Conditions: Pancreatic Cancer Cancer of Pancreas Cancer of the Pancreas Pancreas Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
In light of the central role of extracellular signal-regulated kinases (ERK) in pancreatic cancer, the investigators propose a phase I study to evaluate the ERK inhibitor BVD-523 at the recommended phase 2 dose in combination with nab-paclitaxel plus gemcitabine in patients with newly diagnosed metastatic pancreatic cancer. The primary endpoint will be maximum tolerated dose (MTD) or RP2D and safety. The secondary endpoints include safety, response rate, biochemical response, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints include the assessing the impact of BVD-523 on the MEK/ERK pathway and other major pathway pertain to pancreatic cancer.

Detailed description:

Arms:
arm 1: * Treatment will be given in a 28-day cycle.
* BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals).
* BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel.
* Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes.
* Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes.
* Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in. arm 2: * Treatment will be given in a 28-day cycle.
* First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
* Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
* Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)

Interventions: intervention 1: BVD-523 intervention 2: Nab-paclitaxel intervention 3: Gemcitabine intervention 4: Tumor biopsy
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_001.pdf: 
Protocol Version: 07/07/20 
 
Page 1 of 53 
 
 
Phase Ib study of BVD-523 plus nab-paclitaxel and gemcitabine in patients with metastatic 
pancreatic cancer 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201601098 
Version Date: 07/07/20 
 
Principal Investigator: 
Kian-Huat Lim, M.D., Ph.D. 
Phone: 314-362-6157 
E-mail:  kian-huat.lim@wustl.edu  
 
Sub-Investigators 
 
 
Modality 
Manik Amin, M.D. 
 
 
Medical Oncology 
Caron Rigden, M.D.   
 
Medical Oncology 
Kathryn Robinson, M.D. 
 
Radiology 
Rama Suresh, M.D.   
 
Medical Oncology 
Ben Tan, M.D.  
 
 
Medical Oncology 
Esther Lu, PhD 
 
 
Biostatistician  
Katrina Pedersen, MD 
 
Medical Oncology  
Nikolaos Trikalinos  
 
Medical Oncology 
 
Study Drug(s): 
 
BVD-523 (Ulixertinib) 
Gemcitabine (Gemzar) 
nab-Paclitaxel (Abraxane) 
 
IND #: 
128823 
ClinicalTrials.gov #: 
NCT02608229 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


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Phase Ib study of BVD-523 plus nab-paclitaxel and gemcitabine in patients with metastatic 
pancreatic cancer 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
02/03/16 
Amendment #1 Version 
 
 
 
 
 
 
08/16/16 
Amendment #2 Version 
 
 
 
 
 
 
10/10/16 
Amendment #3 Version  
 
 
 
 
 
 
12/07/16 
Amendment #4 Version 
 
 
 
 
 
 
10/09/18 
Amendment #5 Version 
 
 
 
 
 
 
07/07/20 
 
 
 
 
 
 
 
 
 
 


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Phase Ib study of BVD-523 plus nab-paclitaxel and gemcitabine in patients with metastatic 
pancreatic cancer 
 
 
SCHEMA 
 
Dose De-escalation Cohort 
 
Expansion Cohort 
 
 
 
 
 


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Glossary of Abbreviations 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
CBC 
Complete blood count 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GFR 
Glomerular filtration rate 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ILLN 
Institutional lower limit of normal 
IULN 
Institutional upper limit of normal 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal investigator 
PR 
Partial response 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SD 
Stable disease 
UPN 
Unique patient number 
 


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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 7 
1.1 
Pancreatic Cancer ............................................................................................................. 7 
1.2 
Front-Line Treatment in Metastatic Pancreatic Cancer ................................................... 7 
1.3 
RAS/RAF/MEK/ERK Pathways as a Valid Target for Pancreatic Cancer ...................... 7 
1.4 
BVD-523 (Ulixertinib) ..................................................................................................... 8 
1.5 
Study Rationale .............................................................................................................. 13 
1.6 
Correlative Studies Background..................................................................................... 14 
2.0 
OBJECTIVES .................................................................................................................... 14 
2.1 
Primary Objective .......................................................................................................... 14 
2.2 
Secondary Objectives ..................................................................................................... 14 
2.3 
Exploratory Objectives ................................................................................................... 15 
3.0 
PATIENT SELECTION .................................................................................................... 15 
3.1 
Inclusion Criteria ............................................................................................................ 15 
3.2 
Exclusion Criteria ........................................................................................................... 16 
3.3 
Inclusion of Women and Minorities ............................................................................... 17 
4.0 
REGISTRATION PROCEDURES ................................................................................... 17 
4.1 
Confirmation of Patient Eligibility ................................................................................. 17 
4.2 
Patient Registration in the Siteman Cancer Center Oncore Database ............................ 17 
4.3 
Assignment of UPN ....................................................................................................... 17 
5.0 
TREATMENT PLAN ........................................................................................................ 17 
5.1 
Agent Administration ..................................................................................................... 18 
5.2 
Dose Schema .................................................................................................................. 18 
5.3 
Definition of MTD, DLT, Dose Escalation Criteria, and Toxicity, Response, and DLT 
Evaluations ................................................................................................................................ 19 
5.4 
Dose Expansion Cohort .................................................................................................. 20 
5.5 
General Concomitant Medication and Supportive Care Guidelines .............................. 20 
5.6 
Women of Childbearing Potential .................................................................................. 21 
5.7 
Duration of Therapy ....................................................................................................... 21 
5.8 
Duration of Follow-up .................................................................................................... 22 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 22 
6.1 
Dose Modifications for BVD-523 .................................................................................. 22 
6.2 
Dose Modifications for Gemcitabine and Nab-Paclitaxel.............................................. 22 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 23 
7.1 
Definitions ...................................................................................................................... 24 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
26 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 26 
7.4 
Reporting to the FDA ..................................................................................................... 26 
7.5 
Reporting to Biomed Valley Discoveries, Inc. .............................................................. 27 
7.6 
Timeframe for Reporting Required Events .................................................................... 27 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 27 
8.1 
BVD-523 (Ulixertinib) ................................................................................................... 27 
8.2 
Gemcitabine (Gemzar) ................................................................................................... 28 


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8.3 
Nab-Paclitaxel (Abraxane) ............................................................................................. 30 
9.0 
CORRELATIVE STUDIES .............................................................................................. 32 
9.1 
Fresh Biopsies ................................................................................................................ 32 
10.0 STUDY CALENDAR ....................................................................................................... 33 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 34 
12.0 MEASUREMENT OF EFFECT........................................................................................ 34 
12.1 Antitumor Effect – Solid Tumors ................................................................................... 34 
12.2 Disease Parameters ......................................................................................................... 34 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 35 
12.4 Response Criteria ........................................................................................................... 37 
13.0 DATA AND SAFETY MONITORING ............................................................................ 40 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 40 
14.1 Study Endpoints ............................................................................................................. 41 
14.2 Sample Size Estimates ................................................................................................... 41 
14.3 Accrual ........................................................................................................................... 41 
14.4 Toxicity Monitoring ....................................................................................................... 41 
14.5 Statistical Analysis ......................................................................................................... 41 
15.0 REFERENCES .................................................................................................................. 43 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 45 
APPENDIX B: NON-PERMITTED CONCOMITANT MEDICATIONS ................................. 46 
APPENDIX C: PATIENT’S MEDICATION DIARY ................................................................. 47 
APPENDIX D: BIOMED VALLEY SAE FORM ....................................................................... 48 
APPENDIX E: BIOMED VALLEY PREGNANCY REPORT FORM ...................................... 51 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Pancreatic Cancer 
 
Pancreatic cancer remains the fourth leading cause of cancer-related mortality in 2013 in 
the United States (1) . Surgery is the only curative treatment; however, owing to the paucity 
of early detection methods, about 80% of pancreatic cancer patients are found to have 
unresectable or metastatic disease at the time of diagnosis, and their 5-year survival rate is 
less than 6% (1) .  Novel therapy for pancreatic cancer is desperately needed. 
 
1.2 
Front-Line Treatment in Metastatic Pancreatic Cancer 
 
Gemcitabine has been the cornerstone treatment for patients with pancreatic cancer since 
1997, after it showed a modest survival advantage and better control of disease-related 
symptoms when compared with fluorouracil (5-FU) in a large randomized phase III clinical 
trial (2).  The median overall survival (OS) was 5.65 months for gemcitabine-treated 
patients and 4.41 months for 5FU-treated patients (P=0.0025) (2). During the last decade, 
gemcitabine was combined with various drugs including platinum compounds, taxanes, 
topoisomerase inhibitors, and targeted therapies; however, the only combination that has 
resulted in a meaningful clinical survival advantage was nab-paclitaxel plus gemcitabine 
(3). Comparing with gemcitabine as a single agent, patients received the nab-paclitaxel 
plus gemcitabine had resulted superior survival benefit (8.5 months vs. 6.7months; hazard 
ratio (HR): 0.72; P<0.001).  The progression-free survival (PFS) was also superior in the 
combination arm (5.5 months vs. 3.7 months; HR 0.69; P<0.001) (3). The combination of 
nab-paclitaxel plus gemcitabine has become a viable front-line therapy in patient with 
metastatic pancreatic cancer.  
 
FOLFIRINOX (5-FU, leucovorin, oxaliplatin and irinotecan) is another treatment option 
has shown survival benefit compared with gemcitabine alone.  Based on the ACCORD 
study, FOLFIRINOX resulted in superior median OS (11.6 months vs. 6.8 months; HR: 
0.57; P<0.0001), and superior PFS (6.4 months vs. 3.3 months; HR 0.47; P<0.001) (4); 
however, the regimen was associated with moderate hematological and non-hematological 
toxicities.  Thus, FOLFIRINOX is reserved for patients with good performance status (PS), 
and the adoption of this regimen as the front-line therapy is rather limited.  
 
Although there are two options in the front-line setting for patients with metastatic 
pancreatic cancer, nab-paclitaxel plus gemcitabine has been used wildly because of better 
tolerability; therefore, the combination has been favored as the backbone regimen for 
adding novel therapy to enhance efficacy.  
 
1.3 
RAS/RAF/MEK/ERK Pathways as a Valid Target for Pancreatic Cancer 
 
It is well known that the K-RAS mutation remains the predominant feature of pancreatic 
cancer molecular pathogenesis.  Functional K-ras is a member of the GTP binding protein 
family, the members of which convert extracellular signals into intracellular signals by 


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cycling between the active (Ras-GTP) and inactive (Ras-GDP) states.  Mutated K-ras 
results in constant activation of the Ras pathway by locking Ras into the active GTP-
binding state and further triggering downstream multiple signaling pathways including cell 
proliferation, apoptosis, differentiation and survival (5,6). The K-RAS mutation is 
implicated in tumor initiation (7)  and maintenance (8) , and the presence of the K-RAS 
mutation was detected in 30% of pre-malignant pancreatic lesions (9) and 90% of 
pancreatic cancer specimens (10).  The crucial function of K-ras activation in cancer has 
led to the various strategies developed to down-regulate K-ras; however, the initial 
enthusiasm for this approach has been dampened by inherent complexities in the pathway. 
For example, attempts to block the post-translational modification of K-ras have not 
resulted in any clinical benefit (11).  
 
Difficulty in targeting K-ras has led to an examination of its downstream pathways. 
Research has focused on evaluating inhibitors that block two main K-ras downstream 
signaling pathways: the phosphatidylinositol 3-kinase (PI3K) pathway and the 
RAF/MEK/ERK pathway. Various inhibitors targeting crucial mediators of both pathways 
have been developed in the preclinical and clinical setting. Among them, RAF and MEK 
inhibitors did not demonstrate any significant activity in pancreatic cancer patients (12,13).  
A recent study has suggested that there were several mechanisms of MEK resistance 
including mutation in the binding site of MEK or concurrent upstream amplification of 
KRAS mutation (ref).  ERK inhibition may overcome MEK resistance regardless of the 
resistance mechanism (14). In parallel, a similar study reported rapid ERK activation may 
contribute the resistance of RAF inhibitor (15).  ERK is not only a key effector of the 
crucial pathway in pancreatic cancer, but it is also involved in resistance to RAF and MEK 
inhibitor (16); Therefore, developing ERK inhibitors for pancreatic cancer is a logical and 
promising therapeutic strategy.  In pancreatic cancer cell lines, inhibition of the MEK/ERK 
pathway leads to cell cycle arrest and apoptosis (17,18). Anti-tumor activity resulting from 
ERK inhibition has been seen in human orthotoptic primary pancreatic cancer xenografts, 
strengthening the argument for further development and investigation of ERK inhibitors in 
pancreatic cancer. At present, three small molecules targeting ERK have entered in early 
phase clinical trials.  
 
1.4 
BVD-523 (Ulixertinib) 
 
BVD-523 (BioMed Valley Discoveries, Kansas City) is a small molecule that targets ERK1 
and ERK2 in the sub-nanomolar range.  It is a reversible, ATP-competitive kinase inhibitor 
that selectively inhibits ERK1 and ERK2 without any significant effect on the 75 other 
human kinases (Investigator Brochure, BioMed Valley Discoveries, 2012).  BVD-523 has 
shown potent anti-tumor effects against pancreatic cancer cell lines and pancreatic tumor 
xenografts.  BVD-523 is the leading ERK inhibitor to enter the oncology clinical study.  
The multi-site phase I trial of BVD-523 in patients with solid tumors is ongoing 
(NCT#01781429). 
 
 


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1.4.1 Preclinical Data 
 
In the following sections a short summary of preclinical data is provided.  Detailed 
information is presented in the BVD-523 Investigator’s Brochure.  
 
1.4.1.1 Potential Risk 
 
Preliminary evidence from in vitro and in vivo toxicological assessments of 
BVD-523 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 are mechanistically attributable to MAPK pathway 
inhibition.  
 
Thus, BVD-523’s risk profile 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, 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. 
 
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  


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BVD-523 will be further minimized 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. 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. The severity and 
reversibility of these toxicities, though, are viewed so as to not merit a 
specific monitoring or treatment plan, despite the possibility that GI toxicity 
may be observed during the proposed clinical study.  
 
QTc Prolongation 
The balance of preclinical evidence suggests BVD-523 has low, but 
observable, potential to cause QT prolongation. Given potentially unique 
species sensitivity, as well as possibly unknown consequences following 
chronic dosing, patients dosed with BVD-523 will be monitored for 
potential QTc prolongation and related cardiotoxicities.  
 
Tissue Mineralization 
Tissue mineralization has been observed in rodent toxicology studies of 
BVD-523. The incidence and severity of mineralization was dose-
dependent and effects were observed in 1 or more tissues at toxic doses. In 
animals in which mineralization occurred after treatment 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.  


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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.  
 
1.4.1.2 Pharmacology Studies 
 
BVD-523 is highly efficacious in vivo when administered as a single agent 
in ectopic xenograft models of colon, pancreatic and melanoma cancers, 3 
tumor types in which ERK is known to be highly activated. Notably, partial 
regression was achieved in a colon cancer model (Colo205) when the 
compound was administered at 50 mg/kg (b.i.d.). Biomarker analyses 
confirmed that improved efficacy obtained at higher doses of BVD-523 
correlated with increasing ERK inhibition. 
 
1.4.1.3 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, so BVD-523 is not considered to 
have a significant genetic toxicology risk.  
 
While BVD-523 modestly inhibits the hERG current (IC50 3.4 μM ), no 
significant effects were seen in action potentials recorded from dog Purkinje 
fibers exposed to up to 10 μg/mL, and no significant cardiovascular findings 
were observed upon acute oral dosing of the compound at dose levels up to 
50 mg/kg in dogs (Cmax = 17.3 μM). Thus BVD-523 is considered to have 
a low potential to cause QT prolongation in patients, but, as stated, the study 
will monitor for signs of cardiovascular effects of BVD-523 in humans.  
 
No significant cytochrome P450 (CYP) inhibition has been observed with 


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the compound. In vitro studies suggest that the compound is metabolized 
primarily via oxidation by multiple CYPs, including 3A4, 2D6, and 1A2. 
Furthermore, no significant CYP induction was observed after up to 14 days 
drug treatment in rats, nor during in vitro studies with human hepatocytes. 
These data suggest a limited potential for drug-drug interactions. 
 
BVD-523 HCl salt is orally available in multiple species (absolute 
bioavailability %F = 23% in dog to 100 % in monkey) when formulated as 
a simple suspension in 1% carboxymethylcellulose (CMC) and has a half-
life of 2−4 hours across all species.  
 
BVD-523 was administered to male and female Sprague-Dawley rats in 
several toxicology studies: a GLP study for up to 28 days at dose levels up 
to 50 mg/kg/day twice daily; for up to 14 days at dose levels up to 100 
mg/kg twice daily; and for up to 5 days at dose levels up to 150 mg/kg/dose 
once daily. The incidence and severity of mineralization seen in these 
studies was dose-dependent and effects were observed in 1 or more tissues 
at toxic doses. In animals in which mineralization occurred after treatment 
with BVD-523, significantly increased serum phosphorus and modestly 
decreased serum calcium were seen; these effects were not observed in 
animals in which there was no mineralization. Therefore, the risk of tissue 
mineralization can be assessed by serum phosphorus and calcium 
monitoring. A clinical monitoring strategy similar to this was previously 
employed for related drugs that target the MAPK pathway because those 
compounds likewise elicited mineralization in rodents.  
 
When BVD-523 was administered to male and female Sprague-Dawley rats 
for up to 28 days at a dose level of 25 or 50 mg/kg twice daily, it was poorly 
tolerated. Although most clinical signs and clinical pathology findings 
reversed following 4 weeks of recovery, skin lesions and histopathology 
findings persisted in many tissues at both dose levels after the recovery 
phase. Based on these findings, 25 and 50 mg/kg twice daily dose levels 
were considered severely toxic. Administration of 12.5 mg/kg twice daily 
for 28 days was generally well-tolerated by rats of both sexes; however, this 
dose level was associated with test article-related findings that included: 
swelling in the neck; decreased forelimb strength; multiple clinical 
pathology findings; enlarged lymph nodes, spleen, and mammary gland. 
Based on these findings, the severely toxic dose in 10% of the animals 
(STD10) for BVD-523 when administered for up to 28 days in Sprague-
Dawley rats is 12.5 mg/kg given twice daily (25 mg/kg/day). On Day 28 of 
the dosing phase, this dose level corresponded with a Cmax of 28700 and 
15323 ng/mL and AUC 0-12 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 


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toxicity profile observed shows that BVD-523 was well tolerated in dogs. 
The rat was designated the most sensitive species and rat data were used to 
calculate the starting dose in man. 
 
BVD-523 has a measured UV absorbance at 320 nm, which means that it 
can absorb both UV-A and UV-B. BVD-523 may therefore act as a 
photosensitizing agent in man.  
 
Based on the data accumulated to date, BVD-523 possesses a toxicology 
profile which presents no impediment to its development as an anti-cancer 
agent. 
 
For further information, please refer to the BVD-523 Investigator’s 
Brochure.  
 
1.4.2 Clinical Evaluation  
 
The first-in-class phase I trial of BVD-523 in patients with advanced solid tumors 
is ongoing.  The primary objective of the study is to define the safety and tolerability 
of BVD-523 by determining the dose-limiting toxicity (DLT), the maximum 
tolerated dose (MTD), and the RP2D.  The study has successfully determined that 
the MTD of BVD-523 is 600 mg twice daily.  The DLT at MTD was a grade 3 rash. 
Pharmacokinetic study showed linear and dose proportional up to 600 mg twice 
daily.  Additionally, phosphorylation of ERK substrate RSK was inhibited in 
peripheral blood samples starting at 75 mg twice daily. Metabolic response was 
observed in 5 out 16 evaluable patients assessed by FDG-PET.  Three of 25 patients 
had partial response according to the RECIST 1.1, and 7 had stable disease for at 
least 3 months.  So far, the clinical data suggested that BVD-523 achieved 
pharmacologically relevant exposure, and resulted in early signal of clinical 
efficacy.    
 
1.5 
Study Rationale 
 
In light of the central role of ERK in pancreatic cancer, we propose a phase I study to 
evaluate the ERK inhibitor BVD-523 at the RP2D in combination with nab-paclitaxel plus 
gemcitabine in patients with newly diagnosed metastatic pancreatic cancer.  The primary 
endpoint will be MTD or RP2D and safety. The secondary endpoints include safety, 
response rate, biochemical response, PFS and OS. The exploratory endpoints include the 
assessing the impact of BVD-523 on the MEK/ERK pathway and other major pathway 
pertain to pancreatic cancer. 
 
 


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1.6 
Correlative Studies Background 
 
1.6.1 Pharmacodynamics markers evaluation   
 
Since ERK is a valuable therapeutic target in pancreatic cancer, it is crucial to 
evaluate whether BVD-523 has reached its respective target in tumor. In pancreatic 
cancer, the drug delivery is extremely crucial given the tumor cells are nested in the 
dense stroma.  It is known that the  effectors of signaling pathways are primarily 
activated through phosphorylation; therefore, the ability to evaluate the 
phosphorylation status of effectors involved in signaling pathways are essential in 
understanding whether the targeted therapy has reached its target, and furthermore, 
how the complex signaling network responds to a specific pathway inhibitor, such 
as BVD-523.  In the proposed study, we plan to compare the major effectors of 
KRAS pathways including the phosphorylation of ERK substrate RSK (pRSK) on 
the biopsies done prior and post two weeks administration of single agent BVD-
523.   
 
1.6.2 Determinations of genetic predictors associated with treatment 
response 
 
The biopsy obtained at baseline and at the end of the second cycle (expansion 
cohort) of therapy will be collected for molecular correlative study. Gene 
expression levels will be determined by either RNASeq or transcriptome analysis, 
the changes   between the paired biopsies will be correlated with treatment 
response.  Exome sequencing will be performed to determine whether a particular 
set of genetic alterations would predict treatment response and resistance.  The 
phosphorylation protein by proteomic approach will be compared to investigate 
whether certain signaling pathway activation could contribute treatment response 
or resistance.  Other molecular analysis may be entertained based on the funding 
availability 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the MTD or RP2D of BVD-523 in combination with nab-paclitaxel and 
gemcitabine in patients with metastatic pancreatic cancer. 
 
2.2 
Secondary Objectives 
 
1. To evaluate the safety and toxicity profile of BVD-523 in combination with nab-
paclitaxel and gemcitabine. 
2. To determine biochemical response of BVD-523 in combination with nab-paclitaxel 
and gemcitabine. 


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3. To determine response rate of BVD-523 in combination with nab-paclitaxel and 
gemcitabine. 
4. To determine time to tumor progression of BVD-523 in combination with nab-
paclitaxel and gemcitabine. 
5. To determine PFS of BVD-523 in combination with nab-paclitaxel and gemcitabine. 
6. To determine OS of BVD-523 in combination with nab-paclitaxel and gemcitabine. 
 
2.3 
Exploratory Objectives 
 
1. To assess pharmacodynamics biomarkers of BVD-523 in tumors. 
2. To explore the biomarkers and genetic alterations associated with treatment response.   
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed newly diagnosed treatment-naïve metastatic 
adenocarcinoma of the pancreas with metastatic disease diagnosed no more than 6 
weeks prior to enrollment.  Patients with advanced pancreatic cancer progressed on 5-
FU (or capecitabine) based regimen will be allowed in the expansion cohort. 
 
2. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI, as ≥ 20 
mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. 
 
3. At least 18 years of age. 
 
4. Life expectancy > 3 months. 
 
5. ECOG performance status ≤ 1 (see Appendix A) 
 
6. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mcL 
b. Platelets ≥ 100,000/mcL 
c. Hemoglobin ≥ 9.0 g/dL 
d. Total bilirubin ≤ IULN 
e. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, unless there are liver metastases in which 
case AST and ALT ≤ 5.0 x IULN 
f. Creatinine ≤ 1.5 x IULN OR GFR of ≥ 50 mL/min 
g. Cardiac function ≥ ILLN, e.g., LVEF of > 50% as assessed by MUGA or ECHO, 
QTc < 470 ms 
 
7. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry, for the 
duration of study participation, and for three months following study discontinuation.  


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Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she must inform her treating physician immediately. 
 
8. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Current use or anticipated need for alternative, holistic, naturopathic, or botanical 
formulations used for the purpose of cancer treatment. 
 
2. A history of other malignancy with the exception of those treated with curative intent 
with no evidence of disease for 2 years. 
 
3. Currently receiving any other investigational agents. 
 
4. Known brain metastases or CNS involvement. 
 
5. Significant ascites that require therapeutic paracentesis. 
   
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to BVD-523, gemcitabine, nab-paclitaxel, or other agents used in the 
study. 
 
7. Neuropathy ≥ grade 2. 
 
8. History or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR). 
 
9. History of interstitial lung disease or pneumonitis. 
 
10. Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, 
and CYP3A4, or strong inducers of CYP3A4 (see Appendix B). 
 
11. Gastrointestinal condition which could impair absorption of BVD-523 or inability to 
ingest BVD-523. 
 
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
13. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 7 days of study entry. 
 
14. Known HIV-positivity. 
 


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3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Oncore Database 
 
All patients must be registered through the Siteman Cancer Center database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
This is a phase Ib study of BVD-523 in combination with nab-paclitaxel and gemcitabine in 
patients with metastatic pancreatic adenocarcinoma.  The trial comprises two parts, a dose de-
escalation part and a cohort expansion part at the RP2D. We propose to do a dose de-escalation 
design because of minimal overlapping toxicities between BVD-523 and nab-paclitaxel and 
gemcitabine. The dose de-escalation portion will have a run-in with BVD-523 given as a single 
agent for two weeks prior to initiating the triple drug combination.  A modified Fibonacci design 
will be used for the phase Ib study, starting with a cohort of 6 patients at the target dose 


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combination level. If 0 or 1 out of 6 patients experiences DLT at this level, it will be used for the 
expansion cohort portion.  If 2 DLTs are observed, the dosing of BVD-523 will de-escalate with a 
new cohort of 6 patients. The maximal number of patients needed for this part is 18 and the 
minimal number of patients is 6.  After the determination of MTD, the remaining patients (total 
N=25) will be enrolled to the expansion cohort. 
  
5.1 
Agent Administration 
 
Treatment will be given in a 28-day cycle.  BVD-523 is an oral drug which will be given 
at the protocol-dictated dose on a twice daily basis (at approximately 12-hour intervals).  
Phase Ib patients will take BVD-523 at 450 mg twice daily on its own for two weeks before 
initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel.  BVD-523 should be 
taken in a fasted state (one hour before food or two hours after food).  All capsules should 
be taken within 10 minutes with 8 ounces of water.  If a patient misses a dose, s/he should 
not make up that dose but simply resume dosing with the next scheduled dose.  Patients 
will be instructed to bring all unused capsules and their medication diary (Appendix C) to 
each study visit for an assessment of compliance. 
 
Nab-paclitaxel will be given at a dose of 125 mg/m2 on Days 1, 8, and 15 of each 28-day 
cycle over the course of 30-40 minutes Gemcitabine will be given at a dose of 1000 mg/m2 
on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. 
 
The study has enrolled two patients at level 1 dose in group B arm. Although there was no 
DLT encountered in those two patients, none of them could complete two cycles for 
evaluation of treatment assessment. One patient experienced pneumonitis related to 
gemcitabine and subsequently enrolled in the hospice care. The second patient withdrew 
from the study due to a constellation of low-grade adverse events such as fatigue, fever and 
rash et al.  The patient also had a 3-hour drive, which also contributed to his decision of 
withdrawing from the study.  After discussing with other investigators in the team, the PI 
felt that it is reasonable to start with level -1 dose of BVD-523 at 450 mg twice daily. The 
study will also include patients who progressed on 5-FU based therapy for the expansion 
cohort. 
 
5.2 
Dose Schema 
 
Dose De-Escalation Schedule 
 
BVD-523 
Gemcitabine 
Nab-paclitaxel 
Level -2 
300 mg BID 1000 mg/m2  
Days 1, 8, and 15 
125 mg/m2 
Days 1, 8, and 15 
Level -1 
450 mg BID 
Level 1 (Starting Dose) 
600 mg BID 
              
 
              
Dose Escalation Schedule (Expansion Cohort) 
 
BVD-523 
BID 
Gemcitabine  
Day 1, 8 and 15 
Nab-paclitaxel 
Day 1, 8 and 15 


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Level -1 
300 mg  
800 mg/m2 
100 mg/m2 
Level 1(starting dose) 
450 mg 
800 mg/m2 
100 mg/m2 
Level 2 
450 mg 
1000 mg/m2 
125 mg/m2 
 
Dose escalation for the expansion cohort will not occur until all patients in the cohort have 
completed the first cycle and the Principal Investigator has been able to review all 
toxicities. 
 
5.3 
Definition of MTD, DLT, Dose Escalation Criteria, and Toxicity, Response, 
and DLT Evaluations 
 
5.3.1 Definition of Maximum Tolerated Dose (MTD) 
 
The maximum tolerated dose (MTD) is defined as the Dose Level 1 if 0 or 1 DLTs 
are seen in patients at that dose level or Dose Level -1 if 2+ DLTs are seen in Dose 
Level 1 but only 0 or 1 DLTs are seen in patients at Dose Level -1.  If 2+ DLTs are 
seen in patients at Dose Level -1, the study will be suspended so that further dose 
reductions may be planned prior to enrolling to the expansion cohort. 
 
5.3.2 Dose Limiting Toxicities (DLTs) 
 
Nab-paclitaxel plus gemcitabine is the standard front-line therapy in patients with 
metastatic pancreatic cancer, and the combination has been frequently used as a 
backbone for novel therapy combination.  The toxicity profile of nab-paclitaxel plus 
gemcitabine is well known.  This study is to determine the dose levels for the triple 
drug combination, so only DLTs occurring during the first cycle of the triple 
regimen administration will be considered.   Events that occur prior to the start of 
gemcitabine and nab-paclitaxel will not be considered DLTs. 
 
DLT is defined as BVD-523-related toxicity that occurs during the first cycle that 
results in: 
• ≥ grade 4 hematologic toxicity.   
• ≥ grade 3 hematologic toxicity with complications, e.g., thrombocytopenia 
with bleeding 
• ≥ grade 3 non-hematologic toxicity, except untreated nausea, vomiting, 
constipation, pain, and rash (these become DLTs if the AE persists despite 
adequate treatment), or a doubling of AST/ALT in patients with grade 2 
ALT/AST at baseline 
• ≥ grade 3 nausea, vomiting and diarrhea greater than 72 hours despite 
adequate treatment 
• A treatment interruption exceeding 14 days  in Cycle 1, or inability to being 
Cycle 2 for > 14 days due to BVD-523-related toxicity 
• Any toxicity that attributed to BVD-523 that resulted in delay of nab-
paclitaxel and gemcitabine  by more than 4 weeks 
 
5.3.3 Dose Escalation Criteria 


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Dose escalations (expansion cohort) will proceed as follows: 
Number of Patients 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
0 out of 6 
Enter 6 patients at the next dose level. 
>2 
Dose escalation will be stopped.  Prior dose level is 
defined as MTD or RP2D. 
<1 out of 6 at highest 
dose level below the 
maximally 
administered dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
 
5.3.4 Toxicity, Response, and DLT Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients 
are evaluated from first receiving study treatment until a 30-day follow up after the 
conclusion of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment 
due to treatment related adverse events(s) prior to completion of Cycle 2 and have 
not had any disease assessment. 
 
A patient is evaluable for DLT assessment only during Cycle 1 of treatment (not 
including the lead-in prior to the start of gemcitabine and nab-paclitaxel).  Patients 
experiencing excessive toxicity during the lead-in will be replaced and will not be 
considered evaluable for DLT assessment.  If the patient is not able to be treated on 
Day 1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and can 
experience a DLT.  Once the patient has been treated in Cycle 2, s/he will no longer 
be evaluated for DLTs in all subsequent cycles.   
 
5.4 
Dose Expansion Cohort 
 
The dose expansion cohort will have a dose escalation schema with level 1 and level 2 dose 
levels planned (see 5.2). After determination of the MTD, additional patients (so that the 
total enrolled is 25) will be enrolled at the MTD. These patients will not have the 2-week 
BVD-523-only lead-in. In light of a lead-in study, to ensure the adequate assessment of 
toxicity and safety, the study has a stopping rule in the expansion cohort.      
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive care will be administered as per routine practice. This typically will include 
loperamide as needed for diarrhea, and antiemetic medication for symptoms of nausea or 
emesis. Intravenous fluid support will be provided at the discretion of the treating physician 


Protocol Version: 07/07/20 
 
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for patients who experience significant nausea, emesis, or diarrhea.  For grade 3 or greater 
skin toxicity, dermatology consult is recommended.  Oral antibiotics (such as minocycline 
or doxycycline should be considered at any sign of rash.  Topical cleomycin should also 
be considered at the first sign of rash. 
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 7 days prior to the first dose of study treatment.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 3 months following the last dose of study treatment.  
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 


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Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.8 
Duration of Follow-up 
 
Patients will be followed every month for 2 years or until death, whichever occurs first.  
Patients removed from study for unacceptable adverse events that are considered treatment-
related will be followed until resolution or stabilization of the adverse event. 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications for BVD-523 
 
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 will be at the next lower dose level tested (450 mg BID 
if 600 mg BID was the starting dose, 300 mg BID if 450 mg BID was the starting dose).  
 
Rash is quite common in patients receiving BVD-523. With the first onset of rash, it is 
important to consult dermatology for better management.  
 
6.2 
Dose Modifications for Gemcitabine and Nab-Paclitaxel 
 
Dose Level 
Gemcitabine 
Nab-Paclitaxel 
Full dose 
1000 mg/m2 
125 mg/m2 
1st dose reduction 
800 mg/m2 
100 mg/m2 
2nd dose reduction 
600 mg/m2 
75 mg/m2 
If additional dose 
reduction required 
Discontinue or further possible 
dose reduction at the discretion 
of the PI. 
 
Dose Modifications for Neutropenia and/or Thrombocytopenia 
Cycle Day 
ANC 
(cells/mm3) 
 
Platelet count 
(cells/mm3) 
Dosing Adjustment 
Day 1 
< 1500 
OR 
< 100,000 
Delay doses until 
recovery 
Day 8 
500 to < 1000 
 
OR 50,000 to < 75,000 Reduce 1 dose level 
< 500 
OR 
< 50,000 
Withhold doses1  
Day 15 
if Day 8 doses were reduced or 
given without modification 
500 to < 1000 
OR 50,000 to < 75,000 Reduce 1 dose level 
from Day 8 
< 500 
OR 
< 50,000 
Withhold doses1 
Day 15 
if Day 8 doses were withheld 
≥ 1000 
OR 
≥ 75,000 
Reduce 1 dose level 
from Day 1 
 


Protocol Version: 07/07/20 
 
Page 23 of 53 
500 to < 1000 
OR 50,000 to < 75,000 Reduce 2 dose levels 
from Day 1 
 
< 500 
OR 
< 50,000 
Withhold doses1 
 
 
1 Doses held during a cycle (i.e. D8 or D15) will not be made up. 
 
Dose Modifications for Other Treatment Related Adverse Drug Reactions 
Adverse Drug Reaction 
Gemcitabine 
Nab-Paclitaxel 
Febrile neutropenia 
(Grade 3 or 4) 
Withhold until fever resolves and ANC ≥ 1500; resume at 
next lower dose level 
Peripheral neuropathy (Grade 2) No dose reduction 
Dose reduction allowed PI 
discretion 
Peripheral neuropathy 
(Grade 3 or 4) 
 No dose reduction 
 Withhold until improves to ≤ 
grade 1; resume at next lower 
dose level 
Cutaneous toxicity 
(Grade 2 or 3) 
Reduce to next lower dose level; discontinue treatment if 
toxicity persists 
Gastrointestinal toxicity 
(Grade 3 mucositis or diarrhea) 
Withhold until improves to ≤ grade 1; resume at next lower 
dose level 
Unexplained dyspnea or other 
evidence of severe pulmonary 
toxicity 
Discontinue 
No dose reduction 
Severe hepatic toxicity 
Discontinue 
Do not administer to patients 
with total bilirubin > 1.5 x 
IULN or AST > 10 x IULN 
Hemolytic-Uremic Syndrome 
Discontinue 
No dose reduction 
Capillary Leak Syndrome 
Discontinue 
No dose reduction 
Posterior Reversible 
Encephalopathy Syndrome 
Discontinue 
No dose reduction 
Other grade 3 or 4 non-
hematological toxicity (except 
nausea or vomiting) 
Withhold or reduce by one dose level either one or both drugs  
 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 


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The FDA requires that all serious and unexpected adverse events be reported as outlined in Section 
7.4.  In addition, any fatal or life-threatening adverse experiences where there is a reasonable 
possibility of relationship to study intervention must be reported. 
 
Biomed Valley Discoveries, Inc. requires that all reportable adverse events be reported as outlined 
in Section 7.5. 
 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience  
 


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Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA. 
 
 
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 


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7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 


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• Report any unexpected fatal or life-threatening adverse experiences (Section 7.1.4) 
associated with use of the drug by telephone or fax no later than 7 calendar days 
after initial receipt of the information.   
• Report any serious, unexpected adverse experiences (Section 7.1.2), associated 
with use of BVD-523 as well as results from animal studies that suggest significant 
clinical risk within 15 calendar days after initial receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
7.5 
Reporting to Biomed Valley Discoveries, Inc. 
 
In the event of a reportable adverse event, please send the FDA MedWatch and BioMed 
Valley SAE form (See Appendix D) to the Clinipace Worldwide Safety Associate at 
safety@clinipace.com. 
 
7.6 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
BVD-523 (Ulixertinib) 
 
8.1.1 BVD-523 Description 
 
IUPAC 
Name: 
(S)-4-(5-chlor-2-(isopropylamino)pyridin-4-yl)-N-(1-(3-
chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide hydrochloride 
Molecular Formula: C21H22Cl2N4O2·HCl 
Molecular Weight: 469.79 Daltons 
 
8.1.2 Clinical Pharmacology 
 
In preliminary studies, measurements of phorbol ester-dependent RSK 
phosphorylation of whole blood samples collected from patients dosed orally with 
BVD-523 have demonstrated dose-dependent bioactivity of BVD-523. These ERK 
inhibitory effects are manifest following a single dose of BVD-523 and after 


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repeated dosing, showing biological activity as predicted by the mechanism of 
action of BVD-523.  
 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
In vitro studies using recombinant human enzymes showed that BVD-523 was 
metabolized by CYP1A2, CYP2D6, and CYP3A4, producing 7 potential 
metabolites. Pharmacokinetics samples are being taken from all patients in Part 1 
of the study to measure plasma levels of BVD-523 and selected metabolites. To 
date no formal full analysis of the data has been made.  
 
8.1.4 Supplier(s) 
 
BVD-523 will be supplied by Biomed Valley Discoveries, Inc. 
 
8.1.5 Dosage Form and Preparation 
 
BVD-523 drug substance is manufactured according to cGMP as a mono-
hydrochloride salt and is supplied in hard gelatin. The capsules are manufactured 
according to cGMP at 150 mg (yellow) of BVD-523 per capsule. The capsules are 
packaged in amber HDPE bottles.  
 
8.1.6 Storage and Stability 
 
Bottles of BVD-523 will be stored at controlled room temperature (15oC-25oC) 
environment under temperature monitoring in a location with access limited to 
authorized study personnel. 
 
8.1.7 Administration 
 
BVD-523 is an oral drug which will given at the protocol-dictated dose on a twice 
daily basis (at approximately 12-hour intervals).  Phase Ib patients will take BVD-
523 on its own for two weeks before initiating Cycle 1 treatment with gemcitabine 
and nab-paclitaxel.  BVD-523 should be taken in a fasted state (one hour before 
food or two hours after food).  All capsules should be taken within 10 minutes with 
8 ounces of water.  If a patient misses a dose, s/he should not make up that dose but 
simply resume dosing with the next scheduled dose.   
 
8.2 
Gemcitabine (Gemzar) 
 
8.2.1 Gemcitabine Description 
 
Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.  
Gemcitabine HCl is 2’-deoxy-2’,2’-difluorocytidine monohydrochloride (β-
isomer).  The structural formula is as follows: 


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The empirical formula for gemcitabine HCl is C9H11F2N3O4·HCl.  It has a 
molecular weight of 299.66. 
 
8.2.2 Clinical Pharmacology 
 
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of 
cells through the G1/S-phase boundary.  Gemcitabine is metabolized by nucleoside 
kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. 
Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible 
for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA 
synthesis, resulting in reductions in deoxynucleotide concentrations, including 
dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. 
The reduction in the intracellular concentration of dCTP by the action of the 
diphosphate enhances the incorporation of gemcitabine triphosphate into DNA 
(self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, 
only one additional nucleotide is added to the growing DNA strands, which 
eventually results in the initiation of apoptotic cell death. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
Gemcitabine disposition was studied in 5 patients who received a single 1000 
mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% 
of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and 
the inactive uracil metabolite, 2’-deoxy-2’,2’-difluorouridine (dFdU), accounted 
for 99% of the excreted dose. The metabolite dFdU is also found in plasma. 
  
The active metabolite, gemcitabine triphosphate, can be extracted from peripheral 
blood mononuclear cells. The half-life of the terminal phase for gemcitabine 
triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours. 
 
8.2.4 Supplier(s) 
 
Gemcitabine will be given as per routine care from commercial supply. 
 
8.2.5 Dosage Form and Preparation 
 
Gemcitabine for injection, USP, is available in sterile single-use vials individually 
packaged in a carton containing: 200 mg white to off-white lyophilized powder in 


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a 10-mL size sterile single use vial or 1 g white to off-white lyophilized powder in 
a 50-mL size sterile single use vial. 
 
8.2.6 Storage and Stability 
 
Unopened vials of gemcitabine are stable until the expiration date indicated on the 
package when stored at controlled room temperature 20°C to 25°C and that allows 
for excursions between 15°C and 30°C. 
 
8.2.7 Administration 
 
Gemcitabine should be given as an intravenous infusion over the course of 30 
minutes. 
 
8.2.8 Special Handling Instructions 
 
No special handling instructions. 
 
8.3 
Nab-Paclitaxel (Abraxane) 
 
8.3.1 Nab-Paclitaxel Description 
 
Nab-paclitaxel is an albumin-bound form of paclitaxel with a mean particle size of 
approximately 130 nanometers.  The active agent is paclitaxel, a microtubule 
inhibitor.  The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-
hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-
benzoyl-3-phenylisoserine.  Paclitaxel has the following structural formula: 
 
 
Paclitaxel is a white to off-white crystalline powder with the empirical formula 
C47H51NO14 and a molecular weight of 853.91.  It is highly lipophilic, insoluble in 
water, and melts at approximately 216-217°C. 
 
8.3.2 Clinical Pharmacology 
 
Nab-paclitaxel is a microtubule inhibitor that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization.  This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for vital interphase and 


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mitotic cellular functions.  Paclitaxel induces abnormal arrays or “bundles” of 
microtubules throughout the cell cycle and multiple asters of microtubules during 
mitosis. 
 
8.3.3 Pharmacokinetics and Drug Metabolism 
 
Following intravenous administration of nab-paclitaxel, paclitaxel plasma 
concentrations declined in a biphasic manner, the initial rapid decline representing 
distribution to the peripheral compartment and the slower second phase 
representing drug elimination. The terminal half-life was approximately 27 hours. 
 
In vitro studies with human liver microsomes and tissue slices showed that 
paclitaxel was metabolized primarily to 6αhydroxypaclitaxel by CYP2C8; and to 
two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, 
by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was 
inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, 
dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the 
concentrations used exceeded those found in vivo following normal therapeutic 
doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific 
inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. 
The pharmacokinetics of paclitaxel may also be altered in vivo as a result of 
interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 
and/or CYP3A4. 
 
8.3.4 Supplier(s) 
 
Nab-paclitaxel will be given as per routine care from commercial supply. 
 
8.3.5 Dosage Form and Preparation 
 
It is supplied as a white to yellow, sterile, lyophilized powder for reconstitution 
with 20mL of 0.9% sodium chloride injection, USP prior to intravenous infusion.  
Each single use vial contains 100 mg of paclitaxel (bound to human albumin) and 
approximately 900 mg of human albumin (containing sodium caprylate and sodium 
acetyltryptophanate).  Each milliliter of reconstituted suspension contains 5 mg 
paclitaxel. 
 
8.3.6 Storage and Stability 
 
Store the vials in original cartons at 20°C to 25°C.  Retain the original package to 
protect from bright light. 
 
8.3.7 Administration 
 
Nab-paclitaxel should be given as an intravenous infusion over the course of 30 to 
40 minutes. 


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8.3.8 Special Handling Instructions 
 
No special handling instructions. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Fresh Biopsies 
 
9.1.1 Collection of Specimen(s) 
 
Biopsies will be obtained prior to the start of treatment, at the end of the two week 
BVD-523 lead-in (dose de-escalation patients only), and at the end of the second 
cycle of therapy (expansion cohort patients only).  Three cores will be collected at 
each time point. A baseline biopsy is mandatory for all patients. Tissue will only 
be collected at the end of C2 if deemed safe for the patient and feasible to obtain 
(per PI discretion). Four cores are desired for this study. 
 
9.1.2 Handling of Specimen(s) 
 
All biopsy samples will be placed on wet ice and transferred to the Dr. Kian-Huat 
Lim’s lab.  Tumor specimens will be divided into two potions.  The first one will 
be formalin fixed and paraffin embedded (FFPE), while the second part will be snap 
frozen for further analysis. Two cores biopsy will be obtained and immediately 
placed in special cell culture medium to maintain cell viability. The tumor tissues 
will then be processed and immediately inoculated into the subcutaneous tissue of 
immunocompromised mice. Cell lines may be established from either the primary 
core or xenograft. If successful, the resulting tumors will be used for evaluation for 
treatment response and resistance. 
 
9.1.3 Pharmacodynamics 
 
A panel of biomarkers (pERK, pMEK, pRSK, p4EBP1, pS6 et al) will be evaluated 
by immunohistochemistry analysis to determine the effect of ERK pathway 
inhibition by BVD-523  on the paired biopsies collected in the dose de-escalation 
cohort. Other biomarkers may be evaluated as appropriate.  
 
9.1.4 Predictive Biomarkers  
 
Snap frozen paired core biopsies collected from patients in the expansion cohort 
will be thawed in the presence of RNA LaterTM.  RNA will be made and 
transcriptome analysis will be done either by RNASeq or Affymetrix expression 
array analysis. Change of specific gene expression levels will be correlated with 
patient’s treatment response. 
 


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Whole exome sequencing will be performed on those specimens to assess mutation 
status and burden.    
 
 
 
10.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted within 2 weeks prior to start of protocol 
therapy.  Scans and x-rays must be done no more than 4 weeks prior to the start of the protocol 
therapy.  Cycles are 28 days.  There is a window of +/- 3 days around the lead-in period. There is 
a window of +/- 1 day around each assessment. 
 
 
Baseline 
Lead-in6 
All Cycles 
End of every 
even-numbered 
cycle 
EOT F/U7 
D1 D8 D15 
Informed consent 
X 
 
 
 
 
 
 
 
H&P, ECOG PS 
X 
 
X 
 
 
 
X 
 
CBC 
X 
 
X 
X 
X 
 
 
 
CMP 
X 
 
X 
 
X 
 
 
 
β-hCG1 
X 
 
 
 
 
 
 
 
CA19-9 
X 
 
X 
 
 
 
 
 
ECG 
X 
 
 
X8 
 
 
 
 
MUGA or ECHO2 
X 
 
 
 
 
 
 
 
Radiographic imaging 
X 
 
 
 
 
X 
X 
 
BVD-523 
 
BID daily during each cycle 
 
 
 
Gemcitabine 
 
 
X 
X 
X 
 
 
 
nab-Paclitaxel 
 
 
X 
X 
X 
 
 
 
Research biopsy 
X3 
 
X4 
 
 
X5 
 
 
AE assessment 
Continuously while on treatment and for 30 days after the last day of 
treatment. 
1. Women of childbearing potential only 
2. Echocardiogram preferred; prior approval from PI or designee required for MUGA 
3. Baseline biopsy is mandatory. Biopsy to be collected after patient is deemed eligible but before the start of 
treatment. If a patient needs a standard of care (SOC) biopsy for pathology purposes, the three cores of research 
specimen can be collected during the SOC biopsy/procedure prior to confirmation of eligibility.  
4. For patients in the de-escalation group only. Must be done at the conclusion of the lead-in period before the first 
doses of gemcitabine and nab-paclitaxel. Patient must not have missed any of the three BVD-523 doses preceding 
their biopsy. 
5. End of Cycle 2 only. Expansion cohort patients only. Tissue will be collected if deemed safe and feasible per PI 
discretion. 
6. Patients in the de-escalation group will take BVD-523 as directed for 2 weeks before beginning gemcitabine and 
nab-paclitaxel. There is a window of +/- 3 days to allow for BVD-523 dosing holds. Further extensions of lead-
in period at PI discretion.  
7. Monthly for 2 years following the end of treatment 
8. Cycle 1 only 
9. Optional 
 
 
 


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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form Completion of treatment 
Follow Up Form 
Monthly for 2 years after end of treatment 
Tumor Measurement Form Baseline, end of every even numbered cycles, and end of treatment 
Biopsy Form 
Prior to starting treatment 
End of lead-in (for de-escalation patients only) 
End of Cycle 2 (expansion cohort) 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 


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thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 


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followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 


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Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 


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Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 


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Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
12.4.6 Response Review 
 


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It is strongly recommended that all responses be reviewed by an expert(s) 
independent of the study at the study’s completion.  Simultaneous review of the 
patients’ files and radiological images is the best approach.  
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
During the phase I dose de-escalation, the Principal Investigator will review all patient data at least 
monthly (or before each dose-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC).  During the 
dose expansion, the Principal Investigator will review all patient data at least every six months, 
and provide a semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities separated by cohorts with the number of dose-limiting toxicities 
indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 


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This is a Phase Ib study using BVD-523 plus nab-paclitaxel and gemcitabine in patients with 
metastatic pancreatic cancer.  It includes two phases- dose de-escalation part and expansion part 
at the RP2D. 
 
14.1 
Study Endpoints 
 
The primary endpoint is the MTD or RP2D of BVD-523 in combination with nab-
paclitaxel and gemcitabine using dose de-escalation cohort. The secondary endpoints 
include the safety and toxicity profile, biochemical response (BR), response rate (RR), time 
to tumor progression, progression free survival (PFS) and overall survival (OS) of BVD-
523 in combination with nab-paclitaxel and gemcitabine. The exploratory endpoints are 
pharmacodynamics biomarkers of BVD-523, as well as, the association between 
biomarkers and genetic alterations with treatment response.   
 
14.2 
Sample Size Estimates 
 
For the dose de-escalation phase, a modified Fibonacci design with three dose levels of 
BVD-523 (600 mg, 450 mg, and 300 mg), will be used, so 6 to 18 patients will be needed. 
For the expansion cohort, a total of 25 patients will be treated at RP2D, providing a 
reasonable precision for the estimate of the preliminary efficacy data, according to the 
extensive simulation study regarding the ideal sample size for pilot study.   
 
14.3 
Accrual 
 
The rate of accrual for the study is expected to be about 2-3 patient per month. It is 
estimated the study is expected to complete within two years.  
 
14.4 
Toxicity Monitoring  
 
A modified Fibonacci design will be used for the dose de-escalation phase, starting with a 
cohort of 6 patients at the target dose combination level. If 0 or 1 out of 6 patients 
experiences DLT at this level, it will be used for the expansion cohort portion.  If 2 DLTs 
are observed, the dosing of BVD-523 will de-escalate with a new cohort of 6 patients. The 
maximal number of patients needed for this part is 18 and the minimal number of patients 
is 6.  After the determination of MTD, the remaining patients (total N=25) will be enrolled 
to the expansion cohort. In light of a lead-in study, to ensure the adequate assessment of 
toxicity and safety, the study has a stopping rule in the expansion cohort.  If two or more 
of the first 6 patients in the expansion cohort experience a DLT, then the study PI will 
consult with other study team members for the possibility of exploring the next lower dose 
level.    
 
14.5 
Statistical Analysis 
 
A complete listing of adverse events will also be tabulated, including severity, relationship 
to treatment, onset, duration, and outcome. Laboratory data measured on a continuous scale 


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will be characterized by summary statistics (mean and standard deviation). For those 
patients treated at dose-level of MTD or above, the biochemical response (BR) is defined 
as more than 50% of decrease from baseline CA 19-9 and response rate (RR) is assessed 
according to the  RECIST 1.1.  BR and RR between BVD-523 combination will be 
summarized using contingency table and compared by the Fisher’s Exact test. Time to 
tumor progression is defined as the days from registration to time of progressive disease. 
OS is defined as the days from the date of treatment start and death from any cause. Patients 
alive or lost to follow-up are censored. PFS is defined as the days from the date of treatment 
and death or progression, which occurs first. Patients alive without progression or lost to 
follow-up are censored. The differences in time to tumor progression, PFS and OS for 
BVD-523 combination will be performed using Kaplan-Meier curves and compared by 
log-rank tests. In the correlative studies, biopsies will be obtained prior to the start of 
treatment, 2 weeks after the administration of single agent BVD-523 (for dose de-
escalation patients only), and at the end of the second cycle of therapy (expansion cohort 
only).  Three cores will be collected at each time point. A panel of biomarkers (pERK, 
pMEK, pRSK, p4EBP1, pS6 et al) will be evaluated to determine the effect of ERK 
pathway inhibition by BVD-523 on the paired biopsies collected in the dose de-escalation 
cohort. Other biomarkers may be evaluated as appropriate. The change in exploratory 
endpoints between pre- and post-treatment biopsies will be summarized by descriptive 
statistics, such as means and standard deviation (SD) or frequencies, as appropriate. Their 
association with the clinical response will also be explored by a permutation analysis. 
Taking the relationship between pERK and the clinical response as an example, we will 
first compute the observed test statistics, such as the sample mean difference between 
responders versus non-responders.  Next, we will simulate the null distribution of test 
statistics by randomly shuffling the response status. This will be repeated 10,000 times to 
obtain the distribution of the observed mean differences if there was truly no difference. 
The permutation p-value will equal the proportion of simulations that exceeds the observed 
test statistics from the null distribution.  
 
 


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15.0 
REFERENCES 
 
1. 
Siegel, R., Naishadham, D., and Jemal, A. Cancer statistics, 2013. CA Cancer J Clin 63, 
11-30 
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Modiano, M. R., Cripps, M. C., Portenoy, R. K., Storniolo, A. M., Tarassoff, P., Nelson, 
R., Dorr, F. A., Stephens, C. D., and Von Hoff, D. D. (1997) Improvements in survival 
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D., Bahary, N., Ramanathan, R. K., Tabernero, J., Hidalgo, M., Goldstein, D., Van 
Cutsem, E., Wei, X., Iglesias, J., and Renschler, M. F. (2013) Increased survival in 
pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England journal of 
medicine 369, 1691-1703 
4. 
Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y., Adenis, 
A., Raoul, J. L., Gourgou-Bourgade, S., de la Fouchardiere, C., Bennouna, J., Bachet, J. 
B., Khemissa-Akouz, F., Pere-Verge, D., Delbaldo, C., Assenat, E., Chauffert, B., 
Michel, P., Montoto-Grillot, C., and Ducreux, M. FOLFIRINOX versus gemcitabine for 
metastatic pancreatic cancer. The New England journal of medicine 364, 1817-1825 
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Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J., and Der, C. J. (1998) 
Increasing complexity of Ras signaling. Oncogene 17, 1395-1413 
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Wennerberg, K., Rossman, K. L., and Der, C. J. (2005) The Ras superfamily at a glance. 
J Cell Sci 118, 843-846 
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Rozenblum, E., Schutte, M., Goggins, M., Hahn, S. A., Panzer, S., Zahurak, M., 
Goodman, S. N., Sohn, T. A., Hruban, R. H., Yeo, C. J., and Kern, S. E. (1997) Tumor-
suppressive pathways in pancreatic carcinoma. Cancer Res 57, 1731-1734 
8. 
Fleming, J. B., Shen, G. L., Holloway, S. E., Davis, M., and Brekken, R. A. (2005) 
Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification 
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Klimstra, D. S., and Longnecker, D. S. (1994) K-ras mutations in pancreatic ductal 
proliferative lesions. Am J Pathol 145, 1547-1550 
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(1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. 
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11. 
Van Cutsem, E., van de Velde, H., Karasek, P., Oettle, H., Vervenne, W. L., Szawlowski, 
A., Schoffski, P., Post, S., Verslype, C., Neumann, H., Safran, H., Humblet, Y., Perez 
Ruixo, J., Ma, Y., and Von Hoff, D. (2004) Phase III trial of gemcitabine plus tipifarnib 
compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22, 
1430-1438 
12. 
Bodoky, G., Timcheva, C., Spigel, D. R., La Stella, P. J., Ciuleanu, T. E., Pover, G., and 
Tebbutt, N. C. A phase II open-label randomized study to assess the efficacy and safety 
of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with 
advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. 
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13. 
Kindler, H. L., Wroblewski, K., Wallace, J. A., Hall, M. J., Locker, G., Nattam, S., 
Agamah, E., Stadler, W. M., and Vokes, E. E. Gemcitabine plus sorafenib in patients 
with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II 
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14. 
Hatzivassiliou, G., Liu, B., O'Brien, C., Spoerke, J. M., Hoeflich, K. P., Haverty, P. M., 
Soriano, R., Forrest, W. F., Heldens, S., Chen, H., Toy, K., Ha, C., Zhou, W., Song, K., 
Friedman, L. S., Amler, L. C., Hampton, G. M., Moffat, J., Belvin, M., and Lackner, M. 
R. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther 
11, 1143-1154 
15. 
Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P., Brown, 
R. D., Della Pelle, P., Dias-Santagata, D., Hung, K. E., Flaherty, K. T., Piris, A., Wargo, 
J. A., Settleman, J., Mino-Kenudson, M., and Engelman, J. A. EGFR-mediated re-
activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal 
cancers to RAF inhibition with vemurafenib. Cancer Discov 2, 227-235 
16. 
Morris, E. J., Jha, S., Restaino, C. R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Deng, 
Y., Jin, W., Black, S., Long, B., Liu, J., Dinunzio, E., Windsor, W., Zhang, R., Zhao, S., 
Angagaw, M. H., Pinheiro, E. M., Desai, J., Xiao, L., Shipps, G., Hruza, A., Wang, J., 
Kelly, J., Paliwal, S., Xiaolei, G., Boga, S. B., Zhu, L., Daublain, P., Zhang, L., 
Lutterbach, B. A., Pelletire, M. R., Philippar, U., Siliphaivanh, P., Witter, D., 
Kirschmeier, P., Bishop, W. R., Hicklin, D., Gilliland, G., Jayaraman, L., Zawel, L., 
Fawell, S. E., and Samatar, A. A. Discovery of a novel ERK inhibitor with activity in 
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Gysin, S., Lee, S. H., Dean, N. M., and McMahon, M. (2005) Pharmacologic inhibition 
of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through 
induced expression of p27Kip1. Cancer Res 65, 4870-4880 
18. 
Roy, S. K., Srivastava, R. K., and Shankar, S. Inhibition of PI3K/AKT and MAPK/ERK 
pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and 
apoptosis in pancreatic cancer. J Mol Signal 5, 10 
19. 
Piantadosi, S. (2005) Translational clinical trials: an entropy-based approach to sample 
size. Clinical trials 2, 182-192 
20. 
Kim, P., Liu, X., Lee, T., Liu, L., Barham, R., Kirkland, R., Leesman, G., Kuller, A., 
Ybarrondo, B., Ng, S. C., and Singh, S. Highly sensitive proximity mediated 
immunoassay reveals HER2 status conversion in the circulating tumor cells of metastatic 
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21. 
Lee, J., Kim, S., Kim, P., Liu, X., Lee, T., Kim, K. M., Do, I. G., Park, J. O., Park, S. H., 
Jang, J., Hoe, N., Harvie, G., Kuller, A., Jain, A., Meyer, G., Leesman, G., Park, Y. S., 
Choi, M. G., Sohn, T. S., Bae, J. M., Lim, H. Y., Singh, S., and Kang, W. K. A novel 
proteomics-based clinical diagnostics technology identifies heterogeneity in activated 
signaling pathways in gastric cancers. PLoS One 8, e54644 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development and study coordination services. The Siteman Cancer 
Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: NON-PERMITTED CONCOMITANT MEDICATIONS 
 
CYP3A4 Inhibitors 
Indinavir 
Nelfinavir 
Ritonavir 
Atazanavir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Voriconazole 
Nefazodone 
Saquinavir 
Telithromycin 
 
CYP2D6 Inhibitors 
Bupropion 
Cinacalcet 
Fluoxetine 
Paroxetine 
Quinidine 
CYP1A2 Inhibitors 
Fluvoxamine 
Ciprofloxacin 
CYP3A4 Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampin 
Rifapentine 
 
 
 
 


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APPENDIX C: PATIENT’S MEDICATION DIARY 
Today’s Date:    
 
 
 
 
Agent:  ulixertinib 
Cycle:    
 
 
 
Patient Name:    
 
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___capsules) of ulixertinib twice daily, one hour before or 
two hours after a meal at approximately the same times each day.  Take it with a glass of water and drink the 
glass of water in as little time as possible.  Swallow the capsules whole and do not chew the capsules. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forget to take your ulixertinib, then do not take that dose.  Restart it with the next dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill count 
can be done. 
Day 
Date 
What time was dose taken? 
# of capsules taken 
Comments 
AM dose 
PM dose 
AM dose 
PM dose 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 


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APPENDIX D: BIOMED VALLEY SAE FORM  
 
 


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APPENDIX E: BIOMED VALLEY PREGNANCY REPORT FORM  
  
 
 
 


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