42, 
43, 44, 45, 46, 47).  The Raf>MEK>ERK pathway can also modulate the activity of many 
proteins involved in apoptosis including: Bcl-2, Bad, Bim, Mcl-1, caspase 9, and Survivin (48, 
49, 50, 51, 52, 53, 54, 55, 56, 57, 58).  Therefore, targeting AML cells with an ERK1/2 inhibitor 
such as BVD-523 may be effective in this difficult to treat patient population. 
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders 
characterized by a hypercellular bone marrow, peripheral cytopenias, and morphologic 
dysplasia in erythroid cells, neutrophils and their precursors, and megakaryocytes.  A diagnosis 
of MDS is made based on the identification of dysplasia in at least 10% of cells of any of the 
myeloid lineages in the peripheral blood/bone marrow after exclusion of acute myeloid 
leukemia (AML) and chronic myelomonocytic leukemia (CMML) (59).  The median age at 
diagnosis is 71 years (60).  It is estimated that the current incidence of MDS in the United States 
(US) is approximately15,000 to 20,000 cases; however, given that MDS was not a reportable 
cancer to the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results 
(SEER) database until 2002, it is considered likely that the actual incidence is as much as 7-8-
fold higher (61). 
Several prognostic scoring systems are used to categorize MDS, with higher risk categories 
having shorter median survival and higher risk of progression to AML.  The most widely used 
prognostic scoring system is the International Prognostic Scoring System (IPSS), which 
classifies patients into lower risk categories (low and intermediate-1) and higher-risk categories 
(intermediate-2 and high) (62).  Risk category is calculated based on the percentage of blasts, 
number of cytopenias, and bone marrow cytogenetics.  Median survival in the IPSS 
intermediate-2 and high-risk categories is short (1.1 and 0.4 years, respectively).  Another 
prognostic tool, the World Health Organization (WHO) classification-based Prognostic Scoring 
System (WPSS), incorporates morphological disease characteristics, IPSS cytogenetics, and red 
cell transfusion needs, and categorizes patients into 5 risk categories ranging from very-low risk 
to very-high risk.  Median survival in the very-low risk category is 103 months and is notably 
shorter (12 months) in the very high-risk category.  Furthermore, patients in the very-high risk 
category have a high risk of transformation to AML), whereas the risk is low (0.06%) of 
transformation to AML for the very low-risk group (63).  Overall, it is estimated that 
approximately 30% of patients with MDS will progress to AML. 


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Goals of therapy for high-risk MDS include prolongation of overall survival as well as 
prolongation of time to progression to AML.  Three novel agents have relatively recently been 
approved in the US for the treatment of MDS (azacitidine, decitabine, and lenalidomide); 
however, allogeneic hematopoietic stem-cell transplantation (SCT) remains the only known 
curative procedure (64). 
Similar to AML, the MAPK/ERK pathway is activated in hematopoietic stem cells in MDS 
patients.  Therefore, investigational agents targeting other MAPK components are being 
explored in both monotherapy and combination chemotherapy regimens.  For example, 
inhibitors of MEK family kinases have shown preliminary signs of clinical efficacy in BRAF-
mutant melanoma, and may also prove effective in cancers where RAS GTPase activating 
mutations are present (65, 66, 67). 
The ERK family kinases are MAPK signaling components that have yet to be therapeutically 
targeted.  BVD-523 is a small-molecule inhibitor of ERK kinases that we plan to test in various 
treatment settings.  Understanding the safety and efficacy of BVD-523 will bolster the 
armamentarium of targeted therapies that can be used against the activated MAPK signaling 
pathway in hematologic malignancies. 
1.1 
STUDY DRUG 
BVD-523 is a small molecule that potently inhibits both ERK1 and ERK2 protein kinases in the 
sub-nanomolar range, while not significantly inhibiting any of an array of kinases even at 1000-
fold greater concentrations.  BVD-523 potently inhibits growth and survival in cultured cancer 
cell lines; melanoma, colorectal and pancreatic lines harboring BRAF or RAS mutations are 
among those most susceptible to the drug.  In animals bearing ectopic tumor xenografts, orally 
administered BVD-523 is effective as a single agent, again preferentially in cancers where 
activating mutations in the MAPK pathway cause abundant ERK kinase activation. 
BVD-523 will be administered orally in humans.  The HCl salt of BVD-523 was selected for 
manufacture of drug product in capsule form. 
More information is available in the Investigator’s Brochure for BVD-523.   
1.2 
INDICATION 
Initial indications for BVD-523 are advanced solid and hematologic malignancies, especially 
those known to harbor activating genetic mutations in components of the MAPK pathway such 
as the BRAF or MEK kinases, or members of the RAS GTPase family.  Given this biological 
rationale and relevant preclinical supportive data, AML or MDS are potential indications for 
development. 
1.3 
BACKGROUND TO THE DISEASE 
Contemporary cancer therapy seeks to leverage a molecular level understanding of disease to 
rationally target isolated cancer types, often with agents specifically designed to correct well- 
characterized cellular, biochemical or genetic aberrations.  The modern view of cancer as a 
fundamentally genetic disease has greatly aided the invention and development of several such 
“targeted” therapies.   


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A unique array of oncogenic mutations cluster in the mitogen-activated protein kinase (MAPK) 
pathway, a key signal transduction cascade that controls cell-growth signaling in many tissues 
(70, 71, 72, 73, 74).  As described in detail previously in the Introduction, the MARK/ERK 
pathway is activated in hematopoietic stem cells of both AML and MDS patients.  Therefore, 
investigational agents targeting other MAPK components are being explored in both 
monotherapy and combination chemotherapy regimens.  Activating mutations in RAS GTPase 
family members are found in ~30% of all cancers (75).  The inhibitors of the MEK family of 
kinases have shown preliminary signs of clinical efficacy in BRAF-mutant melanoma and may 
also prove effective in cancers like AML or MDS where the RAS GTPase activating mutations 
are present (65, 66, 67). 
Less frequently, activating mutations have also been observed in MEK family kinases, which 
are the direct substrates of RAF kinases.  MEK kinases phosphorylate and activate the ERK 
kinase gene family.  ERK kinases phosphorylate numerous proteins that act as MAPK pathway 
“effectors”; these substrates directly promote cell division, reduce cell death, and increase cell 
motility and cell differentiation (68, 69).  To date, spontaneous activating mutations in ERK 
kinases have not been observed in human cancers.  Nonetheless, abundant ERK 
phosphorylation reflecting elevated MAPK signaling is frequently observed in cancer contexts 
where extracellular growth factors are elevated or where activating mutations in RAS, BRAF, or 
MEK genes have occurred (74). 
In this setting, therapies targeted against MAPK pathway components have been rationally 
applied in cancers that show activation of the signaling cascade following genetic mutation.  
Notably, vemurafenib (ZELBORAF®) is an inhibitor of mutated BRAF that, when dosed in 
patients with metastatic melanoma harboring specific BRAF activating mutations, for example, 
induces tumor regression and improves overall survival in this defined patient population (75, 
76, 77). 
The development of additional therapies that can modulate the MAPK pathway activity in 
cancer is desirable for several reasons.  First, all drugs exhibit a unique spectrum of side effects 
that often influences their therapeutic utility.  Despite some findings suggestive of mechanism-
related events, the incidence and severity of both BRAF and MEK inhibitor associated toxicities 
may uniquely indicate their use in particular patients.  Likewise, given the potential for drug-
drug interactions, and an increasing emphasis on polypharmacy in targeted oncology regimens, 
it is desirable to have multiple unique agents with discrete pharmacology and prescribing 
characteristics, even when they may share a common, redundant target or modes of inhibition in 
a pathway. 
Additionally, a more fundamental and prominent problem drives the need for additional MAPK 
pathway modulators: increasingly, multiple inhibitors in the pathway exhibit the phenomenon of 
acquired drug resistance (78, 79, 80, 81).  Acquired resistance may limit the clinical efficacy of 
MAPK directed agents even when their initial activity is promising.  The severe consequences 
and complex biology of acquired resistance in patients treated with MAPK signaling inhibitors 
suggest that additional, novel agents targeting the pathway may display improved durability and 
overall efficacy (81). 
Given this background, we plan to assess the safety and efficacy of BVD-523, which is a potent 
and selective inhibitor of the ERK family kinases.  Drugs targeting other components of the 


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MAPK pathway exhibit promising therapeutic activity, while also being limited by unique 
toxicities and limited duration of efficacy.  Targeting the downstream MAPK kinase, ERK, 
could possibly evoke a unique and desirable balance of durable efficacy and suitable tolerability.  
As such, BVD-523 may represent a valuable addition to the armamentarium of drugs useful for 
treating patients whose cancers exhibit the hallmarks of aberrant MAPK pathway activity. 
1.4 
PREVIOUS HUMAN EXPERIENCE 
This study will be the second study conducted with BVD-523 in humans.  The first study, 
Protocol BVD-523-01, “Phase 1 Dose-escalation, safety, pharmacokinetic and 
pharmacodynamics study of BVD-523 in patients with advanced malignancies”, is in 
progress.  Twenty seven patients with advanced malignancies have been treated in the dose-
escalation part (Part 1) of the first-in-man Phase 1 clinical study to investigate the safety of 
BVD-523 and define the MTD and the recommended Phase 2 dose (RP2D). The dose 
escalation phase included dose levels of 10, 20, 40, 75, 150, 300, 600, 750, and 900 mg b.i.d. 
The MTD and RP2D of BVD-523 was established to be 600 mg b.i.d (82).  
 
The most common adverse events included diarrhea, nausea, vomiting or constipation (89%), 
rash (any form), dermatitis, or pruritus (78%), fatigue (70%), decreased appetite (37%), 
dyspnea (33%), and anemia (26%). Pharmacokinetics were generally linear and dose 
proportional up to 600 mg twice a day, and BVD-523 achieved pharmacologically relevant 
exposure (82).  
1.5 
PRECLINICAL DATA 
In this section a short summary of preclinical data is provided.  Detailed information is 
presented in the BVD-523 Investigator’s Brochure (Version 2.0, 21 April 2014).   
1.5.1 
Potential Risk 
Preliminary evidence from in vitro and in vivo toxicological assessments of BVD-523 and data 
to-date from the first-in-human study (BVD-523-01) 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 BVD-523 may potentially include the following: 
Dermatological Lesions 
Dermatological lesions have been seen in rodent GLP toxicology studies of BVD-523.  Several 
of the following findings displayed exposure-dependent increases in incidence and/or severity: 
non-specific dermal inflammation, pustular dermatitis, epidermal ulceration and acanthosis.  
These toxicities appeared to be associated with predominantly reversible pharmacodynamics, 
as the majority of findings were mild and/or of low incidence in animals that underwent dose 
cessation. 
In clinical studies, other drugs that inhibit components of the MAPK pathway exhibit cutaneous 
toxicity.  Multiple investigational inhibitors of MEK1/2 kinases exhibit exposure- dependent, 


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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 the first 18 patients in Part 1 of the first 
study, Protocol BVD-523-01, with two-thirds of patients experiencing rash and one patient with 
a history of squamous cell carcinoma developing a squamous cell carcinoma while on treatment 
with BVD-523. Rash has been treated with topical and/or oral agents (e.g., steroids), and dose 
reductions/interruptions as needed.  
Phototoxicity 
BVD-523 exhibits an absorbance peak in the range of UV-A/UV-B light, specifically at 
~320 nm.  Clinical studies of other drugs that modulate MAPK pathway components have 
exhibited skin phototoxicity. 
Beyond dermatological monitoring (above), potential risks of direct phototoxicities induced by 
BVD-523 will be reduced by advising that patients 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 
Preclinical toxicology studies of BVD-523 have not revealed any exposure-dependent 
ophthalmological toxicities; however, clinical studies of MEK1/2 kinase inhibitors highlight 
ocular toxicities that may reflect mechanistically attributable risks observable in a proportion of 
patients.  Of particular concern are the following dose-limiting toxicities comprising exposure-
dependent, serious adverse events during clinical studies: retinal vein occlusion, retinal 
detachment and related vision abnormalities.  In the ongoing first-in-man Phase 1 study, thru 1-
April-2014, a single AE of vision changes has been reported in a single patient on a low dose of 
BVD-523 (20 mg, b.i.d.).  While it is not definitively understood whether ocular toxicities 
reflect primary pharmacology associated with global inhibition of the MAPK pathway, specific 
management and exclusion criteria are defined in this clinical protocol, as the toxicities could 
potentially severely and irreversibly impact patient well-being. 
Gastrointestinal Toxicity 
Preclinical toxicity studies of BVD-523 have provided evidence of exposure-related, reversible 
gastrointestinal toxicities, and these toxicities have also been observed at high frequency in the 
first 18 patients in the ongoing first-in-man Phase 1 study of advanced malignancies (Protocol 
BVD-523-01), in once case leading to an SAE of renal insufficiency secondary to dehydration.  
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.  


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QTc Prolongation 
The balance of preclinical evidence suggests BVD-523 has low, but observable, potential to 
cause QT prolongation.  Due to potentially unique species sensitivity, as well as possibly 
unknown consequences following chronic dosing, patients dosed with BVD-523 in the first-in-
human study, BVD-523-01, are being monitored for potential QTc prolongation and related 
cardiotoxicities via Holter monitoring.  No clinically significant cardiac abnormalities have 
been seen to date in the first trial (BVD-523-01).  QTc assessment will be performed at baseline 
and on Day 8, at steady state.  
Tissue Mineralization 
Tissue mineralization has been observed in rodent toxicology studies of BVD-523.  The 
incidence and severity of mineralization was dose-dependent and effects were observed in one 
or more tissues at toxic doses.  In animals in which mineralization occurred after treatment with 
BVD-523, significantly increased serum phosphorus and modestly decreased serum calcium 
were seen.  These effects were not observed in animals in which there was no mineralization. 
Tissue mineralization has been reported in rodents with other compounds that target the MAPK 
pathway and published studies suggest that the MAPK pathway is a negative regulator of matrix 
mineralization both in vitro and in vivo. 
Routine clinical laboratory tests, including blood chemistry analyses for calcium and inorganic 
phosphate, will be performed and any indication of abnormalities may result in further 
investigations.  A clinical monitoring strategy similar to this was previously employed for 
related drugs that target the MAPK pathway. 
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). 
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. 
1.5.2 
Pharmacology Studies 
BVD-523 is highly efficacious in vivo when administered as a single agent in ectopic xenograft 
models of colon, pancreatic and melanoma cancers, 3 tumor types in which ERK is known to be 
highly activated.  Notably, partial regression was achieved in a colon cancer model (Colo205) 
when the compound was administered at 50 mg/kg (b.i.d.).  Biomarker analyses confirmed that 
improved efficacy obtained at higher doses of BVD-523 correlated with increasing ERK 
inhibition. 


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1.5.3 
Toxicity and Safety Studies 
When BVD-523 was characterized using in vitro screens against 66 receptors and ion channels, 
no toxicologically significant interactions were identified.  Additionally, BVD-523 was negative 
in bacterial mutation and in vivo micronucleus screening assays; therefore, BVD-523 is not 
considered to have a significant genetic toxicology risk. 
While BVD-523 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 
BVD-523 is considered to have a low potential to cause QT prolongation in patients, but, as 
stated, the first-in-human study will monitor for signs of cardiovascular effects of BVD-523 in 
humans. 
No significant cytochrome P450 (CYP) inhibition has been observed with the compound. 
In vitro studies suggest that the compound is metabolized primarily via oxidation by multiple 
CYPs including 3A4, 2D6, and 1A2.  Furthermore, no significant CYP induction was observed 
after up to 14 days drug treatment in rats, nor during in vitro studies with human hepatocytes.  
These data suggest a limited potential for drug-drug interactions. 
BVD-523 HCl salt is orally available in multiple species (absolute bioavailability %F = 23% in 
dog to 100 % in monkey) when formulated as a simple suspension in 1% carboxymethyl-
cellulose (CMC) and has a half-life of 2-4 hours across all species. 
BVD-523 was administered to male and female Sprague-Dawley rats in several toxicology 
studies: (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 BVD-523, significantly 
increased serum phosphorus and modestly decreased serum calcium were seen.  These effects 
were not observed in animals in which there was no mineralization.  Therefore, the risk of 
tissue mineralization can be assessed by serum phosphorus and calcium monitoring.  A clinical 
monitoring strategy similar to this was previously employed for related drugs that target the 
MAPK pathway because those compounds likewise elicited mineralization in rodents. 
When BVD-523 was administered to male and female Sprague-Dawley rats for up to 28 days 
at a dose level of 25 or 50 mg/kg twice daily, BVD-523 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 BVD-523 


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when administered for up to 28 days in Sprague-Dawley rats is 12.5 mg/kg given twice daily 
(25 mg/kg/day).  On Day 28 of the dosing phase, this dose level corresponded with a Cmax of 
28700 and 15323 ng/mL and AUC0-12 of 264868 and 124341 hr.ng/mL for males and females, 
respectively. 
BVD-523 was administered to male and female beagle dogs for up to 28 days at dose levels of 
15, 5, or 2 mg/kg twice daily.  Initial analysis of the toxicity profile observed shows that 
BVD-523 was well tolerated in dogs.  The rat was designated the most sensitive species and rat 
data were used to calculate the starting dose in man. 
Based on the data accumulated to date, BVD-523 possesses a toxicology profile which presents 
no impediment to its development as an anti-cancer agent. 
For further information, please refer to the BVD-523 Investigator’s Brochure (Version 2.0, 
21 April 2014).   


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2 
RATIONALE FOR THE STUDY 
The overall purpose of this study is to support the development of an oral formulation of 
BVD-523 for the treatment of patients with AML or MDS.  BVD-523 is a highly potent, 
selective, and pharmacologically active inhibitor of ERK family kinases.  The compound has 
demonstrated efficacy as a single agent in preclinical models of colon, pancreatic and 
melanoma cancers (Section 1.5.2), and has potential for application alone or in combination 
with existing cancer chemotherapeutics. 
This study is being performed to assess the safety, tolerability, and preliminary clinical effects 
of BVD-523 given orally, twice daily for 21-day cycles, in patients with AML or MDS.  The 
pharmacokinetics and pharmacodynamics of BVD-523 will also be explored after the first 
doses administered on Day 1 and at steady state on Day 22.  Subsequent assessments may be 
done as indicated after completion of Cycle 1. 
2.1 
RATIONALE FOR THE DOSES AND THE DOSING REGIMEN 
The human Phase 1 starting dose for BVD-523 in the first trial (BVD-523-01) was derived 
from 28-day GLP toxicology studies performed in rodent and non-rodent species and 
calculated as described by Senderowicz (83).  Specifically, our results indicated that toxicity in 
rodents would be used to establish starting dose in patients.  The severely toxic dose in 10% of 
the animals (STD10) for BVD-523 when administered for up to 28 days in Sprague-Dawley 
rats was determined to be 12.5 mg/kg dosed twice daily (25 mg/kg/day).  A standard 10-fold 
reduction of this dose was scaled to establish a starting dose of 13.5 mg twice-daily of BVD-
523 (free base equivalents) or 14.6 mg twice-daily of BVD-523, based on an average body 
surface area of 1.8 m2 consistent with current clinical practice and dosing convenience, the 
proposed starting dose for the first Phase 1 clinical study with BVD-523 in cancer patients 
(BVD-523-01) was 10 mg twice-daily (20 mg/day) (84).   
The starting dose determination for this Phase 1/2 study (BVD-523-02) in AML or MDS 
patients described herein is based on the clinical experience during the dose-escalation study in 
patients with solid tumors.  The dose escalation phase of study BVD-523-01, the first-in-man 
Phase 1 clinical study included 27 patients treated at dose levels of 10, 20, 40, 75, 150, 300, 600, 
750, and 900 mg b.i.d. DLTs were observed in 5 pts: 2 with grade 3 rash (600 mg and 750 mg 
b.i.d.), 1 with grade 3 pruritus and elevated AST (900 mg b.i.d.), 1 with grade 3 diarrhea, 
vomiting, dehydration and elevated creatinine (900 mg b.i.d.), and 1 with grade 2 hypotension, 
elevated creatinine, and anemia (750 mg b.i.d.); the MTD was established at 600 mg b.i.d.  
BVD-523 achieved pharmacologically relevant exposure and manageable tolerability at its 
MTD of 600 mg b.i.d (82).  Ex vivo whole blood assays demonstrated inhibition of 
phosphorylation of RSK, a downstream substrate of the target ERK, at doses ≥ 40 mg, b.i.d.  
Additionally, inhibition of metabolic activity was demonstrated by FDG-PET at 75 mg, b.i.d.  
The 300 mg b.i.d. starting dose for the BVD-523-02 study with AML or MDS patients is based 
upon these results in the solid tumor study.  As the ongoing Phase 1 study progresses, the 
300 mg b.i.d. starting dose in AML or MDS patients may be revised based upon accruing safety 
experience and determination of the RP2D from the solid tumor study. 


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3 
STUDY DESIGN 
3.1 
STUDY DESIGN OVERVIEW 
This is an open-label, multi-center Phase 1/2 study with a dose-escalation phase (Part 1) and a 
cohort expansion phase (Part 2) in patients with Acute Myelogenous Leukemia (AML) or 
Myelodysplastic Syndrome (MDS).  This study will be conducted at up to 6 study centers.  
3.1.1 
Study Objectives 
3.1.1.1 
Primary Objectives 
• 
To define the safety and tolerability of BVD-523 in patients with AML or MDS 
determining the dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and 
the recommended Phase 2 Dose (RP2D). 
• 
To determine the pharmacokinetic profile of BVD-523 and selected metabolites in 
patients with AML or MDS. 
3.1.1.2 
Secondary Objectives 
• 
To assess clinical response in patients with AML or MDS treated with BVD-523 at the 
recommended Phase 2 dose (RP2D). 
• 
To determine the progression-free survival (PFS) and duration of response (DOR) of 
AML or MDS patients treated with BVD-523 achieving CR/CRp. 
3.1.1.3 
Exploratory Objective 
• 
To evaluate pharmacodynamic marker (biomarker) measures. 
3.1.2 
Methodology / Study Design 
BVD-523-02 is an open-label, multicenter, Phase 1/2 study with a dose-escalation phase (Part 1) 
and a cohort expansion phase (Part 2). 
Part 1  Dose-escalation Phase: 
A classic “3+3” design will be used to establish dose limiting toxicities (DLT), maximum 
tolerated dose (MTD), and the recommended Phase 2 dose (RP2D).  Three to six patients per 
treatment cohort will be assigned to receive sequentially higher oral doses of BVD-523 on a 
twice daily schedule (b.i.d.) for 21 days (a “Cycle”), starting at a dose of 300 mg twice daily.  
Patients will receive twice-daily oral doses of BVD-523 until disease progression, unacceptable 
toxicity, or a clinical observation satisfying another withdrawal criterion is noted.  Treatment 
cycles will occur consecutively without interruption, except when necessary to manage adverse 
events.  All dose-escalation decisions will be based on Cycle 1 safety data and doses will not be 
escalated unless the patients receiving the highest current dose have been observed for at least 
21 days (1 cycle). 
The classic 3 + 3 design will be conducted as follows.  Initially, 3 patients will be enrolled to a 
cohort; the occurrence of a single drug-related DLT in one of these 3 patients will prompt 
enrollment of up to 3 additional patients to that same cohort.  When more than 1 DLT occurs in 


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≤ 6 patients in a dosing cohort, dose escalation will be stopped and this dose level will be 
identified as the non-tolerated dose.   
Doses between the non-tolerated dose and the preceding lower dose, where ≤ 1 DLT occurred, 
may be explored to more precisely define the MTD.  This strategy allows for a rigorous 
determination of MTD, especially if the dose increase that resulted in determination of the non-
tolerated dose is relatively large (i.e., > 50%). 
During the study, the Safety Monitoring Committee may request that cohorts be enlarged or that 
evaluation of intermediate doses between 2 planned escalation steps be explored.  Such requests 
will be discussed with the Investigator(s), Sponsor and Medical Monitor, and should be based 
on all data existing at that time, including safety and clinical activity, determinations of 
pharmacokinetics, pharmacodynamics, and cumulative toxicity.  Before each escalation, 
investigators will be consulted to ensure that all involved agree with the escalation decision. 
In addition, intra-patient dose escalation will be allowed after a patient has completed at least 
one cycle at their assigned dose, with escalation up to a dose where at least 3 patients have 
completed at least one cycle. 
Part 2 Cohort-expansion Phase:   
Additional patients with AML or MDS with or without specific genetic mutations indicative of 
MAPK pathway activation will be recruited for treatment at the Recommended Phase 2 Dose 
(RP2D).  Patients will receive twice daily oral doses of BVD-523 in 21-day treatment cycles 
until disease progression, unacceptable toxicity, or another withdrawal criterion is met.  
Treatment cycles will occur consecutively without interruption except when necessary to 
manage adverse events. 
Total enrollment for Part 2 is targeted at approximately 40 patients.  Patients will be enrolled 
into 1 of 2 treatment groups.  Group assignments are made according to the following disease 
characteristics, which correspond to specific inclusion and exclusion criteria for Part 2:  
• 
Group 1: patients with RAS mutant positive AML or MDS; n (evaluable) ≤ 20 
• 
Group 2: patients with RAS mutant negative AML or MDS; n (evaluable) ≤ 20 
Table 3.1 
Study Medication Dosing and Pharmacokinetics/Pharmacodynamics Chart 
 
Study Days 
1 
8± 1 
15± 1 
22± 1 
BVD-523 dosinga 
X 
X 
X 
X 
Pharmacokinetics 
X 
 
 
X 
Pharmacodynamics 
X 
 
 
X 
a 
Dosing is twice daily in 21-day cycles until disease progression.  Patients will take their study medication 
in the clinic on PK days.  Patients may be treated beyond disease progression for additional 21-day cycles 
at the same or escalated dose level (see intra-patient dose escalation Sec 3.1.3) at the Investigator’s 
discretion.  Study medication for a week of dosing should be dispensed at each visit for treatment Cycles 1 
and 2.  For treatment cycles after Cycle 2, study medication will be dispensed to support the entire 3 week 
cycle.  


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3.1.3 
Summary of Dose Escalation 
Table 3.2 
Summary of Dose Escalation 
Observed Safety Outcomes 
Action 
1 DLT in 3 patients 
Expand cohort up to 6 patients 
1 DLT in 6 patients 
Escalate by ≤ 50% to next dose level 
> 1 DLT in ≤ 6 patients 
Stop dose escalation 
Note: DLT is defined in detail in Section 3.1.4.2 below. 
 
Each cohort can only begin when the previous cohort has completed treatment to at least the 
end of Cycle 1 without fulfilling a criterion which would prevent dose escalation.  Intra-patient 
dose escalation will be permitted with consensus among the Principal Investigator, Medical 
Monitor, and Sponsor, to a dose not to exceed that for which 21 days of treatment has been 
deemed safe. 
Although dose escalation decisions will be taken upon review of the data from Cycle 1, safety 
data will also be collected from all patients continuing treatment and these data will be 
reviewed periodically by the Safety Monitoring Committee.  Any detected cumulative toxicity 
may require later dose reductions or other action as appropriate, including having an effect on 
the RP2D. 
3.1.4 
Definition of MTD, DLT, and RP2D 
3.1.4.1 
Definition of Maximum Tolerated Dose (MTD) 
MTD is defined as the highest dose cohort at which < 33% of patients experience BVD-523 
related DLTs in the first 21 days of treatment. 
3.1.4.2 
Definition of Dose Limiting Toxicity (DLT) 
The DLT is defined using the Common Terminology Criteria for Adverse Events Version 4.0 
(CTCAE v4.0) in the first 21 days of treatment.  All toxicities will be considered related to 
BVD-523 if they cannot be definitively explained by underlying disease, intercurrent illness or 
concomitant medications. 
• 
Any treatment emergent study drug related Grade 3 or Grade 4 non-hematologic toxicity 
unless clearly and incontrovertibly unrelated to BVD-523.  Exceptions are Grade 3 or 4 
nausea or vomiting that is controllable by anti-emetics or Grade 3 or 4 diarrhea 
controllable by optimal therapy such as loperamide.  Grade 3 laboratory investigations 
other than serum creatinine, bilirubin, AST or ALT will not be considered a DLT unless 
they are associated with clinical manifestations.  
• 
Study-drug related Grade 4 thrombocytopenia that was not present at study entry and that 
does not resolve within 7 days, unless clearly and incontrovertibly unrelated to BVD-523. 
• 
Febrile neutropenia or Grade 4 neutropenia that was not present at study entry and that 
does not resolve within 7 days, unless clearly and incontrovertibly unrelated to BVD-523. 
• 
Prolonged myelosuppression or pancytopenia with a hypocellular bone marrow and no 
marrow blasts lasting for 6 weeks or more that is not related to disease progression. 


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• 
Any study drug related toxicity that results in treatment delays of > 4 days, except when 
patient is experiencing rash in which case, patient may be off drug for up to 7 days while 
receiving treatment. 
 
All subjects who are not evaluable for toxicity in Cycle 1 due to unrelated AEs will be replaced. 
3.1.4.3 
Definition of Recommended Phase 2 Dose (RP2D) 
The Recommended Phase 2 Dose (RP2D) may be as high as the MTD and will be determined 
in discussion with the Clinical Investigators, the Medical Monitor, and the Sponsor.  
Observations related to pharmacokinetics, pharmacodynamics, and any cumulative toxicity 
observed after multiple cycles may be included in the rationale supporting the RP2D. 
3.2 
SAFETY MONITORING COMMITTEE 
An internal Safety Monitoring Committee (SMC) will be set up to review the safety of 
BVD-523 as the study progresses.  The SMC will consist of Clinical Investigators, the Medical 
Monitor and Sponsor representatives.  The SMC will review any serious Adverse Event (SAE) 
that occurs during the study and will examine the safety of each dose level of BVD-523, 
including toxicities that may occur in later cycles of treatment. 
3.3 
SAFETY REVIEW MEETINGS 
The safety review will be performed in all stages of the dose escalation: 
• 
Prior to starting each new dose level after the initial cohort. 
• 
To stop the dose escalation if the MTD has been reached. 
• 
An update on patient status will be provided to each investigator semi-monthly. 
3.4 
STOPPING RULES 
The entire study or treatment of individual patients may be stopped under defined 
circumstances as outlined in Section 7: Discontinuation Criteria. 
3.5 
CRITERIA FOR EVALUATION 
3.5.1 
Safety 
• 
Vital signs 
• 
Physical examination 
• 
Ophthalmology examination 
• 
Clinical chemistry 
• 
Hematology  
• 
Urinalysis 
• 
ECGs 
• 
Severity of AEs (graded according to the NCI CTCAE Grading System Version 4.03 as 
detailed on web page: http://ctep.cancer.gov). 


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3.5.2 
Efficacy 
• 
Clinical response will be assessed on results of bone marrow biopsies using International 
Working Group 2003 and 2006 criteria for AML or MDS, respectively (1, 2). 
3.5.3 
Pharmacokinetics 
• 
Blood samples will be collected to measure BVD-523 and selected metabolite 
concentration levels.   
• 
At Baseline (Visit 2, Cycle 1) and again on Day 22 (Visit 5, Cycle 1), blood samples will 
be collected prior to administration of the first dose and then post-dosing at the following 
time points: 0.5, 1, 2, 4, 6, 8, and 12 ± 2 hours. 
3.5.4 
Pharmacodynamics 
• 
Blood and/or bone marrow aspirate will be used to evaluate multiple biomarkers of drug 
response including pRSK and total RSK.  Blood and/or bone marrow aspirate will be 
collected to measure ex vivo BVD-523 sensitivity of leukemic cells prior to therapy on 
Day 1 and Day 22.  Additional biomarkers and DNA sequence analysis may be identified 
and measured as appropriate by collection of whole blood prior to dosing initiation and 
after drug levels have reached steady-state.   
3.6 
BLINDING AND RANDOMIZATION 
This study is designed as an open-label study.  All patients will receive treatment with orally 
administered BVD-523. 


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4 
SELECTION OF PATIENTS 
4.1 
NUMBER OF PATIENTS 
In this study, up to approximately 20 patients with AML or MDS, regardless of RAS mutation 
status, will be enrolled in Dose-escalation Part 1.  Three to six patients per treatment cohort 
will be assigned to receive sequentially higher oral doses of BVD-523. 
In the Cohort-expansion Part 2, additional patients with RAS mutant positive AML or MDS and 
RAS mutant negative AML or MDS will be recruited for treatment at the RP2D determined 
from Part 1 above.   
Part 2 patients will receive twice daily oral doses of BVD-523 in 21-day treatment cycles until 
disease progression, unacceptable toxicity, or another withdrawal criterion is met.  Treatment 
cycles will occur consecutively without interruption except when necessary to manage AEs. 
Total enrollment for Part 2 is targeted for up to approximately 40 patients.  Patients will be 
enrolled into 1 of 2 treatment groups.  Group assignments are made according to the following 
disease characteristics: 
• 
Group 1:  Patients with RAS mutant positive AML or MDS; n (evaluable) ≤ 20 
• 
Group 2:  Patients with RAS mutant negative AML or MDS; n (evaluable) ≤ 20. 
4.2 
RECRUITMENT 
This study will be conducted at up to 6 sites.  The study centers will enroll up to approximately 
20 patients for Part 1 and up to approximately 40 additional patients for Part 2 of this study. 
4.3 
INCLUSION CRITERIA 
Patients eligible for inclusion in this trial must fulfill all of the following criteria: 
1. Provide signed and dated informed consent prior to initiation of any study-related 
procedures that are not considered Standard of Care (SOC). 
2. Male or female patients aged ≥ 18 years. 
3. Have either of the following diagnoses: 
• 
Morphologically confirmed AML (except acute promyelocytic leukemia (APL)) 
including leukemia secondary to prior therapy (e.g., chemotherapy, XRT) or 
antecedent hematologic disorder (e.g., MDS or myeloproliferative disorders), who 
have failed to achieve complete remission (CR) or who have relapsed after prior 
therapy and are not candidates for potentially curative therapy.   
• 
Intermediate-2 or High-grade risk MDS (including chronic myelomonocytic leukemia 
(CMML)). 
4. Have received at least one prior therapy.  Patients who are over age 65 and have not 
received therapy for AML are also eligible, if they are not candidates for induction 
chemotherapy. 
5. ECOG performance status of 0 (fully active, able to carry out all pre-disease activities 
without restriction) to 2 (ambulatory and capable of all self-care but unable to carry out 


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any work activities.  Up and about more than 50% of waking hours), measured within 
72 hours before the start of treatment.   
6. Predicted life expectancy of ≥ 3 months. 
7. Adequate renal function [creatinine ≤ 1.5 times ULN (upper limit of normal)] or GFR of 
≥ 50mL/min. 
8. Adequate hepatic function [total bilirubin ≤ 1.5 x UNL; AST (aspartate transaminase) or 
ALT (alanine transaminase) ≤ 3 x UNL or ≤ 5 x UNL if due to liver involvement by 
tumor]. 
9. Adequate cardiac function, ≥ institutional lower limit of normal, e.g., left ventricular 
ejection fraction (LVEF) of ≥ 50% as assessed by multi-gated acquisition (MUGA) or 
ultrasound/echocardiography (ECHO); corrected QT interval (QTc) < 470 ms. 
10. Contraception: 
• 
For women: Negative pregnancy test for females of child-bearing potential; must be 
surgically sterile, postmenopausal (defined as no menstrual cycle for at least 12 
consecutive months), or compliant with an acceptable contraceptive regimen (oral 
contraceptives, condom with spermicide etc.) during and for 3 months after the 
treatment period.  Abstinence is not considered an adequate contraceptive regimen. 
• 
For men: Must be surgically sterile, or compliant with a contraceptive regimen (as 
above) during and for 3 months after the treatment period. 
11. Willing and able to participate in the trial and comply with all trial requirements. 
12. For Part 2 Group 1 of the Study ONLY: 
Positive for RAS mutation at a Clinical Laboratory Improvement Amendments (CLIA)-
certified laboratory prior to study entry.  
4.4 
EXCLUSION CRITERIA 
Patients who fulfill 1 or more of the following criteria will not be eligible for inclusion in this 
trial: 
1. Concomitant malignancies except carcinoma in situ, basal or squamous cell skin 
carcinoma; low grade prostate cancer treated with prostatectomy more than 10 years ago; 
early stage melanoma treated with complete surgical excision more than 5 years ago;  
carcinoma in situ of cervix treated with cone procedure more than 8 years ago. 
2. 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.  Refractory nausea and 
vomiting must also be discussed with the Medical Monitor prior to enrolling such a 
patient. 
3. Uncontrolled or severe intercurrent medical condition. 
4. Patients with rapidly increasing peripheral blood blast counts (significant increase in the 
absolute peripheral blast count with white blood cell (WBC) count > 30,000) or 
uncontrolled (absolute blast count > 30,000) while on hydroxyurea will be excluded. 
5. Known uncontrolled central nervous system (CNS) involvement.  (Stable asymptomatic 
CNS involvement either untreated or being treated with a stable dose (or doses) of intra-


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thecal (IT) therapy can be allowed if there is evidence that the cerebrospinal fluid (CSF) 
cell count is decreased and that patient is responding to IT therapy.) 
6. Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or 
immunotherapy, etc.) within 28 days or 5 half-lives, (whichever is shorter). 
7. Any concurrent or prior use of an investigational drug (including MEK inhibitors) within 
28 days or 5 half-lives (whichever is shorter) prior to the first dose of BVD-523.  A 
minimum of 10 days between termination of the investigational drug and administration 
of BVD-523 is required.  In addition, any drug-related toxicity except alopecia should 
have recovered to Grade 1 or less. 
8. Received chemotherapy regimens with delayed toxicity within the last four weeks (six 
weeks for prior nitrosourea or mitomycin C).  Received chemotherapy regimens given 
continuously or on a weekly basis with limited potential for delayed toxicity within the 
last two weeks. 
9. Ongoing anticoagulant therapy that cannot be held to permit bone marrow sampling.  
Patients who require anticoagulant therapy and cannot be maintained on LMWH should 
not be considered for this study. 
10. Major surgery within 4 weeks prior to first dose. 
11. Pregnant or breast-feeding women. 
12. Any evidence of serious active infections (subjects who have been fever-free for 24 hours 
prior to enrollment and on active treatment would not be considered excluded). 
13. Any important medical illness or abnormal laboratory finding that would increase the risk 
of participating in this study (based on the investigator’s judgment). 
14. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR). 
15. Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6 and 
CYP3A4, or strong inducers of CYP3A4 (for list of non-permitted drugs, see 
Appendix 1).  
 
 
 


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5 
STUDY PLAN AND PROCEDURES 
This clinical study will consist of 2 parts.  In Part 1, patients with AML or MDS will receive 
sequentially higher oral doses of BVD-523. 
Upon completion of Part 1 of this study and determination of RP2D, up to approximately 40 
additional AML or MDS patients with and without RAS mutation will be treated at the RP2D. 
To characterize the pharmacokinetic properties of BVD-523 in patients with AML or MDS, 
blood will be obtained/analyzed during Cycle 1 of Part 1, and during additional cycles in Part 1 
and/or Part 2 as needed, to measure BVD-523 and selected metabolite concentration levels. 
Multiple pharmacodynamics biomarkers will be used to measure response to drug treatment, 
including evaluation of pRSK and total RSK. Additional biomarkers, including peripheral blood 
mononuclear cells (PBMCs), and DNA sequence analysis may be identified and measured as 
appropriate by collection of whole blood prior to dosing initiation and after drug levels have 
reached steady-state.  Leukemic cell genotyping by DNA analysis will be performed to identify 
somatic alterations, relying on either available archived or freshly collected samples.  Blood 
and/or bone marrow aspirate will be collected to determine ex vivo BVD-523 sensitivity on 
leukemic cells prior to therapy on Day 1 and Day 22. 
All patients will be screened and eligibility determined prior to enrollment and start of study 
treatment. 
5.1 
STUDY PATIENT NUMBER 
In Part 1, up to approximately 20 patients are expected to be enrolled. 
In Part 2 of the study, up to approximately 40 patients with measurable disease will be 
enrolled: 
• 
Group 1: patients with RAS mutant positive AML or MDS; n (evaluable) ≤ 20 
• 
Group 2: patients with RAS mutant negative AML or MDS; n (evaluable ≤ 20 
5.2 
DESCRIPTION OF STUDY VISITS FOR PART 1 
Procedures performed in the first cycle are specified in Table 6.3 (Part 1: Schedule of 
Assessments and Procedures).  Patients receiving multiple cycles of treatment will not have 
blood drawn for PK and PD measurements after Cycle 1 (Day 1 and Day 22) unless additional 
PK and PD data are deemed necessary after initial analysis. 
5.2.1 
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 for additional future analyses 
(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. 
• 
Review medical history including all previous cancer treatments. 
• 
Record prior and concomitant medications including start/stop dates, indication, dose and 
frequency taken within 30 days of Cycle 1, Day 1. 
• 
Record demographic data including date of birth, age, gender, race, and smoking status.  
Where full DOB is collected, initials will not be used. 
• 
Measure and record height in cm and weight in kg. 
• 
Perform and record physical examination. 
• 
Assess and record performance status (ECOG) within 72 hours before start of treatment. 
• 
Record vital signs.  Measure body temperature, systolic / diastolic blood pressure (BP) 
and pulse rate. 
• 
Collect blood for a serum pregnancy test for female patients who are not postmenopausal 
or surgically sterile.  If positive, repeat and confirm results prior to Visit 2.  A second 
positive test will result in exclusion of the patient from the study. 
• 
Assess and record current disease status within 28 days.  
• 
Bone marrow aspirate and/or biopsy within 28 days of Visit 1.  Peripheral, Geimsa and 
Iron stained slides will be collected with each bone marrow aspirate or biopsy. Bone 
marrow aspirate and/or biopsy slides will not be shipped to a third party. As such, the site 
may utilize BM aspirates performed in clinical practice as SOC, as long as they are 
collected within the screening window (-28 days). 
• 
Bone marrow cytogenetics in accordance with local pathology requirements.  
(Cytogenetics would preferably include at least 20 clones). 
• 
Collect blood samples for blood chemistries, hematology and calculated creatinine 
clearance within 72 hours before start of treatment, analyze, review and report any 
clinically significant abnormalities to Medical Monitor before dosing. 
• 
Perform and record ophthalmology examination. 
• 
Obtain a 12-lead electrocardiogram (ECG), and echocardiogram (ECHO) or multi-gated 
acquisition (MUGA) for left ventricular ejection fraction (LVEF). 
• 
Collect urine samples for urinalysis within 72 hours before start of treatment. 
• 
For patients enrolled in Part 2 of this study, bone marrow sample and/or peripheral blood 
samples will also be required to obtain necessary RAS genetic information. 
• 
Complete Screening/Enrollment Form and submit to Medical Monitor for review prior to 
treatment of patient. 
5.2.2 
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 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.  


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• 
Record medications including start/stop dates, indication, dose and frequency for any 
changes since Screening Visit. 
• 
Perform and record physical examination. 
• 
Measure and record weight in kg. 
• 
Assess and record performance status (ECOG) if not done during Screening Visit within 
72 hours of start of treatment. 
• 
Record vital signs (body temperature, systolic / diastolic BP and pulse rate). 
• 
ONLY if the screening pregnancy test was performed more than 1 day previously, collect 
blood for a repeat serum pregnancy test for female patients who are not postmenopausal 
or surgically sterile. 
• 
Collect pre-dose blood samples for pharmacokinetic (PK), pharmacodynamic (PD), and 
PBMC analyses. 
• 
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. 
• 
Administer first dose of BVD-523. 
• 
Collect post-dose blood samples for pharmacokinetic (PK), pharmacodynamic (PD), and 
PBMC analyses. 
• 
Assess and record adverse events (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 on an empty stomach, i.e., fasting 
(30-60 minutes before food or 2 hours after food). 
• 
Inform patients of the potential photosensitizing effects of BVD-523 and instruct them to 
avoid sunlight and wear protective clothes, sunglasses, and apply sunblock when outside, 
including when driving a car. 
5.2.3 
Visit 3 (Day 8 ± 1) 
The following procedures will be performed at Visit 3 (Day 8): 
• 
Review medical history. 
• 
Record concomitant medications including start/stop dates, indication, dose and 
frequency taken after Visit 2. 
• 
Perform and record targeted physical examination as appropriate. 
• 
Assess and record performance status (ECOG). 
• 
Record vital signs.  Measure body temperature, systolic / diastolic BP and pulse rate. 
• 
Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• 
Collect urine samples for urinalysis. 
• 
Dispense drug supply for self-dosing, and remind patients of dosing instructions. 
• 
Obtain all unused study drug from patient. 
• 
Assess study drug compliance by pill count. 
• 
Obtain a 12-lead ECG. 
• 
Assess and record AEs. 
 


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5.2.4 
Visit 4 (Day 15 ± 1) 
The following procedures will be performed at Visit 4 (Day 15): 
• 
Review medical history. 
• 
Record medications including start/stop dates, indication, dose and frequency taken after 
Visit 3. 
• 
Perform and record targeted physical examination as appropriate. 
• 
Assess and record performance status (ECOG). 
• 
Record vital signs (body temperature, systolic / diastolic BP and pulse rate). 
• 
Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• 
Collect urine samples for urinalysis. 
• 
Dispense drug supply for self-dosing. 
• 
Obtain all unused study drug from patient. 
• 
Assess study drug compliance by pill count. 
• 
Assess and record AEs. 
5.2.5 
Visit 5 (Day 22 ± 1 of Cycle 1, first day of Cycle 2) 
The following procedures will be performed at Visit 5 (Day 22 of Cycle 1, Day 1 of Cycle 2): 
• 
Review medical history including all cancer treatments received since previous visit. 
• 
Record medications including start/stop dates, indication, dose and frequency taken after 
Visit 4. 
• 
Perform and record targeted physical examination as appropriate. 
• 
Measure and record weight in kg. 
• 
Assess and record performance status (ECOG). 
• 
Bone marrow aspirate and/or biopsy.  Peripheral, Geimsa and Iron stained slides will be 
collected with each bone marrow aspirate or biopsy.  Following Cycles 1 and 2, Day 22 
bone marrow aspirates will be collected only every other cycle, i.e., Cycle 4, etc.  
• 
Bone marrow cytogenetics in accordance with local pathology requirements.  
(Cytogenetics would preferably include at least 20 clones). 
• 
Record vital signs.  Measure body temperature, systolic / diastolic BP and pulse rate. 
• 
Collect pre-dose blood samples for pharmacokinetic (PK), pharmacodynamic (PD), and 
PBMC 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. 
• 
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 


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serum pregnancy test is positive, withdraw patient from study and contact Medical 
Monitor. 
• 
Administer BVD-523 and dispense drug supply for self-dosing for Cycle, if appropriate, 
and remind patient of dosing instructions. 
• 
Collect post-dose blood samples for pharmacokinetic (PK), pharmacodynamic (PD), and 
PBMC 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. 
• 
Assess and record disease status (every 2 cycles).  
• 
Obtain all unused study drug from patient. 
• 
Assess study drug compliance by reviewing pill count. 
• 
Assess and record AEs. 
5.2.6 
Treatment Discontinuation Visit 
At the time of study drug discontinuation, the Treatment Discontinuation Visit should be 
completed for all patients as soon as possible after the last dose of study drug, and every effort 
should be made to perform the procedures required.  
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 AML or 
MDS is initiated prior to 30 days ± 3 days.  Only information about AEs and SAEs will be 
collected at this visit. 
The following procedures will be performed at Treatment Discontinuation Visit: 
• 
Review medical history  
• 
Record medications including start/stop dates, indication, dose and frequency. 
• 
Perform and record physical examination. 
• 
Assess and performance status (ECOG). 
• 
Record vital signs.  Measure body temperature, systolic / diastolic BP and pulse rate. 
• 
Perform and record ophthalmology examination. 
• 
Perform urine pregnancy test for female patients who are not postmenopausal or 
surgically sterile.  If urine test is positive, collect blood for a serum pregnancy test. 
• 
Assess and record disease status. 
• 
Bone marrow aspirate and/or biopsy.  Peripheral, Geimsa and Iron stained slides will be 
collected with each bone marrow aspirate or biopsy.  Collection not needed if termination 
is due to progression. 
• 
Bone marrow cytogenetics in accordance with local pathology requirements.  
(Cytogenetics would preferably include at least 20 clones).  Collection not needed if 
termination is due to progression.  Collect blood samples for blood chemistries, 
hematology and creatinine clearance. 


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• 
Collect urine samples for urinalysis. 
• 
Assess and record AEs. 
• 
Obtain all unused study drug from patient. 
• 
Assess study drug compliance by reviewing pill count. 
5.2.7 
Unscheduled Visits 
Additional visits can be performed as appropriate and at the discretion of the investigator. 
5.3 
STUDY VISITS FOR PART 1 CYCLE 2 
Cycle 2 visits and procedures are similar to Cycle 1, although no PK/PD measurements will be 
made unless specifically requested by Investigator.  Refer to Table 6.3 for Cycle 2 assessments 
and procedures.  Bone Marrow aspirates will be obtained at Cycle 1, Day 22 and every 2 cycles 
thereafter. 
5.4 
DESCRIPTION OF STUDY VISIT FOR PART 1 CYCLE 3 AND EACH 
SUBSEQUENT CYCLE OF PART 1 
Cycle 3 and subsequent cycles have one scheduled visit per cycle.  No PK/PD measurements 
will be made unless specifically requested by Investigator.  Refer to Table 6.3 for Cycle 3 
assessments and procedures. 
5.4.1 
Cycle 3 and Subsequent Cycles Visit (Day 1 ± 1 of each cycle) 
The following procedures will be performed at Cycle 3 and Subsequent Cycles Visit: 
• 
Review medical history 
• 
Record medications including start/stop dates, indication, dose and frequency taken since 
previous visit. 
• 
Perform and record targeted physical examination as appropriate. 
• 
Assess and record performance status (ECOG). 
• 
Measure weight in kg. 
• 
Record vital signs.  Measure body temperature, systolic / diastolic BP and pulse rate. 
• 
Perform ECG if appropriate (Patients with a normal ECG during Cycle 1 need not have 
repeat ECGs during subsequent cycles). 
• 
Collect blood samples for blood chemistries, hematology and creatinine clearance. 
• 
Collect urine samples for urinalysis. 
• 
Perform urine pregnancy test for female patients who are not postmenopausal or 
surgically sterile.  If urine test positive, test, collect blood for a serum pregnancy test. 
• 
Assess and record disease status (every 2 cycles). 
• 
Assess and record AEs. 
• 
Obtain all unused study drug from patient. 
• 
Assess study drug compliance by reviewing pill count. 
• 
Bone marrow aspirate and/or biopsy.  Peripheral, Geimsa and Iron stained slides will be 
collected with each bone marrow aspirate or biopsy.  Following Cycles 1 and 2, Day 22 
bone marrow aspirates will be collected only every other cycle, i.e., Cycles 4, 6, etc.  


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• 
Bone marrow cytogenetics in accordance with local pathology requirements.  
(Cytogenetics would preferably include at least 20 clones). 
• 
Dispense BVD-523 for 21 days ±4 days of Cycle.  Extra doses may be dispensed at the 
Investigator’s discretion to insure continuous dosing. 
5.5 
DESCRIPTION OF STUDY VISITS FOR PART 2 
Study procedures for Part 2 will be the same as those for Part 1.  If clinical experience gained in 
Part 1 requires significant deviations in Part 2 from the procedures in Part 1, these changes will 
be addressed in a protocol amendment. 
6 
METHODS OF ASSESSMENT AND CRITERIA FOR EVALUATION 
All trial data will be recorded on the electronic case report forms (eCRFs) (TEMPO™).  
Photographs will be taken in the event a patient experiences a rash, and the photos will be 
uploaded into the eCRF.  Blood and biopsy specimens will be sent to a third party laboratory 
vendor for analysis. 
6.1 
DEMOGRAPHIC DATA 
At Visit 1 (Screening), patient demographic data will be collected.  These include date of birth, 
age, gender, race, ethnicity, AML or MDS subtype and molecular abnormalities (when 
available). 
6.2 
MEDICAL HISTORY 
At Visit 1 (Screening), a complete medical history will be obtained from each patient.  For 
female patients of child-bearing potential, the date of the last menstrual period will be noted.  
Smoking history and prior cancer therapy will be recorded.  Data will be reviewed at Visit 2 
(Baseline) and updated at subsequent visits. 
6.3 
CONCOMITANT MEDICATIONS 
A detailed history of medications, including prior anti-cancer therapies, and procedures will be 
documented for each patient at Visit 1 (Screening) and Visit 2 (Baseline).  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 which are known to be strong 
inhibitors of CYP3A4, CYP2D6, and CYP1A2, or strong inducers of CYP3A4, are not 
permitted during the study (for list of non-permitted drugs, see Appendix 1). 
Hydroxyurea will be allowed for all subjects during Cycle 1 of treatment unless subject does not 
meet inclusion criterion for hydroxyurea use based on kinetics of leukemia.  After Cycle 1, 
hydroxyurea will not be allowed for any subject on study. 
6.4 
PHYSICAL EXAMINATION 
• 
Height in centimeters (cm) will be measured at Visit 1 (Screening). 
• 
Body weight in kilogram (kg) will be measured at screening and at the beginning of each 
cycle. 


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• 
Body temperature will be measured at each visit. 
• 
Systolic and diastolic BP and pulse rate will be measured at each visit after the patient 
has been in a supine position for 5 minutes.  Blood pressure should be assessed on the 
same arm during the study. 
Full physical examination evaluations at screening should include general appearance, skin, 
neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological examinations.  Subsequent targeted physical exams should include body systems as 
appropriate. 
Information about the physical examination must be present in the source documentation at the 
study site.  The result of the physical examination prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions Case Report Form.  
Clinically relevant findings made after the start of study drug, which meet the definition of an 
adverse event, must be recorded on the Adverse Event Case Report Form. 
6.5 
SAFETY ASSESSMENTS 
Safety evaluations will be conducted at baseline, on Days 1, 8, 15, 22, 29, 36, 43, and, in 
patients who continue treatment, every 3 weeks or if clinically indicated thereafter.  These 
evaluations will include a targeted physical examination, electrocardiography in subjects where 
clinically indicated and clinical laboratory studies.  An ophthalmologic assessment will be 
conducted at baseline, at the end of study and at other visits by an ophthalmologist if clinically 
indicated. 
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, cholesterol and triglycerides (at screening and first 
day of Cycle 1). 
• 
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. 
Blood chemistry will be analyzed at each trial center by a certified laboratory and a report of the 
laboratory values will be sent to the trial center.  The investigator or designee will review the 
laboratory report within 24 hours (except during clinic holidays, when review will be performed 
within 72 hours) 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.  Any laboratory value that remains abnormal at the 
end-of-study (EOS) and that is considered clinically significant will be followed according to 


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accepted medical standards for up to 30 days or until resolution of the abnormality or return to 
baseline. 
Ophthalmologic examinations include best-corrected visual acuity, visual field examination 
intraocular pressure, external eye examination, and dilated fundoscopy.  For additional details 
refer to study manual. Note: any patient experiencing vision changes must stop taking BVD-523 
and have an ophthalmic evaluation.  Study drug may be re-started when symptoms resolve.  
Toxicity will assessed using the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.03. 
6.6 
PHARMACOKINETICS 
Please refer to Section 6.9. 
6.7 
PHARMACODYNAMICS 
Multiple biomarkers intended to demonstrate inhibition of the molecular target and mechanism 
of action will be investigated, including pRSK and total RSK.  Additional biomarkers, 
including PBMCs, and DNA sequence analysis may be identified and measured as appropriate 
by collection of whole blood prior to dosing initiation and after drug levels have reached steady-
state. 
Leukemic cell genotyping by DNA analysis may be performed to identify somatic alterations, 
relying on either available stored samples or freshly collected samples.  Additional blood and/or 
bone marrow aspirate samples may also be collected to determine ex vivo BVD-523 sensitivity 
on leukemic cells by collection of whole blood prior to dosing initiation and after drug levels 
have reached steady-state. 
6.8 
EFFICACY 
All responses will be documented.  The following is a summary of the response criteria; the 
detailed criteria based on the published references will be used for analysis.  
MDS – The response criterion for evaluation of MDS is based on the International Working 
Group (IWG) criteria published in 2006 (2).  


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Table 6.1 
Table 3 from IWG 2006 MDS Response Criteria 
 
Reference: (2). 
Please note that all other responses are collected as “Less than PR” within the eCRF. 
AML – The response criteria for AML will be based on modified recommendation of the 
International Working Group (IWG) published in 2003 (1).  Information regarding 
transfusion dependence will be noted as a visit assessment and space provided in the 
eCRF. 
Table 6.2 
Table 4 from IWG 2003 AML Response Criteria 
Response 
Peripheral Blood 
Bone Marrow 
CR 
ANC > 1.0 x 109/L, Platelets ≥ 100 x 109/L, independence 
from red cell and platelet transfusions over the past week 
≤ 5% blasts 
CRp 
ANC > 1.0 x 109/L, Platelets < 100 x 109/L, independence 
from red cell transfusions over the past week 
≤ 5% blasts 
Cri 
ANC < 1.0 x 109/L 
≤ 5% blasts 
PR 
ANC > 1.0 x 109/L, Platelets ≥ 100 x 109/L 
Decrease of ≥ 50% in blasts to 
level of 5% to 25% 
ANC = absolute neutrophil count; CR=complete remission; CRp=complete remission with incomplete platelet 
recovery; Cri=CR with incomplete blood count recovery; PR=partial remission.   
Reference (1). 
Please note that all other responses are collected as “Less than PR” within the eCRF. 


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6.9 
PHARMACOKINETIC PROCEDURES 
6.9.1 
Blood Sampling and Processing 
Samples for PK analysis of BVD-523 and selected metabolites will be obtained from all patients 
during their first cycle of treatment (Cycle 1).  PK samples may also be obtained from patients 
at unscheduled times or intervals if deemed scientifically or clinically justified at the 
Investigator’s discretion. 
At Visit 2 (Baseline), blood samples will be collected prior to dosing, and then at 0.5, 1, 2, 4, 6, 
8, and 12 ± 2 hours post-dose after the administration of the first dose of the first cycle.  At Day 
22 (Visit 5; at steady-state), blood samples will be collected prior to dosing and then, 0.5, 1, 2, 4, 
6, 8, and 12 ± 2 hours post-dose.  Steady state refers to patients who have received at least 5 
days, or 10 consecutive doses, of investigational product. If patient is not at steady state at Day 
22 (Visit 5), these assessments will be rescheduled and completed at the next visit in which 
steady state is achieved. Comprehensive information on blood sample acquisition, handling and 
storage are to be found in the study manual.  Sample tube labels should include the patient 
identification number/protocol code, sample number and visit number and will be detailed in the 
study laboratory manual. 
Samples will be stored at -70°C (refer to study manual) at the study center until shipment under 
appropriate conditions to the analytical laboratory.  The analytical laboratory will measure 
plasma concentrations of BVD-523 using a validated method. 
6.9.2 
Pharmacokinetic Endpoints 
Blood BVD-523 and selected metabolite concentration levels will be measured at specified time 
points (see Section 3.5.3). 
Table 6.4 lists the various parameters that will be calculated. 


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Table 6.3 
Part 1 and 2: Schedule of Assessments and Procedures 
 
Cycle 1 
Day 1 through 21 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21 day cycles, visit on 
1st day of cycle 
 
Visit 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
 -X Tx 
Final Study Visit/ 
Early 
Discontinuation 
Visit Day 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ± 1 
36 ± 1 
43 ± 1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical historya 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
 
 
 
Measure height (cm) 
X 
 
 
 
 
 
 
 
 
Measure weight (kg) 
X 
X 
 
 
X 
 
 
X 
X 
Physical examination* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmology examb 
X 
 
 
 
 
 
 
 
X 
Pregnancy testc,d 
X 
Xc 
 
 
Xd 
 
 
Xd 
Xd 
Study drug dispensed 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug administratione 
 
X 
 
 
X 
 
 
 
 
Pharmacokinetic samplesf,g 
 
Xf,g 
 
 
Xf,g 
 
 
 
 
Pharmacodynamic samplesf,g 
 
Xf,g 
 
 
Xf,g 
 
 
 
 
PBMC samplesf,g 
 
Xf,g 
 
 
Xf,g 
 
 
 
 
Assess current disease 
status** 
X 
 
 
 
X 
 
 
X 
X 
Bone marrow aspirates and/or 
biopsyh 
Xk 
 
 
 
Xk 
 
 
Xk 
Xk 
Bone marrow cytogeneticsh 
Xk 
 
 
 
Xk 
 
 
Xk 
Xk 
Clinical lab testsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 6.3 
Part 1 and 2: Schedule of Assessments and Procedures 
 
Cycle 1 
Day 1 through 21 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21 day cycles, visit on 
1st day of cycle 
 
Visit 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 
 -X Tx 
Final Study Visit/ 
Early 
Discontinuation 
Visit Day 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ± 1 
36 ± 1 
43 ± 1 
 
Electrocardiogram (ECG)j 
X 
 
X 
 
 
 
 
 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance by pill count 
 
 
X 
X 
X 
X 
X 
X 
X 
Obtain unused drug 
 
 
X 
X 
X 
X 
X 
X 
X 
ECHO cardiogram or MUGA 
X 
 
 
 
 
 
 
 
 
Table footnotes: 
a 
Full medical history at screening, review/update of history only at subsequent visits. 
b 
Ophthalmological examinations will be performed by an ophthalmologist at screening, at study termination and if clinically indicated. 
c 
ONLY if the screening serum pregnancy test was performed more than 1 day previously. 
d 
After screening and baseline, urine pregnancy test which if positive, confirm with serum test. 
e 
Study drug to be taken twice daily, first dose in clinic on days when PK sampling occurs i.e., Cycle 1 on Visit 2 (Day 1) and Visit 5 (Day 22), remaining 
doses on all other days to be self-administered by patient. 
f 
PK blood samples will be collected prior to first morning dose and at 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 12 ±2 hours post-dose.   
Pharmacodynamic and PBMC blood samples will be collected prior to first morning dose and at 4 hours post-dose. 
g 
Pharmacodynamic, PK, and PBMC blood samples are required at baseline where feasible.  Additional biomarkers and DNA sequence analysis may be 
identified and measured as appropriate by collection of whole blood prior to dosing initiation and after drug levels have reached steady-state.  Leukemic cell 
genotyping by DNA analysis may be performed to identify somatic alterations, relying on either available stored samples or freshly collected samples. 
h 
Bone marrow aspirate and/or biopsy.  Peripheral, Geimsa and Iron stained slides to be provided with each bone marrow aspirate or biopsy.  Bone marrow 
cytogenetics (cytogenetics should include at least 20 clones). Bone marrow aspirates may be used to evaluate biomarkers of drug response. 
i 
Chemistry (to include calcium and inorganic phosphorus), hematology and urinalysis.  After Cycle 2, clinical chemistry (to include calcium and inorganic 
phosphorus), hematology and urinalysis may be performed once per cycle or more frequently at the investigator’s discretion. 
j 
Patients with a normal ECG in Cycle 1 need not have repeat ECGs in subsequent cycles.  Patients should be supine for 5 minutes prior to the ECG. 
k 
Bone marrow aspirates will be obtained at Screening, Cycle 1-Day 22, and every other cycle thereafter.    At treatment discontinuation visit, bone marrow 
aspirates will not be obtained if termination is due to disease progression.   
* 
Physical examinations should be symptom driven after the Screening Visit. 
** Assessments of current disease status will be obtained at Screening, Cycle 1–Day 22, and every other cycle thereafter. 


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Table 6.4 
Pharmacokinetic Parameters to be Estimated after Dose 1 and at Steady State 
Cmax 
Peak plasma concentration determined manually by visual inspection of plasma concentration vs. time figures on the untransformed (linear) scale 
of measurement 
tmax 
Time to reach the peak plasma concentration determined manually by visual inspection of plasma concentration vs. time figures on the 
untransformed (linear) scale of measurement 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours post dosing, calculated by linear/log trapezoidal method 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to time of last observation after dosing calculated by linear/log trapezoidal method 
λz 
Elimination rate constant, determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration- time 
curve.  The correlation coefficient (r2) for the goodness of the fit of the regression line through the data points has to be 0.85 or higher, for the 
value to be considered reliable.  If the WinNonlin data points are not on the linear portion of the terminal slope, the data points will be selected 
manually prior to calculation of lambda z 
t1/2 
Terminal half-life, defined as 0.693 divided by lambda z 
 
 


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7 
DISCONTINUATION CRITERIA 
7.1 
EARLY DISCONTINUATION OF THE STUDY 
It is agreed that for reasonable cause, either the Investigator or the Sponsor may terminate this 
study, provided a written notice is submitted at a reasonable time in advance of intended 
termination.  If 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 a severe local reaction or drug-related SAE occurs at any time during the study, the Safety 
Monitoring Committee will review the case immediately. 
The study will be immediately suspended and no additional BVD-523 doses will be 
administered pending review and discussion of all appropriate study data by the SMC 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 BVD-523 by the Investigator and/or Medical Monitor, 
based upon close temporal relationship or other factors: 
• 
Death 
• 
Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia, or respiratory 
distress) 
The study will not be restarted until all parties have agreed to the course of action to be taken 
and the Institutional Review Board/Ethic Committee (IRB/EC) (s) has/have been notified. 
7.2 
DISCONTINUATION OF INDIVIDUAL PATIENTS 
Patients are to be withdrawn from the study for any of the following reasons: 
• 
Withdrawal of informed consent 
• 
Disease progression (at the discretion of the PI)  
• 
Unacceptable toxicity 
• 
Changes in the patient's condition which render the patient unacceptable for further 
treatment in the judgment of the PI 
• 
At least 3 interruptions of BVD-523 intake of > 7 days each, or 8 consecutive days 
• 
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 do not lead to patient withdrawal 
unless they constitute a significant risk to the patient’s safety. 
 


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Patients can voluntarily withdraw from the trial for any reason at any time.  They are to be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, became lost 
to follow up for any reason, or if any of the following occurs: 
• 
Discovery of patient ineligibility 
• 
Significant errors in treatment compliance of at least three interruptions of 7 days each, 
any treatment interruption of ≥8 consecutive days, or incomplete dosing for greater than 
7 days 
• 
Missed / unscheduled / off-schedule / incomplete / incorrect assessments that result in 
patients being put at risk. 
 
In Part 1 of the study, patients who withdraw at any time due to unrelated AEs preceding the last 
visit of Cycle 1 (Day 22) will constitute an early discontinuation and must be replaced in order 
to ensure proper data accrual for dose escalation decisions.  A patient who experiences a DLT in 
Cycle 1 and withdraws before Day 22 either because of the toxicity or otherwise, will 
nonetheless have that DLT counted in the assessment of potential cohort expansion and/or dose 
escalation (Table 3.2). 
In Part 2 of the study, patients who withdraw at any time preceding the last visit of Cycle 2 
(Day 43) will constitute an early discontinuation and will not be replaced and will be evaluated 
in the Intent to Treat 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. 
 


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8 
TREATMENT 
The safety and PK of BVD-523 will be tested in sequentially increasing doses starting at 
300 mg twice daily, initially in patient cohorts of 3 patients (for tabular summary, see 
Table 3.2).  Dose escalations of BVD-523 will occur in 100% increments in cohorts until one 
patient experiences a study related ≥ Grade 2 toxicity (excluding alopecia or diarrhea), after 
which dose increases will be ≤ 50%.  If one patient in a 3 patient cohort experiences a DLT as 
defined in Table 3.2, up to 3 additional patients will be treated at this dose level.  If more than 
one DLT occurs in ≤ 6 patients, this dose level will be defined as the non-tolerated dose and 
dose escalation will be stopped. 
Doses will not be escalated unless the patient(s) receiving the highest current dose have been 
observed for at least 3 weeks and dose-limiting side effects have been reported in less than 2 of 
6 patients assigned to a given dose.  Before each escalation, Clinical Investigators will be 
consulted to ensure that all involved agree with the escalation decision.  Once the RP2D has 
been identified, up to 40 additional patients with pre-defined genetic types will be treated at this 
dose in Part 2. 
Patients experiencing DLT or unacceptable toxicity will have their treatment interrupted until 
the toxicity returns to ≤ Grade 1 or pre-treatment baseline (whichever is more severe).  
Resumption of BVD-523 treatment may then be at the next lower dose level where the safety 
profile has previously been established or between the dose level yielding unacceptable toxicity 
and the previous dose level, aligning with capsule dose availability. 
8.1 
DOSING AND ADMINISTRATION OF STUDY MEDICATION 
8.1.1 
Dispensing Directions 
Dispensing instruction will be provided in Pharmacy Instructions in the study manual. 
8.1.2 
Dosing Information 
BVD-523 is to be taken twice daily orally with at least 8 ounces of water for 21 days, at 12-hour 
± 2 hour intervals.  The study medication should be taken at the same time each day on an 
empty stomach, i.e., fasting (30-60 minutes before food or 2 hours after 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.  
Since this is a second-in-human study relatively little human toxicity has thus far been 
experienced.  Therefore, dose modifications for any toxicity seen will be developed as data are 
accrued.  However, patients experiencing DLT or unacceptable toxicity will have their treatment 
interrupted until the toxicity returns to ≤ Grade 1 or pre-treatment baseline.  BVD-523 treatment 
may then be re-initiated at the next lower dose level where the safety profile has previously been 
established, or between the dose level yielding unacceptable toxicity and the previous dose 
level, aligning with capsule dose availability.  Such dose adjustments will be done in 
consultation with the Investigators and Medical Monitor of the study. 


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8.1.3 
Dosing Instructions for the Study Participants 
Patients will be instructed to take their study medication twice daily at 12-hour ±2 hour 
intervals.  The study medication should be taken with at least 8 ounces water at the same time 
each day on an empty stomach (30-60 minutes before food or 2 hours after food). 
Drug Storage 
Information will be provided in the study manual. 
Drug Accountability 
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 
Standard Operating Procedures. 
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 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 
RESCUE MEDICATIONS AND CONCOMITANT TREATMENTS 
All medications administered from 30 days prior to the commencement of study treatment 
(Day 1) through the end of the treatment period (Day 22) will be recorded on the eCRF.  Any 
changes of dosages of medication will also be noted. 
8.3 
TREATMENT COMPLIANCE 
The investigator will dispense the study medication only for use by patients enrolled in the 
study as described in this protocol.  The study medication is not to be used for reasons other 
than those described in this protocol. 
The investigator or other study staff will supervise study drug treatment given in the clinic and 
instruct the patient on study medication self-administration at Visit 2 (Baseline).  Patients will 
be asked to bring their study medication container with them at each visit and compliance with 


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protocol-defined study drug intake will be checked by pill count.  In case of non-compliance, 
the patients will be instructed again. 


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9 
ADVERSE EVENT MANAGEMENT 
9.1 
DEFINITION OF AN ADVERSE EVENT 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient 
administered a medicinal product that does not necessarily have a causal relationship with this 
treatment.  An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the study (investigational) 
product.  This includes an exacerbation of pre-existing conditions or events, intercurrent 
illnesses, drug interaction, or the significant worsening of the indication under investigation 
that is not recorded elsewhere in the eCRF under specific efficacy assessments.  Anticipated 
fluctuations of pre-existing conditions, including the disease under study that does not represent 
a clinically significant exacerbation or worsening, need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study.  AE 
information will be elicited by asking the patient a 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. 
9.2 
DEFINITION OF A SERIOUS ADVERSE EVENT 
A Serious Adverse Event (SAE) is any untoward medical occurrence that occurs at any dose 
(including after the ICF is signed and prior to dosing) that: 
• 
Results in death 
• 
Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• 
Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital anomaly/birth defect 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 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. 
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 


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within the safety reporting period, then the event should be reported using the term “disease 
progression” with a CTCAE severity of Grade 5. 
9.3 
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
Recording and reporting of adverse events should be in accordance with the FDA “Guidance 
for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies” of 
December 2012. 
Any AE is to be recorded in the eCRF.  In order to avoid vague, ambiguous, or colloquial 
expressions, the AE should be recorded in standard medical terminology rather than the 
patient’s own words.  Whenever possible, the investigator should combine signs and symptoms 
that constitute a single diagnosis. 
The existence of an AE may be concluded from a spontaneous report of the patient; from the 
physical examination; or from special tests, e.g., ECG, laboratory assessments, or other study-
specified tests (source of AE). 
The reporting period begins from the time that the patient provides informed consent through 
and including 30 calendar days after the last administration of BVD-523.  AEs may occur in 
the specified follow-up period.  Any SAE occurring after the reporting period must be 
promptly reported if a causal relationship to the investigational drug is suspected.  If the patient 
begins a new anticancer therapy, the safety reporting period ends at the time the new treatment 
is started, however, death must always be reported when it occurs during the 30-day reporting 
period irrespective of intervening treatment. 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug.  The action taken and the outcome must also be recorded.  In the event 
that a rash is noted and reported as an AE, the rash should be documented with photographs as 
soon as it is reported through resolution.  Patients must give consent for photographs to be 
taken. 
9.4 
INTENSITY OF ADVERSE EVENTS 
The severity of the AE will be graded according to the NCI CTCAE Grading Scale Version 
4.03 (see the NCI CTCAE web page at http://ctep.cancer.gov for details).  For AEs not covered 
by NCI CTCAE, the severity will be characterized as “mild”, “moderate”, or “severe” 
according to the following definitions: 
• 
Mild events are usually transient and do not interfere with the patient’s daily activities. 
• 
Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities. 
• 
Severe events interrupt the patient’s usual daily activities. 
 


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9.5 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY DRUG 
The investigator will 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 adverse event is unlikely to have been caused by study drug. 
Possibly related 
It is unclear whether the adverse event may have been caused by study 
drug. 
Related 
The adverse event is likely to have been caused by study drug. 
 
9.6 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All AEs occurring during the study are to be followed up in accordance with good medical 
practice until they are resolved, stabilized or judged no longer clinically significant or, if a 
chronic condition, until fully characterized.  Any AEs that are considered drug-related 
(possibly related, related) must be followed until resolution or until stabilization.  Any AE of 
rash should be documented until resolution with photographs. 
9.7 
POST STUDY ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All unresolved AEs should be followed by the investigator until the events are resolved, the 
patient is lost to follow-up, or the AE is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each patient to report any subsequent event(s) that the patient, or 
the patient’s personal physician, believes might reasonably be related to participation in this 
study.  Prior to the conclusion of the study at the site the investigator should notify the Safety 
Associate (see Section 9.8) of any death or AE occurring at any time after a patient has 
discontinued or terminated study participation that may reasonably be related to this study.  
After study conclusion the investigator should notify BioMed Valley Discoveries, Inc., or their 
designee, Clinipace Worldwide (CPWW), of any death or AE they are aware of occurring at 
any time after a patient has discontinued or terminated study participation that may reasonably 
be related to this study.  BioMed Valley Discoveries, Inc., should also be notified if the 
investigator should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a patient that has participated in this study. 
9.8 
REGULATORY ASPECTS OF ADVERSE EVENT REPORTING 
Unexpected serious suspected adverse reactions are subject to expedited reporting to FDA.  
ALL SAEs must be entered into the eCRF within 24 hours of first knowledge of the event by 
study personnel.  It is important that the investigator provide his/her assessment of relationship 
to study drug at the time of the initial report.  Entry of an SAE into the eCRF triggers an 
automatic alert to the CPWW safety team.  Timely notification of an event supersedes the 
requirement to have all information at the time of the initial report.   


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The following information must be reported on the eCRF SAE report form: 
• 
Protocol number 
• 
Site and/or Investigator number 
• 
Patient number 
• 
Demographic data 
• 
Brief description of the event 
• 
Onset date and time 
• 
Resolution date and time, if the event resolved 
• 
Current status, if event not yet resolved 
• 
Any concomitant treatment and medication 
• 
Investigator’s assessment of whether the SAE was related to Investigative product or not 
• 
Outcome of the event if available 
The CPWW Safety Associate will contact the site for clarification of data entered onto the 
eCRF, or to obtain missing information.  In the event of questions regarding SAE reporting, the 
site may contact: 
Safety Associate 
Clinipace Worldwide, Inc. 
safety@clinipace.com 
BioMed Valley Discoveries, Inc., or their designee CPWW, is responsible for submitting reports 
of AEs associated with the use of the drug that are both serious and unexpected to FDA 
according to 21 CFR 312.32 and the draft guidance (2010).  All investigators participating in 
ongoing clinical studies with the study medication will receive copies of these reports for 
prompt submission to their Institutional Review Board (IRB) or Ethics Committee (EC). 
9.8.1 
Overdose 
No information on treatment of overdose of BVD-523 is currently available.  In the event of an 
overdose, the overdose should be reported as an AE and the Medical Monitor should be 
notified. 
9.8.2 
Pregnancies 
Pregnancy per se is not considered an AE unless there is cause to believe that the investigational 
drug may have interfered with the effectiveness of a contraceptive medication.  Hospitalization 
for normal delivery of a healthy newborn should not be considered a SAE. 
Each pregnancy in a patient or partner of a patient on BVD-523 must be reported to the 
Sponsor within 24 hours of learning of its occurrence.  If a patient becomes pregnant, study 
drug administration must be discontinued immediately.  The pregnancy should be followed 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. 


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The avoidance of pregnancy or fathering a child is suggested for 3 months following the 
discontinuation of BVD-523 therapy.  No information is currently available regarding the 
effects of BVD-523 on fertility, gestation or subsequent child development. 
Any pregnancy within 3 months post-study should be reported to the study investigator and to 
CPWW. 


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10 STATISTICAL METHODS 
10.1 GENERAL CONSIDERATIONS 
10.1.1 
Statistical and Analytical Plans 
A formal detailed statistical analysis plan (SAP) will be created prior to the review of any data. 
The purpose of this Phase 1/2 dose escalation study is to determine the maximum tolerated 
dose (MTD), the dose limiting toxicity (DLT), and the recommended Phase 2 dose (RP2D) of 
orally administered BVD-523 in patients with AML or MDS.  Groups of 3−6 patients will be 
treated at each dose level until the maximum tolerated dose is reached.  All patients meeting 
the eligibility criteria and receiving at least 1 dose of BVD-523 will be evaluable for safety. 
10.1.2 
Determination of Sample Size 
The sample size for Part 1 of this study was determined by clinical rather than statistical 
considerations.  Approximately 20 patients will be treated in Part 1 of this study (Dose 
Escalation) to establish dose limiting toxicities (DLT), maximum tolerated dose (MTD), and 
the recommended Phase 2 dose (RP2D). 
After the completion of Part 1 of this study, up to 40 additional AML or MDS patients with or 
without RAS mutations will be treated with the RP2D of BVD-523.  The purpose of the second 
phase of this study is to document that there is some evidence of a response.  With 20 subjects in 
each group, there is an 88% probability of seeing at least one positive response in each group if 
the true response rate is at least 10%. 
The observation of DLTs in more than 33% of patients in any Part 2 cohort with at least 6 
patients enrolled at any time during Part 2 will trigger temporary stopping of patient enrollment 
and revision of the definition of the MTD and RP2D in the specific cohort.  Subsequent patients 
will be treated with a dose lower than the initial RP2D and this dose will be determined in 
discussion with the Clinical Investigators, the Medical Monitor, and the Sponsor. 
Up to 6 study centers are expected to enroll patients for this study. 
10.1.3 
Blinding and Randomization 
This clinical study is open-label, and all patients enrolled will be treated with BVD-523. 
10.2 ANALYSIS DATASETS 
10.2.1 
Population to be Analyzed 
The safety population will consist of all patients receiving at least 1 dose of study medication. 
10.2.2 
Modified Intent-to-treat 
The modified intent-to-treat (mITT) population will consist of all patients who have a 
screening visit/sign the informed consent. 


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10.2.3 
Per Protocol 
The per-protocol (PP) population for efficacy evaluations will consist of all patients of the 
mITT population who completed the study without a major protocol deviation. 
10.2.4 
Definition of Study Days 
In the first treatment cycle, a total of 5 visits are planned for Part 1 of this clinical study.  In 
subsequent Cycles there will be up to 4 visits.  Patients in Part 2 of the study will receive a total 
of up to 5 visits in the first treatment Cycle, and 4 visits in subsequent Cycles.  The study visits 
are defined as summarized in Table 10.1. 
Table 10.1 
Per Cycle Study Visit Definitions 
Visit Description 
Study Day 
Visit 1: Screening 
Day -28 to -1 
Visit 2: Baseline / Drug Dispensing / Initiation of Treatment 
Day 1 ± 0 
Visit 3: Treatment Phase 
Day 8 ± 1 
Visit 4: Treatment Phase 
Day 15 ± 1 
Visit 5: Final Visit 
Day 22 ± 1 
 
10.3 DATA PRESENTATION 
10.3.1 
Demographic 
Demographic characteristics of patients will be summarized in appropriate tables and analyzed 
with descriptive statistics. 
The following characteristics will be summarized in the mITT, PP, and safety population: 
• 
Age 
• 
Gender 
• 
Race 
• 
Ethnicity 
• 
AML or MDS including relapsed or refractory status 
• 
Bone marrow cytogenetics 
• 
RAS 
10.3.2 
Baseline Characteristics 
Baseline characteristics will be summarized in appropriate tables and with descriptive statistics. 
The following characteristics will be summarized in the mITT, PP, and safety population: 
• 
Body weight 
• 
Height 
• 
ECOG performance status 


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• 
Previous chemotherapy 
• 
Previous immunotherapy 
10.3.3 
Medical History and Physical Examination 
Descriptive statistics will be generated to summarize data.  For continuous variables, 
descriptive statistics may include the number of patients, mean, standard deviation, median, 
minimum, maximum; frequencies and percentages may be displayed for categorical data. 
10.3.4 
Concomitant Medications or Treatments 
The number and percentage of patients taking concomitant medication will be summarized.  
All data will be recorded as follows: 
• 
Prior use ended before first day of trial medication 
• 
Concomitant use on or after first day of trial medication (initiation date, stop date) 
10.3.5 
Primary Endpoints 
MTD – See Section 3.1.4.1. 
RP2D – See Section 3.1.4.3. 
Measurement of preliminary clinical effects on AML or MDS response.   
10.3.6 
Secondary Endpoints 
Pharmacokinetic profile of BVD-523 and selected metabolites.  
Determination of PFS and DOR of patients achieving CR/CRp. 
No formal efficacy analysis will be conducted. 
10.3.7 
Pharmacokinetic Data 
Blood BVD-523 and Selected Metabolite Concentration Levels 
Systemic BVD-523 exposure as measured in blood samples will be summarized per time point 
by means of descriptive statistics.  Measured concentrations will be presented by a by-patient 
listing, sorted by site, patient identifier and dose. 
10.3.8 
Safety Data 
All safety summaries will be provided for the Safety population. 
Summaries for safety variables (physical examinations, vital signs, clinical laboratory analyses) 
will be given.  All safety variables will be presented in by-patient listings, sorted by site and 
patient identifier. 


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10.3.9 
Adverse Events (AE) 
Adverse events will be coded using the MedDRA coding dictionary.  A listing of all events, 
with seriousness, severity, relationship, sequelae and begin and end times will be provided.  
Narratives for any serious adverse events will be provided. 
Deaths, serious adverse events (SAEs), and AEs leading to discontinuation of trial medication 
will be summarized by primary system organ class (SOC) and preferred terms.  Listings will be 
provided. 
10.4 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the Sponsor, the IRB/EC and the Health Authorities. 


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


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


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


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


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12 REFERENCES 
1. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, 
Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, 
Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International 
Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. 
Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
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Appendix 1 
Non-Permitted Concomitant Medications 
INHIBITORS 
INHIBITORS 
INHIBITORS 
CYP3A 
CYP2D6 
CYP1A2 
indinavir 
bupropion 
fluvoxamine 
nelfinavir 
fluoxetine 
ciprofloxacin 
lopinavir/ritonavir 
paroxetine 
enoxacin 
clarithromycin 
quinidine 
 
itraconazole 
 
 
ketoconazole 
 
 
voriconazole 
 
 
nefazodone 
 
 
saquinavir 
 
 
telithromycin 
 
 
boceprevir 
 
 
conivaptan 
 
 
posaconazole 
 
 
telaprevir 
 
 
mibefradil1 
 
 
grapefruit juice 
 
 
INDUCERS 
 
 
CYP3A 
carbamazepine 
avasimibe2 
phenytoin 
rifampin 
St. John’s Wort 
 
 
1Withdrawn from the United States market because of safety reasons 
2Not a marketed drug 
Strong inhibitors: ≥ 5-fold increase in AUC or > 80% decrease in CL 
Strong inducers: ≥ 80% decrease in AUC 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664.htm#classInhibit; Table 5 (inhibitors) and Table 6 (inducers), dated 7-28-11; Accessed 10-01-15 

SAP_001.pdf: 
 
 
DOCUMENT: 
Statistical Analysis Plan 
PROTOCOL NUMBER:
BVD-523-02 
 
Phase 1/2 Dose-Escalation, Safety, Clinical Activity, 
Pharmacokinetic and Pharmacodynamic Study of the ERK1/2 
Inhibitor BVD-523 in Patients with Acute Myelogenous 
Leukemia or Myelodysplastic Syndromes 
 
SAP VERSION: 
Part 2 Final Version 1 
SAP DATE: 
21 December 2017 
PROTOCOL DATE: 
Version 1: 10 March 2014 
 
Version 1.1: 28 April 2014 
 
Version 2: 18 November 2015 
SPONSOR: 
BioMed Valley Discoveries, Inc. 
PREPARED BY: 
Clinipace Worldwide 
AUTHOR(S): 
Chao Li, MS, MPH 
 
Scott W. Miller, PhD 




Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION .............................................................................................................7 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS .......................................7 
2.1 
Study Objectives ......................................................................................................7 
2.1.1 
Primary Objectives.........................................................................................7 
2.1.2 
Secondary Objectives.....................................................................................7 
2.1.3 
Exploratory Objectives ..................................................................................7 
2.2 
Treatment Groups ....................................................................................................7 
2.3 
Study Endpoints .......................................................................................................8 
2.3.1 
Primary Endpoint ...........................................................................................8 
2.3.2 
Secondary Endpoints .....................................................................................8 
2.3.3 
Exploratory Endpoints ...................................................................................8 
3 
STUDY DESIGN...............................................................................................................8 
3.1 
Overall Study Design ...............................................................................................8 
3.2 
Schedule of Study Assessments .............................................................................11 
4 
SAMPLE SIZE CONSIDERATIONS .............................................................................15 
5 
ANALYSIS POPULATIONS .........................................................................................16 
5.1 
Safety .....................................................................................................................16 
5.2 
Modified Intent-to-Treat ........................................................................................16 
5.3 
Per Protocol ............................................................................................................16 
5.4 
Pharmacokinetic .....................................................................................................16 
5.5 
Pharmacodynamic ..................................................................................................16 
6 
CONSIDERATIONS FOR DATA ANALYSIS .............................................................17 
6.1 
Programming Environment ....................................................................................17 
6.2 
Strata and Covariates .............................................................................................17 
6.3 
Subgroups ..............................................................................................................17 
6.4 
Multiple Comparisons and Multiplicity .................................................................17 
6.5 
Significance Level .................................................................................................17 
6.6 
Statistical Notation and Methodology ...................................................................17 
7 
DATA HANDLING METHODS ....................................................................................18 
7.1 
Visit Windows .......................................................................................................18 
7.2 
Data Derivations and Definitions ...........................................................................19 
7.3 
Missing Data ..........................................................................................................19 
7.3.1 
Date Values ..................................................................................................19 


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7.3.2 
Non-Date Values ..........................................................................................20 
8 
STUDY POPULATION ..................................................................................................21 
8.1 
Subject Disposition ................................................................................................21 
8.2 
Demographic and Baseline Characteristics ...........................................................21 
8.3 
Prior and Concomitant Medications ......................................................................22 
8.4 
Medical History .....................................................................................................22 
8.4.1 
Prior Cancer Surgery Related to AML or MDS ..........................................22 
8.4.2 
Previous Chemotherapy ...............................................................................22 
8.4.3 
Previous Immunotherapy .............................................................................23 
8.4.4 
Previous Hormonal Therapy ........................................................................23 
8.4.5 
Previous Radiation Therapy .........................................................................23 
8.4.6 
Previous Stem Cell Therapy ........................................................................23 
8.4.7 
Previous Transfusion/Blood Product Use ....................................................23 
8.4.8 
Prior MEK Therapies ...................................................................................23 
8.5 
Inclusion/Exclusion Criteria ..................................................................................23 
8.6 
Protocol Deviations ................................................................................................23 
9 
EFFICACY ANALYSIS .................................................................................................24 
9.1 
Primary Endpoint Analysis ....................................................................................24 
9.2 
Secondary Endpoint Analyses ...............................................................................24 
9.2.1 
PK profile .....................................................................................................25 
9.2.2 
Response ......................................................................................................25 
9.3 
Other Efficacy Analyses ........................................................................................26 
9.4 
Interim Analysis .....................................................................................................26 
10 SAFETY ..........................................................................................................................26 
10.1 
Exposure to Study Drug .........................................................................................27 
10.2 
Adverse Events ......................................................................................................27 
10.3 
Serious Adverse Events and Death ........................................................................29 
10.4 
Laboratory Evaluations ..........................................................................................29 
10.5 
Vital Signs ..............................................................................................................30 
10.6 
Electrocardiograms ................................................................................................30 
10.7 
Physical Examinations ...........................................................................................31 
10.8 
ECOG Performance Status ....................................................................................31 
10.9 
Bone Marrow Assessment .....................................................................................31 
11 PHARMACOKINETIC ANALYSES .............................................................................31 
12 OTHER ANALYSES ......................................................................................................32 
12.1 
Pharmacodynamics Analyses.................................................................................32 


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12.2 
Analysis for RAS mutation ....................................................................................33 
12.3 
Interim Analysis .....................................................................................................33 
13 END OF STUDY ANALYSIS ........................................................................................33 
14 TABLE OF CONTENTS FOR DATA DISPLAYS ........................................................34 
14.1 
Demographics Summary Figures and Tables ........................................................34 
14.2 
Efficacy Summary Figures and Tables ..................................................................35 
14.3 
Safety Summary Figures and Tables .....................................................................35 
14.3.1 
Adverse Events ............................................................................................35 
14.3.2 
Serious Adverse Events, Deaths and Other Significant Adverse Events .....36 
14.3.3 
Narratives .....................................................................................................37 
14.3.4 
Laboratory Results .......................................................................................37 
14.4 
Other Summary Figures and Tables ......................................................................38 
14.5 
Listings ...................................................................................................................38 
15 REVISIONS TO SAP ......................................................................................................42 
16 REFERENCES ................................................................................................................43 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AML 
AMS 
ANC 
ATC 
BM 
BID 
CFB 
CML 
CMML 
CPWW 
Acute Myelogenous Leukemia 
Acute Myelodysplastic Syndrome 
Absolute Neutrophil Count 
Anatomical Therapeutic Chemical 
Bone Marrow 
Twice Daily 
Change from Baseline 
Chronic Myeloid Leukemia 
Chronic Myelomonocytic Leukemia 
Clinipace Worldwide 
CR 
CRF 
CRi 
CRp 
CTCAE 
DLT 
DOR 
ECOG 
ITT 
Complete Remission 
Case Report Form 
Complete Response with incomplete blood count recovery 
Complete Response with incomplete platelet recovery 
Common Terminology Criteria for Adverse Events 
Dose Limiting Toxicity 
Duration of Response 
Eastern Cooperative Oncology Group 
Intent-to-Treat 
Max 
MDS 
MedDRA 
MEK 
Min 
MTD 
MUGA 
NCI-CTCAE 
PBMC 
PD 
PFS 
PK 
PP 
PR 
RP2D 
SAE 
SAP 
STD 
SOC 
WHO 
Maximum 
Myelodysplastic Syndromes  
Medical Dictionary for Regulatory Activities 
Mitogen-activated protein kinase/extracellular signal-related kinase 
Minimum 
Maximum Tolerated Dose 
Multi-gated Acquisition 
National Cancer Institute Common Terminology Criteria AE Severity 
Peripheral blood mononuclear cell 
Pharmacodynamics 
Progression Free Survival 
Pharmacokinetics 
Per Protocol 
Partial Remission 
Recommended Phase 2 Dose 
Serious Adverse Event 
Statistical Analysis Plan 
Standard Deviation 
System Organ Class 
World Health Organization 
 


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1 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the 
summary and analysis of safety, tolerability, pharmacodynamics (PD), pharmacokinetics 
(PK), and preliminary efficacy data from Protocol BVD-523-02.  Background information is 
provided for the overall study design and objectives.  The reader is referred to the study 
protocol and case report forms (CRFs) for details of study conduct and data collection.   
 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS 
2.1 
STUDY OBJECTIVES 
2.1.1 
Primary Objectives 
The primary objectives of the study are:  
 
• To determine the safety and tolerability of BVD-523 in subjects with Acute 
Myelogenous Leukemia (AML) or Myelodysplastic Syndromes (MDS) by 
determining the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and 
the recommended Phase 2 Dose (RP2D). 
• To determine the pharmacokinetic profile of BVD-523 and selected metabolites in 
subjects with AML or MDS. 
2.1.2 
Secondary Objectives 
Secondary objectives of this study are:  
• To assess clinical response in subjects with AML or MDS treated with BVD-523 at 
the recommended Phase 2 Dose (RP2D). 
• To determine the progression-free survival (PFS) and duration of response (DOR) of 
AML or MDS subjects treated with BVD-523 achieving CR (Complete Remission) / 
CRp (Complete Remission with incomplete platelet recovery). 
2.1.3 
Exploratory Objectives 
• To evaluate pharmacodynamic marker (biomarker) measures. 
2.2 
TREATMENT GROUPS 
This Phase 1/2 study is single-arm. 
In Phase 1 (Dose Escalation) the treatment group is subjects treated with orally administered 
BVD-523 BID. 


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In Phase 2 (Cohort Expansion) the treatment group is subjects treated with orally 
administered BVD-523 BID at the RP2D in one of two groups: RAS mutant positive or RAS 
mutant negative.  
2.3 
STUDY ENDPOINTS 
2.3.1 
Primary Endpoint 
The primary safety endpoints are the DLTs and MTD for BVD-523 administered alone in 
subjects with AML or MDS (Part 1) and the MTD for BVD-523 administered at the RP2D 
dose in subjects with AML or MDS with or without RAS mutant positive disease (Part 2).   
As this is a Phase 1/2 study, there is no formal primary efficacy endpoint; however, clinical 
response will be assessed. 
2.3.2 
Secondary Endpoints 
Secondary endpoints are: 
• Pharmacokinetic (PK) profile of BVD-523 and selected metabolites 
• Progression Free Survival (PFS) and Duration of Response (DOR) in subjects 
achieving Complete Response (CR) or Complete Response with incomplete platelet 
response (CRp) 
2.3.3 
Exploratory Endpoints 
• Pharmacodynamic markers (biomarker)  
3 
STUDY DESIGN 
3.1 
OVERALL STUDY DESIGN 
This study is an open label, Phase 1/2 clinical trial in subjects with AML or MDS.  The trial 
has a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2).   
 
Part 1 – Dose-escalation Phase: The dose-escalation phase is a 3+3 design to determine the 
dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 
dose (R2PD) of BVD-523 given twice-daily.  The starting dose of BVD-523 will be 300 mg 
BID.  Treatment will be administered in continuous, sequential 21 day Cycles until disease 
progression, unacceptable toxicity, or another withdrawal condition is met.  Dose-escalation 
decisions will be based on Cycle 1 data.  Within-subject dose escalations are allowed after 
completing one Cycle at the initial dose, pending complete Cycle 1 data for the dose to be 
escalated to.  The MTD will be determined based on the highest dose associated with no 
more than 1 DLT in fewer than 6 subjects.  Cohorts will be based on 3 subjects, but can be 
enlarged as deemed necessary by the Safety Monitoring Committee.  Once a dose associated 
with more than 1 DLT in fewer than 6 subjects has been identified, intermediate doses may 
be examined to obtain a better estimate of the MTD. 
 


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Part 2 – Cohort-expansion Phase:  Approximately 40 additional subjects will be recruited to 
one of two groups: 
• Group 1: RAS mutant positive AML or MDS (n ≤ 20) 
• Group 2: RAS mutant negative AML or MDS (n ≤ 20) 
Subjects in both groups will receive treatment at the Recommended Phase 2 Dose (RP2D).  
Subjects will receive twice daily oral doses of BVD-523 in 21-day treatment cycles until 
disease progression, unacceptable toxicity, or another withdrawal criterion is met.  Treatment 
cycles will occur consecutively without interruption except when necessary to manage 
adverse events. 
 
DLTs 
For this study, Dose Limiting Toxicities (DLTs) are based upon the first Cycle (first 21 days 
of treatment), defined as (where Grade refers to CTCAE v 4.0 categorization): 
 
• Any treatment-emergent study drug related Grade 3 or Grade 4 non-hematologic toxicity 
unless clearly and incontrovertibly unrelated to BVD-523.  Exceptions are Grade 3 or 4 
nausea or vomiting that is controllable by anti-emetics or Grade 3 or 4 diarrhea 
controllable by optimal therapy such as loperamide.  Grade 3 laboratory investigations 
other than serum creatinine, bilirubin, AST or ALT will not be considered a DLT unless 
they are associated with clinical manifestations.  
• Study-drug related Grade 4 thrombocytopenia that was not present at study entry and that 
does not resolve within 7 days, unless clearly and incontrovertibly unrelated to BVD-523. 
• Febrile neutropenia or Grade 4 neutropenia that was not present at study entry and that 
does not resolve within 7 days, unless clearly and incontrovertibly unrelated to BVD-523. 
• Prolonged myelosuppression or pancytopenia with a hypocellular bone marrow and no 
marrow blasts lasting for 6 weeks that is not related to disease progression. 
• Any study drug related toxicity that results in treatment delays of > 4 days, except when 
subject is experiencing rash in which case, subject may be off drug for up to 7 days while 
receiving treatment. 
All subjects who are not evaluable for toxicity in Cycle 1 due to unrelated AEs will be 
replaced. 
Dose escalation will proceed according to the following rules: 
Observed Safety Outcomes 
Action 
1 DLT in 3 subjects 
Expand cohort up to 6 subjects 
1 DLT in 6 subjects 
Escalate by ≤ 50% to next dose level 
> 1 DLT in ≤ 6 subjects 
Stop dose escalation 
 
MTD 
The Maximum Tolerated Dose (MTD) will be determined based on the highest dose cohort at 
which <33% of subjects experience BVD-523 related DLTs in the first 21 days of treatment.  


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Once a non-tolerated dose has been identified, intermediate doses may be examined to obtain 
a better estimate of the MTD. 
 
 
RP2D 
The Recommended Phase 2 Dose (RP2D) may be as high as the MTD, and will be 
determined based upon discussions of the study Clinical Investigators, Medical Monitor, and 
Sponsor.  Observations related to pharmacokinetics, pharmacodynamics, and any cumulative 
toxicity observed after multiple cycles may be included in the rationale supporting the RP2D. 


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3.2 
SCHEDULE OF STUDY ASSESSMENTS 
Table 3.1 
Part 1 and 2: Schedule of Assessments and Procedures 
 
Cycle 1 
Day 1 through 21 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21 day cycles, visit 
on 1st day of cycle 
 
Visit 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 -X 
Tx 
Final Study Visit/ Early Discontinuation 
Visit Day 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ± 1 
36 ± 1 
43 ± 1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history [a] 
 X [a] 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
 
 
 
Measure height (cm) 
X 
 
 
 
 
 
 
 
 
Measure weight (kg) 
X 
X 
 
 
X 
 
 
X 
X 
Physical examination * 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmology exam [b] 
X 
 
 
 
 
 
 
 
X 
Pregnancy test [c,d] 
X 
X [c] 
 
 
X [d] 
 
 
X [d] 
X [d] 
Study drug dispensed 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug administration [e] 
 
X 
 
 
X 
 
 
 
 
Pharmacokinetic samples [f,g] 
 
X [f,g] 
 
 
X [f,g] 
 
 
 
 
Pharmacodynamic samples [f,g] 
 
X [f,g] 
 
 
X [f,g] 
 
 
 
 
PBMC samples [f,g] 
 
X [f,g] 
 
 
X [f,g] 
 
 
 
 
Assess current disease status ** 
X 
 
 
 
X 
 
 
X 
X 
Bone marrow aspirates and/or biopsy [h] 
X [k] 
 
 
 
X [k] 
 
 
X [k] 
X [k] 
Bone marrow cytogenetics [h] 
X [k] 
 
 
 
X [k] 
 
 
X [k] 
X [k] 
Clinical lab tests [i] 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 3.1 
Part 1 and 2: Schedule of Assessments and Procedures 
 
Cycle 1 
Day 1 through 21 
Cycle 2 
Day 22 through 42 
Cycle 3-X 
21 day cycles, visit 
on 1st day of cycle 
 
Visit 
1 
Screening 
2 
Baseline 
3 
Tx 
4 
Tx 
5 
Tx 
6 
Tx 
7 
Tx 
8 -X 
Tx 
Final Study Visit/ Early Discontinuation 
Visit Day 
-28 to -1 
1 ± 0 
8 ± 1 
15 ± 1 
22 ± 1 
29 ± 1 
36 ± 1 
43 ± 1 
 
Electrocardiogram (ECG)[j] 
X 
 
X 
 
 
 
 
 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance by pill count 
 
 
X 
X 
X 
X 
X 
X 
X 
Obtain unused drug 
 
 
X 
X 
X 
X 
X 
X 
X 
ECHO cardiogram or MUGA 
X 
 
 
 
 
 
 
 
 
 
Table footnotes: 
a     Full medical history at screening, review/update of history only at subsequent visits. 
b     Ophthalmological examinations will be performed by an ophthalmologist at screening, at study termination and if clinically indicated. 
c     ONLY if the screening serum pregnancy test was performed more than 1 day previously. 
d     After screening and baseline, urine pregnancy test which if positive, confirm with serum test. 
e     Study drug to be taken twice daily, first dose in clinic on days when PK sampling occurs i.e., Cycle 1 on Visit 2 (Day 1) and Visit 5 (Day 22), remaining 
doses on all other days to be self-administered by patient. 
f      PK blood samples will be collected prior to first morning dose and at 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 12 ±2 hours post-dose.    
Pharmacodynamic and peripheral blood mononuclear cells (PBMC) blood samples will be collected prior to first morning dose and at 4 hours post-dose. 
g     Pharmacodynamic, PK and PBMC blood samples are required at baseline where feasible.  Additional biomarkers and DNA sequence analysis may be 
identified and measured as appropriate by collection of whole blood prior to dosing initiation and after drug levels have reached 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.  Leukemic cell genotyping by DNA analysis may be performed to 
identify somatic alterations, relying on either available stored samples or freshly collected samples. 
h     Bone marrow aspirate and/or biopsy.  Peripheral, Geimsa and Iron stained slides to be provided with each bone marrow aspirate or biopsy.  Bone marrow 
aspirate and/or biopsy slides will not be shipped to a third party. As such, the site may utilize BM aspirates performed in clinical practice as SOC, as long as 
they are collected within the screening window (-28 days).  Bone marrow cytogenetics (cytogenetics should include at least 20 clones). Bone marrow 
aspirates may be used to evaluate biomarkers of drug response. 
i      Chemistry (to include calcium and inorganic phosphorus), hematology and urinalysis.  After Cycle 2, clinical chemistry (to include calcium and inorganic 
phosphorus), hematology and urinalysis may be performed once per cycle or more frequently at the investigator’s discretion. 
j      Patients with a normal ECG in Cycle 1 need not have repeat ECGs in subsequent cycles.  Patients should be supine for 5 minutes prior to the ECG. 
k     Bone marrow aspirates will be obtained at Screening, Cycle 1-Day 22, and every other cycle thereafter.    At treatment discontinuation visit, bone marrow 
aspirates will not be obtained if termination is due to disease progression.   


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*     Physical examinations should be symptom driven after the Screening Visit. 
**   Assessments of current disease status will be obtained at Screening, Cycle 1–Day 22, and every other cycle thereafter. 


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Table 3.2 
Pharmacokinetic Parameters to be Estimated after Dose 1 and at Steady State 
Cmax 
Peak plasma concentration determined manually by visual inspection of plasma concentration vs. time 
figures on the untransformed (linear) scale of measurement 
tmax 
Time to reach the peak plasma concentration determined manually by visual inspection of plasma 
concentration vs. time figures on the untransformed (linear) scale of measurement 
AUC0-12 
Area under the plasma concentration time curve from 0 to 12 hours post-dosing, calculated by linear/log 
trapezoidal method 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to time of last observation after dosing 
calculated by linear/log trapezoidal method 
λz 
Elimination rate constant, determined by linear regression of at least 3 points on the terminal phase of 
the log-linear plasma concentration-time curve.  The correlation coefficient (r2) for the goodness of the 
fit of the regression line through the data points has to be 0.85 or higher, for the value to be considered 
reliable.  If the WinNonlin data points are not on the linear portion of the terminal slope, the data points 
will be selected manually prior to calculation of λz  
t1/2 
Terminal half-life, defined as 0.693 [ln(2)] divided by λz 
 


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Table 3.3 
Study Medication Dosing and Pharmacokinetics/Pharmacodynamics Chart 
 
Study Days 
1 
8 ± 1 
15 ± 1 
22 ± 1 
BVD-523 dosing [a] 
X 
X 
X 
X 
Pharmacokinetics 
X 
 
 
X 
Pharmacodynamics 
X 
 
 
X 
a      Dosing is twice daily in 21-day cycles until disease progression.  Patients will take their study medication in the 
clinic on PK days.  Patients may be treated beyond disease progression for additional 21-day cycles at the same 
or escalated dose level at the Investigator’s discretion.  Study medication for a week of dosing should be 
dispensed at each visit for treatment Cycles 1 and 2.  For treatment cycles after Cycle 2, study medication will 
be dispensed to support the entire 3 week cycle.  
4 
SAMPLE SIZE CONSIDERATIONS 
The expected sample size is 60 subjects: 20 in Part 1 and 40 in Part 2 (20 subjects each in RAS 
mutant positive and RAS mutant negative groups).  This sample size was selected based on the 
sample size for similar Phase 1 oncology clinical trials. 


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5 
ANALYSIS POPULATIONS 
The following population definitions will be used in study summaries and analyses.   
5.1 
SCREENED 
The Screened Population will consist of all patients who have signed the informed consent. The 
screened population will be used for disposition tables. 
5.2 
SAFETY 
The Safety Population will consist of all subjects receiving at least 1 dose of study drug.   
Demographic and baseline characteristics will be tabulated for the Safety population. The Safety 
population will be used for all safety analyses.  Safety analyses from Part 1 will be presented 
overall as well as broken down by dose level.  Safety analyses from Part 2 will be presented 
overall as well as broken down by dose level, specifically at the RP2D dose of 600 mg. 
5.3 
MODIFIED INTENT-TO-TREAT 
The modified Intent-to-Treat (mITT) Population will consist of all subjects who have a screening 
visit / sign the informed consent and had no screening failures/were eligible for treatment 
regardless of whether or not they have received treatment. Demographic and baseline 
characteristics will be tabulated for the mITT population.  Additionally, the mITT population 
will be used for calculating response in Part 2. 
5.4 
PER PROTOCOL 
The Per Protocol (PP) Population will consist of all subjects in the mITT population who receive 
at least 1 dose of study drug, complete the first protocol-specified tumor measurement evaluation 
(except for study drug-related AE), and complete the study without a major protocol deviation 
(see Section 8.6). Demographic and baseline characteristics will be tabulated for the PP 
population.  Additionally, the PP population will be used for calculating MTDs in Part 1 and 
response in Part 2. 
5.5 
PHARMACOKINETIC 
The PK population will consist of all subjects who receive at least 1 dose of study drug and have 
sufficient, valid PK samples to estimate key parameters for at least 1 of the days of sampling. PK 
summaries will be based on the PK population. 
5.6 
PHARMACODYNAMIC 
The PD population will consist of all subjects who receive at least 1 dose of study drug and have 
sufficient, valid PD samples to estimate key parameters for at least 1 of the days of sampling. PD 
summaries will be based on the PD population. 
 


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6 
CONSIDERATIONS FOR DATA ANALYSIS 
6.1 
PROGRAMMING ENVIRONMENT 
All analyses will be conducted using SAS® version 9.2 or higher. 
6.2 
STRATA AND COVARIATES 
No covariates will be accounted for in Part 1.  In Part 2, analyses will be conducted separately by 
RAS mutation status (positive or negative). 
6.3 
SUBGROUPS 
There are no planned subgroup analyses. 
6.4 
MULTIPLE COMPARISONS AND MULTIPLICITY 
There are no planned adjustments for multiplicity. 
6.5 
SIGNIFICANCE LEVEL 
Unless otherwise noted, all statistical analyses will be conducted with a significance level (α) of 
0.05 and utilize two-sided testing.  
6.6 
STATISTICAL NOTATION AND METHODOLOGY 
Unless stated otherwise, the term “descriptive statistics” refers to the number of subjects (n), 
mean, median, standard deviation (STD), minimum (min), and maximum (max) for continuous 
data and frequencies and percentages for categorical data.  Min and max values will be rounded 
to the precision of the original value, means and medians will be rounded to 1 decimal place 
greater than the precision of the original value, and STDs will be rounded to 2 decimal places 
greater than the precision of the original value.  Percentages will be rounded to the nearest whole 
number (zeroes are not displayed) with values of “< 1%” and “> 99%” shown as necessary for 
values falling near the boundaries.  P-values will be presented with 3 decimal places and values 
less than 0.001 will be presented as < 0.001. 
Unless otherwise noted, all data collected during the study will be included in data listings and 
will be sorted by study part (Part 1 or Part 2), subject number, and then by date/time for each 
subject number.  For Part 2, subjects will additionally be sorted by RAS mutation status.   


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7 
DATA HANDLING METHODS 
7.1 
VISIT WINDOWS 
All study data will be presented at the nominal visit obtained from the eCRFs, if available.  
Study day is defined as (date of visit – date of treatment initiation + 1).  That is, study day 1 
indicates the date of treatment initiation.  In the case of early termination visit, the date of the 
visit will be used to calculate the nominal visit for the analysis.  
 
If there are two or more assessments within a nominal visit, then the assessment that is closest to 
the scheduled time point/target day will be used in the analysis.  If there is more than one closest 
value, then the evaluation occurring after the target day and prior to the date of last dose will be 
used in the analysis. 
All values will be included in the data listings. 
Study visit periods will be windowed as applicable according to the following: 
Visit 
Nominal Study Day 
Study Day Window 
Screening 
 
-28 to -1 
Baseline  
(pre-dose and post-single dose) 
1 
N/A  
(Other visits are scheduled based on this visit) 
Cycle 1 
 
 
     Day 8 
8 
7 to 9 
     Day 15 
15 
14 to 16 
Cycle 2 
 
 
     Day 1 
22 
21 to 23 
     Day 8 
29 
28 to 30 
     Day 15 
36 
35 to 37 
Cycles 3-X 
 
 
     Day 1 
21*X + 1 
-1 to +1 
 
Values will be presented for all scheduled study visits according to the nominal visit obtained 
from the CRF.  If an unscheduled visit falls in a visit window with an existing nominal visit 
assessment, the nominal assessment will be used for summary presentation.  If no nominal visit 
assessment exists for a visit window with unscheduled visit(s), then the latest unscheduled visit 


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within the visit window will be used.  If multiple nominal assessments are collected within the 
same visit, the latest value and corresponding date will be used for summary presentation.   
All values will be included in the data listings. 
7.2 
DATA DERIVATIONS AND DEFINITIONS 
Baseline Definition 
Baseline measurement is defined as the last pre-treatment measurement obtained prior to the 
initial administration of BVD-523. 
 
Change from Baseline 
The change from baseline will be calculated by subtracting the baseline values from the 
individual post-procedure values.  If either the baseline or post-procedure value is missing, the 
change from baseline is set to missing as well. 
 
Study days on or after the initial dose of BVD-523 will be computed as Study Day = Date – 
Study Drug Start Date + 1.  For pre-dosing dates, Study Day = Date – Study Drug Start Date. 
Age will be calculated from the date of birth to informed consent visit date.  Note, that if 
multiple dates occur for the screening visit, the convention as described at the end of 
Section 7.3.1 will be used.  
Treatment-emergent events will be considered as any event occurring after the first dose of study 
drug and prior to a subject’s termination, withdrawal, or completion of the study.   
The following will define prior medication use versus concomitant medication use: 
• Prior use ended before the first day of study drug 
• Concomitant use is on or after the first day of study drug (initiation date, stop date). 
7.3 
MISSING DATA 
7.3.1 
Date Values 
In cases of incomplete dates (e.g., pertaining to AE, concomitant medication, medical history, 
etc.), the missing component(s) will be assumed as the most conservative value(s) possible.  For 
example, if the start date has a missing day value, the first day of the month will be imputed for 
study day computations (i.e., treatment-emergent status, etc.).  If day is missing for an end date, 
the last day of the month will be imputed.  Similar logic will be assumed for missing month and 
year components.   
Date imputation will only be used for computational purposes e.g., treatment-emergent status, 
etc.  Actual data values as they appear in the original CRFs will be shown in the data listings. 


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7.3.2 
Non-Date Values 
Every effort will be made to obtain the protocol-required data for all study assessments that are 
scheduled for each scheduled visit for all subjects who have been enrolled.  No data imputation 
will be applied to missing study data except for imputing visit dates to classify AE and 
concomitant medication data into the study phase of “pre-treatment,” “during treatment,” or 
“post-treatment.” 


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8 
STUDY POPULATION 
Unless otherwise stated, all study population analyses will be performed on the Safety 
Population. 
8.1 
SUBJECT DISPOSITION 
Subject disposition will be presented for all subjects.  The composition of the analysis 
populations and those who were screen fails, enrolled, completed or discontinued from the study 
will be summarized by dose cohort and overall with descriptive statistics.  Reasons for early 
discontinuation will be presented with frequencies and percentages for all categories.   
The frequency and percentage of subjects who are screen fails, subjects who receive at least one 
dose of BVD-523 or not, subjects who have completed the study as per protocol or not, and 
subjects who withdrew prematurely from the study with their reasons for discontinuation (death, 
anaphylaxis, withdrawal of informed consent, disease progression, unacceptable toxicity, change 
in the subject’s condition that renders the subject unacceptable for further treatment in the special 
treatment of PI, at least 3 interruptions of BVD-523 intake of >7 days each, or 8 consecutive 
days, subject becomes pregnant, subject is lost to follow-up, or other) will be summarized by 
treatment group and overall (all treatment groups combined) separately for Study Parts 1 and 2.  
The total number of mITT subjects in each treatment group for each study part will be used as 
the denominator for the calculation of percentages. 
 
The number and percentage of subjects in each of the analysis populations as specified in Section 
5 will also be tabulated similarly. 
 
A listing of analysis population, study completion, and early termination with the primary reason 
for early withdrawal will also be provided. 
 
8.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristic data will be summarized with descriptive statistics for 
(including but not limited to): age, gender, race, AML or MDS subtype (including relapsed or 
refractory status), bone marrow molecular cytogenetics, RAS positive or negative status 
(optional for Part 1, required for Part 2), body weight and height, ECOG performance status, 
previous chemotherapy, and previous immunotherapy.    
 
Demographic and baseline characteristics will be summarized descriptively by treatment group and 
overall for each study part using the Safety, mITT, and PP populations.  
 
Demographic and baseline characteristics include, but are not limited to: age (years), gender, 
ethnicity, race, weight (kg), height (cm), Eastern Cooperative Oncology Group (ECOG) 
Performance Score, cancer type (AML or MDS), bone marrow cytogenetics, RAS mutation 
status, previous chemotherapy and previous immunotherapy.  Age will be calculated in years 
from date of birth to the date of informed consent as an integer value.    


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8.3 
PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded according to the World Health Organization Drug Dictionary (WHO 
Drug, March 2015).  A summary of all medications will then be provided using the WHO Drug 
ATC classification and preferred term. 
 
All medications taken except for BVD-523 will be classified into prior or concomitant 
medications.   
• A prior medication is defined as any medication taken within 28 days prior to the 
initiation of BVD-523 irrespective of whether it is continued into the study.   
• A concomitant medication is defined as any medication taken after the initiation of BVD-
523 and up to 30 calendar days after the last administration of BVD-523.  
If a medication falls into both prior and concomitant time phase then it will be presented in both 
time phases.  All medications except for BVD-523 will be summarized by WHO Drug ATC 
classification and preferred term with regards to treatment groups for each study part and time 
phase. 
 
At each level (WHO Drug ATC classification and Preferred Term) of summarization, a subject 
will be counted only once per drug class or preferred term.  For example, if a subject reports 
multiple concomitant medications with the same drug class, then that drug class will only be 
incremented by one. Similarly, if a subject reports multiple concomitant medications with the 
same preferred term, then that preferred term will only be incremented by one. 
Whether medications are taken for AEs or not will also be provided.  The medication with 
indication equals to the AE verbatim which also has “Concomitant Medications” as the response 
to the question of “Any Treatment Required?” will be deemed as the medication taken for the 
AE.  Medications taken for AEs will be tabulated by WHO Drug ATC classification and 
preferred term with regards to treatment groups for each study part. 
 
Subject listing of medications will also be presented by time phase. 
8.4 
MEDICAL HISTORY 
Medical history will be summarized with descriptive statistics by medical history code.  A 
comprehensive data listing will also be included.  Specific intervention of interest include prior 
cancer surgery related to AML or MDS, chemotherapy,  immunotherapy, hormonal, radiation, 
stem cell treatment and MEK therapies. 
8.4.1 
Prior Cancer Surgery Related to AML or MDS 
Prior cancer surgeries related to AML or MDS will be summarized by indication (diagnostic, 
therapeutic, or other) and time prior to enrollment into the trial.  They will be summarized by 
descriptive statistics for each study part.  A listing will also be provided in the order of 
occurrences within a subject. 
8.4.2 
Previous Chemotherapy  
Previous chemotherapy information includes description/name of the chemotherapy, start/stop 
date, reason for therapy, best response from the therapy, total number of cycles completed, best 


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response, and reason for discontinuation.  They will be summarized by descriptive statistics for 
each study part.  A listing of previous chemotherapy information will also be provided in the 
order of occurrences within a subject. 
8.4.3 
Previous Immunotherapy 
Previous immunotherapy data including type of immunotherapy/name (monoclonal antibodies, 
cancer vaccine, other immunotherapy), start/stop date, and reason for discontinuation (completed 
regimen, disease progression, other) will be listed by time of occurrence within a subject. 
8.4.4 
Previous Hormonal Therapy 
Previous hormonal therapy including type, start/stop date, reason for therapy, best response for 
therapy, total number of cycles completed, and reason for discontinuation (completed regimen, 
disease progression, other) will be listed by time of occurrence within a subject. 
8.4.5 
Previous Radiation Therapy 
Previous radiation therapy including type, total dose, delivery site, start/stop date, reason for 
therapy, best response for therapy, total number of cycles completed, and reason for 
discontinuation (completed regimen, disease progression, other) will be listed by time of 
occurrence within a subject. 
8.4.6 
Previous Stem Cell Therapy 
Previous stem cell therapy including type, start/stop date, reason for therapy, best response for 
therapy, total number of cycles completed, and reason for discontinuation (completed regimen, 
disease progression, other) will be listed by time of occurrence within a subject. 
8.4.7 
Previous Transfusion/Blood Product Use 
Previous transfusion/blood product use blood product, date, amount transfused, and relevant test 
results (e.g. hemoglobin, platelets, or other) will be listed by time of occurrence within a subject. 
8.4.8 
Prior MEK Therapies 
Prior MEK therapies including type, start/stop date, duration (days), reason for therapy, best 
response for therapy and reason for discontinuation (completed regimen, disease progression, 
other) will be listed by time of occurrence within a subject. 
8.5 
INCLUSION/EXCLUSION CRITERIA 
Inclusion and exclusion criteria failures will be included in a data listing. 
8.6 
PROTOCOL DEVIATIONS 
Protocol deviations will be summarized with descriptive statistics by cohort and category.  All 
protocol deviations will be reported, but prior to generating Part 1 TFLs or Part 2 TFLs the list of 
protocol deviations will be reviewed and each classified as either major or minor. A listing of all 
events will also be included.  Protocol deviation categories are: 


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• Inclusion/exclusion criteria 
• Informed consent issue 
• Out of window visit 
• Protocol required evaluation not completed 
• Physician decision 
• Subject refused 
• Prohibited medication 
• Pharmacokinetic data 
• Other 
Impacts of the above protocol deviations on the analysis population will be determined by the 
study team before study closure and documented in the SAP. 
 
The frequency and percentage of subjects with each protocol deviation along with the impact on 
the analysis population will be presented by treatment group and overall for each study part 
using the mITT Population.  A listing of subjects with protocol deviation(s) will also be 
provided. 
9 
EFFICACY ANALYSIS 
Unless otherwise stated, efficacy analyses will be performed on both the modified ITT and PP 
populations. 
9.1 
PRIMARY ENDPOINT ANALYSIS 
As this is a Phase 1/2 study, there is no formal primary efficacy endpoint. 
The primary safety endpoints are the DLTs and MTD for BVD-523 administered alone in 
subjects with AML or MDS (Part 1) and preliminary efficacy (AML/MDS response) of BVD-
523 administered at the RP2D dose in subjects with AML or MDS with or without RAS mutant 
positive disease (Part 2).  The MTD and RP2D will be determined based upon the observed 
DLTs at each dose level as described in the protocol.  
9.2 
SECONDARY ENDPOINT ANALYSES 
While no formal efficacy analyses will be conducted, secondary efficacy endpoints are: 
• Pharmacokinetic (PK) profile of BVD-523 and selected metabolites 
• Progression Free Survival (PFS) and Duration of Response (DOR) in subjects achieving 
Complete Response (CR) or Complete Response with incomplete platelet response (CRp) 


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9.2.1 
PK profile 
Pharmacokinetic analyses are discussed in Section 11 of this SAP. 
9.2.2 
Response 
Subject response will be determined differently depending on disease type (MDS or AML). 
 
MDS – The response criterion for evaluation of MDS is based on the International Working 
Group (IWG) criteria published in 2006. 
Table 9.1 
Table 3 from IWG 2006 MDS Response Criteria 
Response 
Peripheral Blood 
Complete Response 
(CR) [for 4 weeks] 
Peripheral: Normal peripheral counts with persistent granulocyte count >=1.0*109/L, 
platelet count ≥100*109/L 
Marrow: Normal bone marrow with persistent marrow blasts <=5%; persistent dysplasia 
will be noted 
Partial Response (PR) 
[for 4 weeks] 
Peripheral: Normal peripheral counts with granulocyte count ≥1.0*109/L and platelet 
count >=100*109 
Marrow: Normal bone marrow with marrow blasts >5% but were reduced by 50% or 
more 
Marrow Complete 
Response (mCR)  
[for 4 weeks] 
Reduction of bone marrow blasts to <=5% without normalization of peripheral counts 
Hematological 
Improvement (HI) 
[for at least 8 weeks]* 
Erythroid Response (HI-E) : Major Response: Hemoglobin increase >=1.5g/dL or RBC 
transfusion independence  
Platelet Response (HI-P) : Major Response : Absolute increase of platelet count <20 to 
>20*109/L and by at least 100%, or if more than 20*109/L, by an absolute increase of at 
least 30**109/L 
Neutrophil Response (HI-N) : Major Response: Granulocyte increase >=100%, and by an 
absolute increase ≥0.5*109/L   
Less than Partial 
Remission** 
 
*Abnormal baseline counts were the averages of at least two measurements over at least one week prior to therapy, 
not influenced by transfusions. 
**Added as a response option in Note to File dated 21JUL2015. 


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AML – The response criteria for AML will be based on the modified recommendation of the 
International Working Group (IWG) published in 2003.  Information regarding 
transfusion dependence will be noted as a visit assessment and space provided in the 
eCRF. 
Table 9.2 
Table 4 from IWG 2003 AML Response Criteria 
Response 
Peripheral Blood 
Bone Marrow 
Complete Remission 
(CR) 
ANC > 1.0 x 109/L, Platelets ≥ 100 x 109/L, 
independence from red cell and platelet transfusions 
over the past week 
≤ 5% blasts 
Complete Remission 
with Incomplete 
Platelet Recovery 
(CRp) 
ANC > 1.0 x 109/L, Platelets < 100 x 109/L, 
independence from red cell transfusions over the past 
week 
≤ 5% blasts 
Complete Response 
with Incomplete 
Blood Count 
Recovery (Cri) 
ANC < 1.0 x 109/L 
≤ 5% blasts 
Partial Remission 
(PR) 
ANC > 1.0 x 109/L, Platelets ≥ 100 x 109/L 
Decrease of ≥ 50% in blasts to 
level of 5% to 25% 
Less than Partial 
Remission* 
 
 
ANC = absolute neutrophil count 
*Added as a response option in Note to File dated 21JUL2015 
9.3 
OTHER EFFICACY ANALYSES 
There are no other efficacy analyses. 
9.4 
INTERIM ANALYSIS 
There will not be a formal interim analysis; however, TFLs will be generated for Part 1 after a 
MTD is determined; i.e. as Part 2 is ongoing.  
10 SAFETY 
Safety analyses will be performed using the Safety Population. Safety will be assessed by 
examining all adverse events reported during the study including the incidence, and relationship 
to BVD-523.  In addition, safety evaluations will be conducted at Baseline, Days 1, 8, 15, 22, 29, 
36, 43, and, in subjects who continue treatment, every 3 weeks or if clinically indicated 
thereafter.  These evaluations will include a targeted ECG where clinically warranted, and 
clinical laboratory analytes (hematology, chemistry, urinalysis and pregnancy test).  An 
ophthalmologic assessment will also be conducted at baseline, at the end of study and at other 
visits by an ophthalmologist if clinically indicated. 


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10.1 EXPOSURE TO STUDY DRUG  
All exposure and compliance data will be provided in data listings. 
Descriptive statistics will be provided for the total (cumulative) doses taken and total duration of 
treatment by treatment group for each study part.  The total duration of treatment is calculated as 
(treatment stop date – treatment start date) + 1.  If treatment stop date is missing, the date of final 
clinic visit will be used.  By subject listing of study drug exposure will also be presented by 
study part and treatment group for each treatment cycle and all cycles combined. Treatment 
compliance is accessed by reviewing pill count. Patient frequencies will be provided for the 
summary of treatment compliance. 
10.2 ADVERSE EVENTS 
An adverse event is defined as any untoward medical occurrence in a subject administered a 
medicinal product that does not necessarily have a causal relationship with this treatment.  This 
includes an exacerbation of pre-existing conditions or events, inter-current illnesses, drug 
interaction, or the significant worsening of the indication under investigation that is not recorded 
elsewhere in the eCRF under specific efficacy assessments.  The reporting period of an AE 
begins from the time that the subject provides informed consent through and including 30 
calendar days after the last administration of BVD-523 (or at the time when a subject begins a 
new anticancer therapy).  Anticipated fluctuations of pre-existing conditions, including the 
disease under study that does not represent a clinically significant exacerbation or worsening, 
need not be considered AEs. 
 
The severity of an AE will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03 with values of Grade 1 to 
Grade 5 (increased in severity). For AEs not covered by NCI CTCAE, the severity will be 
characterized as “mild,” “moderate,” or “severe” according to the following definitions: 
• Mild events are usually transient and do not interfere with the subject’s daily activities. 
• Moderate events introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities. 
• Severe events interrupt the subject’s usual daily activities.  
 
All AE relationship to the study drug, BVD-523, are classified as “unrelated,” “possibly related,” 
or “related.” 
 
AE Coding 
Any AE including SAE in verbatim term will be coded in accordance with the Medical 
Dictionary for Regulatory Activities (MedDRA®) dictionary version 17.1 to a system organ 
class (SOC) and preferred term (PT) within each SOC.  Analysis of AEs will then be performed 
using SOCs and PTs. 
 
Dose Limiting Toxicities, Maximum Tolerated Dose, and Recommended Phase 2 Dose 


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As specified in Section 3.1, a DLT is defined as a BVD-523 related toxicity1 in the first 21 days 
of treatment that results in:  
 
• Any treatment-emergent study drug related Grade 3 or Grade 4 non-hematologic toxicity 
unless clearly and incontrovertibly unrelated to BVD-523.  Exceptions are Grade 3 or 4 
nausea or vomiting that is controllable by anti-emetics or Grade 3 or 4 diarrhea controllable 
by optimal therapy such as loperamide.  Grade 3 laboratory investigations other than serum 
creatinine, bilirubin, AST or ALT will not be considered a DLT unless they are associated 
with clinical manifestations.  
• Study-drug related Grade 4 thrombocytopenia that was not present at study entry and that 
does not resolve within 7 days, unless clearly and incontrovertibly unrelated to BVD-523. 
• Febrile neutropenia or Grade 4 neutropenia that was not present at study entry and that does 
not resolve within 7 days, unless clearly and incontrovertibly unrelated to BVD-523. 
• Prolonged myelosuppression or pancytopenia with a hypocellular bone marrow and no 
marrow blasts lasting for 6 weeks that is not related to disease progression. 
• Any study drug related toxicity that results in treatment delays of > 4 days, except when 
subject is experiencing rash in which case, subject may be off drug for up to 7 days while 
receiving treatment. 
 
As specified in Section 3.1, the MTD is defined as the highest dose level at which no more than 
1 of 6 subjects experiences BVD-523 related DLTs in the first 21 days of treatment.  The RP2D 
may be as high as the MTD and will be determined in discussion with the Clinical Investigators, 
the Medical Monitor, and the Sponsor.  Observations related to pharmacokinetics (PK), 
pharmacodynamics (PD), and any cumulative toxicity observed after multiple cycles may be 
included in the rationale supporting the RP2D. 
 
Treatment Emergent Adverse Event 
A treatment emergent adverse event (TEAE) is any AE temporally associated with the use of 
BVD-523 (from BVD-523 initiation until 30 calendar days after the last administration of 
BVD-523), whether or not considered related to the study drug.  If the onset of an AE is missing 
and the AE resolution date is either after the initial BVD-523 dose date or missing, then the AE 
will be considered treatment emergent. 
 
AE Summaries   
A subject who reported multiple AEs that map to a common PT or SOC is counted only once for 
that PT or SOC at the highest severity reported and at the greatest relationship to study drug. 
The number and percentage of subjects who experienced at least one AE as well as subjects who 
experienced at least one TEAE will be tabulated by SOC and PT with respect to dose level 
treatment group for each study part.  The same tabulation will also be applied to any treatment 
emergent SAEs and any TEAEs leading to premature discontinuation from the study as well as 
to any DLTs. 
                                                 
1 All toxicities will be considered related to BVD-523 if they cannot be definitively explained by underlying disease, 
intercurrent illness or concomitant medications. 


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The number and percentage of subjects who experience at least one TEAE will also be tabulated 
by SOC and PT within each dose level treatment group with respect to relationship to study drug 
(unrelated and at least possibly related [combining events classified as either possibly related or 
related]) and severity (Grade 1 to Grade 5 and ≥Grade 3). The tabulation by relationship 
(unrelated and at least possibly related) will also be applied to any treatment emergent SAEs 
(TESAEs).  
 
Subject listings will also be provided for all AEs, all SAEs, all AEs leading to early 
discontinuation from the study, all AEs leading to study drug interruptions and length of 
interruptions. 
 
Bar graphs of AEs in CTCAE Term will be displayed in decreasing order of incidence from most 
common to least common.  Each bar in the plot will represent an AE in CTCAE Term.  Severity 
of AE (grades) will be embedded in each bar using the percentages of subjects in each AE grade.  
These plots will be provided for all AEs, TEAEs, treatment-emergent SAEs, and AEs leading to 
premature discontinuation from the study. 
10.3 SERIOUS ADVERSE EVENTS AND DEATH 
Separate data listings and summaries will be presented for all SAEs and deaths.   
10.4 LABORATORY EVALUATIONS 
Laboratory assessments and change from baseline will be summarized with descriptive statistics 
by panel, test, dose of BVD-523, and time point.  Additionally, abnormal results will be 
summarized with frequencies and percentages by clinical significance, panel, test, treatment 
group, and time point.  The clinical significance of lab tests will also be summarized by shift 
tables. 
A data listing will display all laboratory test results and findings.   
Laboratory evaluations obtained from the following clinical laboratory tests will be collected at 
Screening, Baseline, Days 8, 15, 22, 29, 36, 43, and, in subjects who continue treatment, every 3 
weeks or if clinically indicated thereafter: 
• Hematology – hemoglobin, hematocrit, white blood cells (WBC) count with differential, 
red blood cells (RBC) count, and platelet count. 
• Blood Chemistry – albumin, alkaline phosphatase (ALP), total bilirubin, calcium, 
chloride, creatinine, glucose, inorganic phosphorus, potassium, total protein, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), sodium, blood urea nitrogen 
(BUN), uric acid, cholesterol and triglycerides (at screening and first day of Cycle 1).   
• If total bilirubin concentration is increased above 1.5 times the upper normal limit, 
total bilirubin should be differentiated into direct and indirect reacting bilirubin. 
• Urinalysis – specific gravity, pH, semi-quantitative “dipstick” evaluation of glucose, 
protein, bilirubin, ketones, leukocytes, and blood.  Abnormal findings by dipstick will 
trigger a full microscopic examination including RBC, WBC, and casts.   


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10.5 VITAL SIGNS 
Descriptive statistics for systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), 
pulse rate (bpm), temperature (°C), height (cm), and weight (kg) will be presented by study visit 
and treatment group visit for each study part.  Also, changes in these vital signs from baseline to 
each subsequent visit will be tabulated by dose level for each study part.  Note that height is only 
collected at Screening and weight is only collected at Screening and at the beginning of each 
cycle of treatment.  
A Listing of vital signs will also be provided. 
10.6 ELECTROCARDIOGRAMS  
Subjects will have ECG measured at Screening and on Cycle 1, Day 8.  Subjects with normal 
ECGs do not need to have subsequent ECGs.  ECG parameters [Heart Rate (bpm), RR (msec), 
PR (msec), QRS (msec), QT (msec), and QTcF (msec)] collected.  These ECG findings will be 
summarized with frequencies and percentages by dose and time point.  ECG results will also be 
categorized as ‘Normal’, ‘Abnormal, Not Clinically Significant’, or ‘Abnormal, Clinically 
Significant’ and any clinically significant abnormalities described.   


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10.7 PHYSICAL EXAMINATIONS 
Full physical examinations at Screening will include examination of general appearance, skin, 
eyes, ears, nose, throat, head, neck, chest, lungs, heart, abdomen, back, lymph nodes, extremities, 
musculoskeletal, neurological examinations and other.  Subsequent targeted physical exams 
should include body systems as appropriate.   
 
The frequency and percentage of subjects with each examination finding (‘Normal’, ‘Abnormal 
Clinically Significant’, ‘Abnormal Not Clinically Significant’, and ‘Not Done’) will be tabulated 
for each body system by study visit and dose level treatment group for each study part.   
A listing of physical examination findings will also be presented.   
10.8 ECOG PERFORMANCE STATUS 
The ECOG performance status is a rating scale used to assess how a subject's disease is 
progressing as well as how the disease affects the daily living abilities of the subject.  The score 
values are 0 – 5, where 0 indicates “fully active, able to carry on all pre-disease performance 
without restriction” and 5 indicates the subject has died.  It will be assessed at Screening, 
Baseline, Study Days 8, 15, 22, 29, 36, 43, and in subjects who continue treatment, every 3 
weeks or if clinically indicated thereafter. 
 
The frequencies and percentages of subjects’ ECOG performance status will be provided by 
study visit and dose level treatment group for each study part.  A listing of ECOG performance 
status will also be provided. 
10.9 BONE MARROW ASSESSMENT 
Bone marrow assessments (aspiration or biopsy, cytogenetics) will be collected at prior to 
therapy on Day 1 and Day 22, every 2 cycles thereafter, as well as at the Final Study Visit.  Bone 
marrow aspirate/biopsy will be examined for: adequacy, fibrosis, cellularity, iron stores, ringed 
sideroblasts, histiocytes, dysplasia, bone marrow differential, and myeloid to erythroid ratio.  
Aspirate/biopsy samples will also be examined for biomarkers of drug response, e.g. pRSK and 
total RSK.  Cytogenetics assessments will examine for common mutations.   
11 PHARMACOKINETIC ANALYSES 
Analyses of serum concentrations collected at Baseline (Visit 2, Cycle 1) and Day 22 (Visit 5, 
Cycle 1).  Samples will be collected prior to administration of first daily dose and then post-
dosing at 0.5, 1, 2, 4, 6, 8, and 12 ± 2 hours. 
Descriptive statistics will be used to summarize concentration assessments and estimated PK 
parameters by treatment group and time point.  Comprehensive data listings will also be 
included. 
Samples for PK analysis of BVD-523 and selected metabolites will be obtained from all Part 1 
subjects during their first cycle of treatment (Cycle 1).  PK samples may also be obtained from 
additional subjects in Part 2 depending on the outcome of initial PK analysis. 


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At Visit 2 (Baseline) blood samples will be collected prior to dosing, and then at 0.5, 1, 2, 4, 6, 8, 
and 12 (± 2 hours) post-dose after the administration of the first dose of the first cycle.  At 
Day 22 (Visit 5; at steady-state) blood samples will be collected prior to dosing and then, 0.5, 1, 
2, 4, 6, 8, and 12 ± 2 hours post-dose. Steady state refers to patients who have received at least 5 
days, or 10 consecutive doses, of investigational product. If patient is not at steady state at Day 
22 (Visit 5), these assessments will be rescheduled and completed at the next visit in which 
steady state is achieved. 
Below is the list of various PK parameters that will be calculated after Dose 1 (Day 1) and at 
Steady State (Day 22). 
PK  
Parameter 
(plasma) 
Description 
Cmax 
Peak plasma concentration determined manually by visual inspection of plasma concentration vs. 
time figures on the untransformed (linear) scale of measurement 
tmax 
Time to reach the peak plasma concentration determined manually by visual inspection of plasma 
concentration vs. time figures on the untransformed (linear) scale of measurement 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours postdose, calculated by linear/log 
trapezoidal method 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to time of last observation after dosing 
calculated by linear/log trapezoidal method 
λz 
Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal 
phase of the log-linear plasma concentration-time curve.  The correlation coefficient (r2) for the 
goodness of the fit of the regression line through the data points has to be 0.85 or higher for the value 
to be considered reliable.  If the WinNonlin data points are not on the linear portion of the terminal 
slope, the data points will be selected manually prior to calculation of λz 
t1/2 
Terminal half-life, defined as 0.693 (ln 2) divided by λz 
 
PK concentration and PK parameters will be provided by Covance.  Descriptive statistics [n, 
arithmetic mean, standard deviation, coefficient of variation (CV), median, minimum, maximum, 
geometric mean, geometric standard deviation geometric CV] will be used to summarize PK 
parameters by treatment.  For t1/2 and tmax, regular descriptive statistics and 95% confidence 
intervals about the arithmetic mean will be calculated, if possible, for each dose, but not 
geometric mean, geometric standard deviation, and geometric CV.  Refer to the Covance Sample 
Analysis Outline document for additional details re. the PK analyses.  
 
A listing of blood PK concentrations and parameters will be provided. 
12 OTHER ANALYSES 
12.1 PHARMACODYNAMICS ANALYSES 
Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism 
of action will be investigated (pRSK and total pRSK) from blood and/or bone marrow aspirate 
samples.  Additional biomarkers, including peripheral blood mononuclear cells (PBMCs) and/or 
DNA sequence analysis, may be identified and measured as appropriate.  Descriptive statistics 
will be provided for pharmacodynamics data in a summary table and a listing will present all 
data. 


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12.2 ANALYSIS FOR RAS MUTATION 
Analysis for RAS mutation may be performed in subjects in Part 1.  For subjects enrolled in Part 
2 RAS mutation information (RAS positive or negative status) will be required to confirm 
eligibility.   
 
 Descriptive statistics and listing of RAS mutation data will be provided. 
12.3 INTERIM ANALYSIS 
Once all subjects enrolled into Part 1 of the study have been assessed for at least one full 
treatment cycle, an analysis of Part 1 safety and efficacy will be conducted in order to facilitate 
the discussions regarding MTD and RP2D; however, no formal interim analysis is planned for 
the study. 
13 END OF STUDY ANALYSIS 
A final analysis will be conducted after the last subject completes or discontinues the study and 
the resulting clinical database has been cleaned, quality checked, and locked. 


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14 TABLE OF CONTENTS FOR DATA DISPLAYS 
Tables, Figures, and Listings to be generated for the trial are summarized below; examples are 
provided in a separate attachment. 
 
14.1 DEMOGRAPHICS SUMMARY FIGURES AND TABLES 
Part II 
Part II: Study Population 
 
Table 
Title 
Population 
Part II - Table 14.1.1.1 
Summary of Analysis Populations 
Enrolled Population 
Part II - Table 14.1.1.2 
Subject Disposition 
Screened Population 
Part II - Table 14.1.2 
Protocol Deviations 
Screened Population 
Part II - Table 14.1.3.1 
Demographic and Baseline Characteristics 
Safety Population 
Part II - Table 14.1.3.2 
Demographic and Baseline Characteristics 
mITT Population 
Part II - Table 14.1.3.3 
Demographic and Baseline Characteristics 
PP Population 
Part II - Table 14.1.4.1 
Medical History 
Safety Population 
Part II - Table 14.1.4.2 
Previous Cancer Surgery 
Safety Population 
Part II - Table 14.1.4.3 
Previous Stem Cell Transplant 
Safety Population 
Part II - Table 14.1.4.4 
Transfusion/Blood Product Use 
Safety Population 
Part II - Table 14.1.4.5 
Prior MEK Therapies 
Safety Population 
Part II - Table 14.1.4.6 
Previous Therapies 
Safety Population 
Part II - Table 14.1.5 
On Study Procedures 
Safety Population 
Part II - Table 14.1.6.1 
Prior Medications 
Safety Population 
Part II - Table 14.1.6.2 
Concomitant Medications 
Safety Population 
Part II - Table 14.1.6.3 
Concomitant Medications Taken for Adverse Events 
Safety Population 
Part II - Table 14.1.7.1 
Treatment Compliance 
Safety Population 
Part II - Table 14.1.7.2 
Exposure to Study Drug 
Safety Population 
Part II - Table 14.1.8 
Pregnancy Test Results 
Enrolled Population 


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14.2 EFFICACY SUMMARY FIGURES AND TABLES 
Table 
Title 
Population 
Part II - Table 14.2.1.1.1 
AML Disease Response by Bone Biopsy (IWG 2003) 
mITT Population 
Part II - Table 14.2.1.1.2 
AML Disease Response by Bone Biopsy (IWG 2003) 
PP Population 
Part II - Table 14.2.1.2.1 
MDS Disease Response by Bone Biopsy (IWG 2006) 
mITT Population 
Part II - Table 14.2.1.2.2 
MDS Disease Response by Bone Biopsy (IWG 2006) 
PP Population 
 
 
 
Figure 
Title 
Population 
N/A 
 
 
14.3 SAFETY SUMMARY FIGURES AND TABLES 
14.3.1 
Adverse Events 
Table 
Title 
Population 
Part II - Table 14.3.1.1 
Dose Limiting Toxicities                                               Safety Population 
Part II - Table 14.3.1.2
Details of Dose Limiting Toxicities                              Safety Population 
Part II - Table 14.3.1.3 
Summary of Dose Limiting Toxicities 
Safety Population 
Part II - Table 14.3.1.4
Doses Selected as MTD and RP2D                              Safety Population 
Part II - Table 14.3.1.4.1.1
Frequency and Reasons for Dose 
Delays/Interruptions 
Safety Population 
Part II - Table 14.3.1.4.1.2
Frequency and Reasons for Dose Reductions 
Safety Population 
Part II - Table 14.3.1.4.2.1
Duration of Dose Delays/Interruptions                          Safety Population 
Part II - Table 14.3.1.4.2.2
Duration of Dose Reductions                                        Safety Population 
Part II - Table 14.3.1.5.1
Overview of Adverse Events                                         Safety Population 
Part II - Table 14.3.1.5.2
Treatment Emergent Adverse Events                            Safety Population 
Part II - Table 14.3.1.5.3
Treatment Emergent Adverse Events Leading to 
Premature Discontinuation from the Study 
Safety Population 
Part II - Table 14.3.1.5.4.1
Treatment Emergent Adverse Events Leading to 
Dose Delays 
Safety Population 
Part II - Table 14.3.1.5.4.2
Treatment Emergent Adverse Events Leading to 
Dose Interruptions                                                  
Safety Population 
Part II - Table 14.3.1.5.5
Treatment Emergent Adverse Events Leading to 
Dose Reductions                                                  
Safety Population 
Part II - Table 14.3.1.5.6
Treatment Emergent Adverse Events by 
Relationship to BVD-523                                              
Safety Population 
Part II - Table 14.3.1.5.7.1
Treatment Emergent Adverse Events by Severity         Safety Population 
Part II - Table 14.3.1.5.7.2
Treatment Emergent Adverse Events by ≥Grade 3       Safety Population 
 
Figure 
Title 
Population 
Part II - Figure 14.3.1.5.2
Bar Graph of Treatment Emergent Adverse Events       Safety Population 


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Part II - Figure 14.3.1.5.3
Bar Graph of Treatment Emergent Adverse Events 
Leading to Premature Discontinuation  from the 
Study                                                   
Safety Population 
Part II - Figure 14.3.1.5.5
Bar Graph of Treatment Emergent Adverse Events 
by Relationship to BVD-523                                          
Safety Population 
Part II - Figure 14.3.1.5.7
Bar Graph of Treatment Emergent Adverse Events 
by Severity                                                   
Safety Population 
 
 
 
14.3.2 
Serious Adverse Events, Deaths and Other Significant Adverse Events 
Table 
Title 
Population 
Part II - Table 14.3.2.1
Treatment Emergent Serious Adverse Events  
Safety Population 
Part II - Table 14.3.2.2
Treatment Emergent Serious Adverse Events Leading to 
Premature Discontinuation from the Study                          
Safety Population 
Part II - Table 14.3.2.3.1
Treatment Emergent Serious Adverse Events Leading to 
Dose Delays                                                 
Safety Population 
Part II - Table 14.3.2.3.2
Treatment Emergent Serious Adverse Events Leading to 
Dose Interruptions                                                  
Safety Population 
Part II - Table 14.3.2.4
Treatment Emergent Serious Adverse Events Leading to 
Dose Reductions                                                  
Safety Population 
Part II - Table 14.3.2.5
Treatment Emergent Serious Adverse Events by 
Relationship to BVD-523 
Safety Population 
Part II - Table 14.3.2.6.1
Treatment Emergent Serious Adverse Events by 
Severity 
Safety Population 
Part II - Table 14.3.2.6.2
Treatment Emergent Serious Adverse Events by ≥Grade 
3 Severity 
Safety Population 
Part II - Table 14.3.2.7.1
Deaths 
Safety Population 
Part II - Table 14.3.2.7.2
Deaths by Relationship 
Safety Population 
 
 
 
Figure 
Title 
Population 
Part II - Figure 14.3.2.1
Bar Graph of Treatment Emergent Serious Adverse 
Events                                                   
Safety Population 
Part II - Figure 14.3.2.2 
Bar Graph of Treatment Emergent Serious Adverse 
Events Leading to Premature Discontinuation from 
the Study                                                    
Safety Population 
Part II - Figure 14.3.2.5
Bar Graph of Treatment Emergent Serious Adverse 
Events by Relationship to BVD-523                                
Safety Population 
Part II - Figure 14.3.2.6
Bar Graph of Treatment Emergent Serious Adverse 
Events by Severity                                                  
Safety Population 
14.3.3 
Narratives 
N/A  
 
 
 


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14.3.4 
Laboratory Results 
Table 
Title 
Population 
Part II - Table 14.3.4.1.1 
 
Laboratory Evaluations: Hematology 
Safety Population 
Part II - Table 14.3.4.1.2 
 
Hematology Laboratory Values 
Safety Population 
Part II - Table 14.3.4.2.1 
  
Laboratory Evaluations: Clinical Chemistry  
Safety Population 
Part II - Table 14.3.4.2.2 
  
Clinical Chemistry Laboratory Values      Safety Population 
Part II - Table 14.3.4.3.1 
  
Laboratory Evaluations: Urinalysis 
Safety Population 
Part II - Table 14.3.4.4 
  
Laboratory Evaluations: Bone Marrow 
Aspirate Results                     
Safety Population 
Part II - Table 14.3.4.5 
  
Cytogenetics                       Safety Population 
Part II - Table 14.3.5.1  
Physical Examinations                 Safety Population 
Part II - Table 14.3.5.2 
  
ECOG Performance Status              Safety Population 
Part II - Table 14.3.5.3.1 
  
Electrocardiogram 
Safety Population 
Part II - Table 14.3.5.3.2 
  
Categorized Electrocardiogram  
Safety Population 
Part II - Table 14.3.5.4 
  
Ophthalmological Examinations 
Safety Population 
Part II - Table 14.3.5.5 
  
Vital Sign 
Safety Population 
 
 
 
Figure 
Title 
Population 
N/A 
 
 
 
 
 
14.4 OTHER SUMMARY FIGURES AND TABLES 
Table 
Title 
Populations 
Part II - Table 14.4.1 
  
Pharmacokinetic Parameters from Blood 
PK Population 
Part II - Table 14.4.2 
 
Fluid Pharmacodynamics 
PD Population 
14.5 LISTINGS 
Part II 
16.2.1 Subject Disposition  
Part II – Listing 16.2.1.1 Listing of Subject Disposition 
Part II – Listing 16.2.1.2 Listing of Subject Visits 
16.2.2 Protocol Deviations 
Part II – Listing 16.2.2.1 Listing of Protocol Deviations 
Part II – Listing 16.2.2.2.1 Listing of Inclusion/Exclusion Criteria Deviations - Inclusion 
Part II – Listing 16.2.2.2.2 Listing of Inclusion/Exclusion Criteria Deviations – Exclusion (1) 
Part II – Listing 16.2.2.2.3 Listing of Inclusion/Exclusion Criteria Deviations – Exclusion (2) 


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16.2.3 Subjects Excluded from the Efficacy Analysis 
Part II – Listing 16.2.3.1 Listing of Subjects Excluded  from mITT Population 
Part II – Listing 16.2.3.2 Listing of Subject Excluded  from PP Population 
Part II – Listing 16.2.3.3 Listing of Subject Excluded  from PK Population 
Part II – Listing 16.2.3.4 Listing of Subject Excluded  from PD Population 
16.2.4 Demographic Data 
Part II – Listing 16.2.4.1 Listing of Subject Demographics 
Part II – Listing 16.2.4.2 Listing of Baseline Characteristics 
Part II – Listing 16.2.4.3 Listing of Cytogenetics 
Part II – Listing 16.2.4.4 Listing of Medical History 
Part II – Listing 16.2.4.5 Listing of Previous Cancer Surgery 
Part II – Listing 16.2.4.6 Listing of Previous Stem Cell Transplant 
Part II – Listing 16.2.4.7 Listing of Transfusion/Blood Product Use 
Part II – Listing 16.2.4.8 Listing of Prior MEK Therapies 
Part II – Listing 16.2.4.9 Listing of Previous Medications 
Part II – Listing 16.2.4.10 Listing of Previous Therapies 
Part II – Listing 16.2.4.11 Listing of Concomitant Medications 
Part II – Listing 16.2.4.12 Listing of Concomitant Medication Taken for Adverse Events 
Part II – Listing 16.2.4.13 Listing of On Study Procedures  
16.2.5 Compliance and/or Drug Concentration Data 
Part II – Listing 16.2.5.1 Listing of Exposure to Study Drug 
Part II – Listing 16.2.5.2 Listing of Treatment Compliance  
Part II – Listing 16.2.5.3 Listing of BVD-523 Dose History 
16.2.6 Individual Efficacy Response Data 
Part II – Listing 16.2.6.1 AML Disease Response per IWG 2003 
Part II – Listing 16.2.6.2 MDS Disease Response per IWG 2006 
16.2.7 Adverse Event Listings 
Part II – Listing 16.2.7.1 Listing of Relationship of WHO Drug ATC Classification and Preferred Term with 
Verbatim  
Part II – Listing 16.2.7.2 Listing  of RP2D from Part I 
Part II – Listing 16.2.7.3.1 Listing of Treatment Emergent Adverse Events 
Part II – Listing 16.2.7.3.2 Listing of Treatment Emergent Adverse Events Leading to Premature 
Discontinuation from the Study 
Part II – Listing 16.2.7.3.3 Listing of Treatment Emergent Adverse Events Leading to Study Drug 
Delays/Interruptions and Length of Delays/Interruptions 
Part II – Listing 16.2.7.3.4 Listing of Treatment Emergent Adverse Events Leading to Study Drug 
Reductions and Length of Reductions 


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Part II – Listing 16.2.7.3.5 Listing of Treatment Emergent Adverse Events Related to BVD-523 
Part II – Listing 16.2.7.3.6 Listing of Treatment Emergent Adverse Events by Severity 
Part II – Listing 16.2.7.4 Listing of Treatment Emergent Serious Adverse Events 
Part II – Listing 16.2.7.5 Listing of Deaths 
 
16.2.8 Listings of Individual Laboratory Measurements 
Part II – Listing 16.2.8.1 Listing of Normal Ranges for Laboratory Values 
Part II – Listing 16.2.8.2.1 Listing of Laboratory Evaluations: Hematology Results 
Part II – Listing 16.2.8.2.2 Listing of Abnormal and Clinically Significant Hematology Results 
Part II – Listing 16.2.8.3.1 Listing of Laboratory Evaluations: Clinical Chemistry Results 
Part II – Listing 16.2.8.3.2 Listing of Abnormal and Clinically Significant Clinical Chemistry Results 
Part II – Listing 16.2.8.4.1 Listing of Laboratory Evaluations: Urinalysis Results 
Part II – Listing 16.2.8.4.2 Listing of Abnormal and Clinically Significant Urinalysis Results 
Part II – Listing 16.2.8.5 Listing of Pregnancy Testing Results 
Part II – Listing 16.2.8.6 Listing of Rash Photographs 
Part II – Listing 16.2.8.7.1 Listing of Bone Marrow Aspirate / Biopsy Sample 
Part II – Listing 16.2.8.7.2 Listing of Bone Marrow Aspirate / Biopsy Results (1) 
Part II – Listing 16.2.8.7.3 Listing of Bone Marrow Aspirate / Biopsy Results (2) 
Part II – Listing 16.2.8.7.4 Listing of Bone Marrow Aspirate / Biopsy Results (3) 
Part II – Listing 16.2.8.7.5 Listing of Bone Marrow Aspirate / Biopsy Results (4) 
Part II – Listing 16.2.4.8 Listing of Vital Sign  
Part II – Listing 16.2.4.9 Listing of Physical Examinations  
Part II – Listing 16.2.4.10 Listing of ECOG Performance Status 
Part II – Listing 16.2.4.11 Listing of Electrocardiograms  
Part II – Listing 16.2.4.12 Listing of Ophthalmology Examination  
16.2.9 Other Listings 
Part II – Listing 16.2.9.1 Listing of Pharmacokinetic Concentration Measured from Blood  
Part II – Listing 16.2.9.2 Listing of Pharmacokinetic Parameters 
Part II – Listing 16.2.9.3 Listing of Pharmacodynamics 
 


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15 REVISIONS TO SAP 
The SAP dated 09DEC2015 was finalized/signed for Part 1, under protocol amendment 2.  This 
version of the SAP has been revised to update the list of TFL shells for Part 2. 


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16 REFERENCES 
Bruce D et al.  Revised Response Criteria for Malignant Lymphoma.  J Clin. Oncol. 2007; 
25(5):579-586. 
 
Cheson BD et al.  International Working Group for Diagnosis, Standardization of Response 
Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia.  Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia.  J Clin Oncol.  2003;21(24): 4642-4649. 
 
US FDA 1999, Guidance for Industry: Population Pharmacokinetics. February 1999. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm072137.pdf