A Phase 2 Basket Trial of Ulixertinib (BVD-523) in Combination With Hydroxychloroquine in Patients With Advanced GI Malignancies Harboring Mitogen-activated Protein Kinase (MAPK) Pathway Mutations (BVD-523-HCQ)
Phase: PHASE2
Conditions: Tumor, Solid, Gastrointestinal Cancer
Sponsor: BioMed Valley Discoveries, Inc

 
 
CONFIDENTIAL 
 
Page 1 of 82 
 
 
A phase 2 basket trial of ulixertinib (BVD-523) in combination 
with hydroxychloroquine in patients with advanced 
gastrointestinal malignancies harboring MAPK pathway 
mutations (BVD-523-HCQ) 
 
Investigational Product 
Ulixertinib (BVD-523) 
Phase 
2 
Sponsor  
BioMed Valley Discoveries, 
Inc. 
Address: BioMed Valley 
Discoveries, Inc. 
4435 Main Street, Suite 550 
Kansas City, MO 64111 
IND 
IND 115451 
NCT number 
NCT05221320 
Protocol Version 
Version 3.0: 28 Aug  2023 
 
CONFIDENTIAL STATEMENT 
This document is the sole property of BioMed Valley Discoveries, Inc.  This 
document and any and all information contained herein has to be considered 
and treated as strictly confidential.  This document shall be used only for the 
purpose of the disclosure herein provided.  No disclosure or publication shall 
be made without the prior written consent of BioMed Valley Discoveries, Inc. 
 
 

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DOCUMENT HISTORY 
 
Document 
Date 
Overall Rationale 
Original Protocol v. 1.0 
19 October 2021 
Not applicable  
Amended protocol v. 2.0 
02 May 2023 
Updated definition of evaluable patients 
Amended Protocol v.3.0 
28 August 2023 
Updated header  
Updated inclusion criteria language  
Updated Appendix 3 (Conmeds) 
 
 

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PROTOCOL APPROVAL SIGNATURE PAGE 
SPONSOR: BIOMED VALLEY DISCOVERIES, INC 
I have read and understand the contents of version 2.0 of this clinical protocol for Study No. 
BVD-523-HCQ dated 02 May 2023 and I agree to meet all obligations of the sponsor as 
detailed in all applicable regulations and guidelines. In addition, I will inform the Principal 
Investigator and all other investigators of all relevant information that becomes available during 
the conduct of this study. 
Approved By: 
 
 
 
 
 
Brent L. Kreider, PhD. 
President, BioMed Valley Discoveries, Inc. 
 
Date 
 

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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of version 2.0 of this clinical protocol for Study No. 
BVD-523-HCQ dated 02 May 2023 and will adhere to the study requirements as presented, 
including all statements regarding confidentiality. In addition, I will conduct the study in 
accordance with current Good Clinical Practices and applicable FDA regulatory requirements: 
Principal Investigator: 
Name:   
 
Title:   
 
Institution:    
Address:   
 
Address: 
 
Phone:  
 
Fax:  
 
 
 
 
 
 
 
  
Signature 
 
Date 
 
 
 
 
 

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Table of Contents 
DOCUMENT HISTORY ............................................................................................................. 2 
1 
STATEMENT OF COMPLIANCE .......................................................................................10 
2 
ABBREVIATION AND DEFINITION OF TERMS ................................................................11 
3 
PROTOCOL SUMMARY ....................................................................................................14 
3.1 
Synopsis .....................................................................................................................14 
3.2 
Schema ......................................................................................................................17 
3.3 
Schedule of Activities ..................................................................................................18 
4 
INTRODUCTION ...............................................................................................................22 
4.1 
Study Rationale ..........................................................................................................22 
4.2 
Gastrointestinal Malignancies .....................................................................................22 
4.3 
MAPK-Mutated Gastrointestinal Malignancies ............................................................22 
4.4 
MAP Kinase Inhibition .................................................................................................23 
4.4.1 
Mechanisms of Resistance ..................................................................................24 
4.4.2 
Pre-Clinical Experience ........................................................................................24 
4.5 
Investigational Intervention .........................................................................................25 
4.5.1 
Ulixertinib .............................................................................................................25 
4.5.2 
Previous Human Experience ................................................................................25 
4.5.3 
Hydroxychloroquine .............................................................................................29 
4.5.4 
Dose Rationale ....................................................................................................30 
4.5.5 
Drug-Drug Interaction Assessment ......................................................................31 
4.5.6 
Clinical Experience ..............................................................................................31 
5 
OBJECTIVES AND ENDPOINTS ......................................................................................32 
5.1 
Primary Objectives ......................................................................................................32 
5.2 
Secondary Objective ...................................................................................................32 
5.3 
Exploratory Objective ..................................................................................................32 
6 
STUDY DESIGN ................................................................................................................33 
6.1 
Overall Design ............................................................................................................33 
6.2 
Number of Patients .....................................................................................................34 
6.3 
Number of Study Sites ................................................................................................34 
6.4 
End of Study ...............................................................................................................34 

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7 
STUDY POPULATION .......................................................................................................34 
7.1 
Inclusion Criteria .........................................................................................................34 
7.2 
Exclusion Criteria ........................................................................................................37 
7.3 
Lifestyle Considerations ..............................................................................................39 
7.3.1 
Contraception ......................................................................................................39 
7.4 
Screen Failures ...........................................................................................................40 
7.5 
Strategies for Recruitment ..........................................................................................40 
8 
STUDY DRUGS .................................................................................................................40 
8.1 
Dosing and Administration ..........................................................................................40 
8.1.1 
Study Drug Compliance .......................................................................................41 
8.2 
Investigational Product Supplies .................................................................................41 
8.2.1 
Preparation and Dispensing .................................................................................42 
8.2.2 
Ulixertinib .............................................................................................................42 
8.2.3 
Hydroxychloroquine .............................................................................................42 
8.2.4 
Product Storage and Stability ...............................................................................42 
8.3 
Dose Interruptions.......................................................................................................42 
8.4 
Dose Reductions ........................................................................................................42 
8.5 
Dose Modifications Guidelines ....................................................................................43 
8.6 
Supportive Care ..........................................................................................................48 
8.7 
Concomitant Medications and Therapies ....................................................................48 
8.7.1 
Radiotherapy .......................................................................................................48 
8.7.2 
Prohibited Therapy ..............................................................................................48 
8.7.3 
Cautionary Therapy .............................................................................................49 
8.8 
Duration of Therapy ....................................................................................................49 
8.8.1 
Criteria for the Discontinuation of Treatment ........................................................50 
8.8.2 
Criteria for the Discontinuation of Study ...............................................................50 
8.8.3 
Withdrawal of Consent .........................................................................................51 
8.8.4 
Lost to Follow-Up .................................................................................................52 
9 
STUDY PROCEDURES .....................................................................................................52 
9.1 
Screening ...................................................................................................................52 
9.2 
Treatment Period ........................................................................................................52 

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9.3 
End of Treatment ........................................................................................................52 
9.4 
Safety Follow-Up ........................................................................................................52 
9.5 
Follow-Up ...................................................................................................................52 
10 
STUDY ASSESSMENTS ...............................................................................................53 
10.1 
General Assessments .................................................................................................53 
10.1.1 
Patient Consent ...................................................................................................53 
10.1.2 
Medical History ....................................................................................................53 
10.1.3 
Prior and Concomitant Medications .....................................................................53 
10.1.4 
Tumor Mutation Testing .......................................................................................54 
10.2 
Safety Assessments ...................................................................................................54 
10.2.1 
Physical Examinations and Vital Signs ................................................................54 
10.2.2 
Adverse Events ....................................................................................................54 
10.2.3 
Laboratory Assessments .....................................................................................54 
10.2.4 
12-Lead Electrocardiograms (ECG) .....................................................................56 
10.2.5 
Echocardiogram ...................................................................................................56 
10.2.6 
Ophthalmologic Exam ..........................................................................................56 
10.3 
Efficacy Assessments .................................................................................................57 
10.3.1 
Disease Assessment ...........................................................................................57 
10.3.2 
Correlative Studies...............................................................................................57 
10.3.3 
Tissue ..................................................................................................................58 
11 
ADVERSE EVENTS .......................................................................................................59 
11.1 
Definitions ...................................................................................................................59 
11.1.1 
Adverse Events ....................................................................................................59 
11.1.2 
Serious Adverse Events .......................................................................................59 
11.2 
Adverse Event Reporting ............................................................................................60 
11.2.1 
Severity Assessment ...........................................................................................60 
11.2.2 
Relationship to Study Drug ..................................................................................61 
11.2.3 
Action Taken and Outcome ..................................................................................61 
11.2.4 
Reporting Serious Adverse Events ......................................................................61 
11.3 
Special Situations .......................................................................................................62 
11.3.1 
Pregnancy or Breastfeeding .................................................................................62 

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11.3.2 
Hy’s Law Cases ...................................................................................................63 
11.3.3 
Medication Error ..................................................................................................64 
11.4 
Safety Oversight .........................................................................................................64 
12 
STATISTICAL CONSIDERATIONS ................................................................................65 
12.1 
General Considerations ..............................................................................................65 
12.2 
Sample Size Determination .........................................................................................65 
12.3 
Population for Analyses ..............................................................................................65 
12.4 
Data Analysis ..............................................................................................................66 
12.4.1 
Demographic and Baseline Characteristics ..........................................................66 
12.4.2 
Prior and Concomitant Medications .....................................................................66 
12.4.3 
Study Drugs .........................................................................................................66 
12.5 
Primary Endpoint Analysis ..........................................................................................66 
12.5.1 
Safety and Tolerability .........................................................................................66 
12.5.2 
Confirmed Overall Response Rate .......................................................................67 
12.6 
Secondary Endpoints Analysis ....................................................................................67 
12.6.1 
Progression-Free Survival ....................................................................................67 
12.7 
Other Endpoints Analysis ............................................................................................67 
12.7.1 
Pharmacokinetics ................................................................................................67 
12.7.2 
Pharmacodynamics .............................................................................................68 
12.7.3 
Laboratory Evaluations ........................................................................................68 
12.7.4 
Other Safety Evaluations .....................................................................................68 
13 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............68 
13.1 
Regulatory, Ethical, and Study Oversight Considerations ...........................................68 
13.1.1 
Informed Consent Process...................................................................................68 
13.1.2 
Study Discontinuation and Closure ......................................................................69 
13.1.3 
Confidentiality and Privacy ...................................................................................70 
13.1.4 
Future Use of Stored Specimens and Data ..........................................................70 
13.1.5 
Key Roles and Study Governance .......................................................................71 
13.1.6 
Data Handling and Record Keeping .....................................................................73 
13.1.7 
Protocol Deviations ..............................................................................................74 
13.1.8 
Publication and Data Sharing Policy ....................................................................74 

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13.1.9 
Conflict of Interest Policy .....................................................................................74 
13.1.10 Insurance .............................................................................................................74 
14 
REFERENCES ...............................................................................................................75 
Appendix 1: ECOG Performance Status40 .................................................................................78 
Appendix 2: List of QTc Prolonging Agents ...............................................................................79 
Appendix 3: Prohibited Concomitant Medications .....................................................................81 
 
List of Figures 
Figure 1: Study Schema ............................................................................................................17 
 
List of Tables 
Table 1: Schedule of Assessments and Procedures .................................................................18 
Table 2: Schedule of Correlative Sample Collection ..................................................................21 
Table 3: Frequency of RAS mutations by cancer type11 ............................................................23 
Table 4: Previous Human Experience with Ulixertinib ...............................................................26 
Table 5: Ulixertinib and Hydroxychloroquine Dose Levels .........................................................43 
Table 6: Treatment-related adverse event management guidelines ..........................................44 
Table 7: Laboratory Assessments .............................................................................................55 
Table 8: Severity assessment ...................................................................................................60 
 
List of Appendices 
Appendix 1: ECOG Performance Status40 .................................................................................78 
Appendix 2: List of QTc Prolonging Agents ...............................................................................79 
Appendix 3: Prohibited Concomitant Medications .....................................................................81 
 
 
 
 

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

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2 
 ABBREVIATION AND DEFINITION OF TERMS 
Abbreviation 
Definition/Explanation 
ACI 
As clinically indicated 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AML 
Acute myelogenous leukemia 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BCVA 
Best-corrected distance visual acuity 
β-hCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BP 
Blood pressure 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
CA 
Cancer antigen 
CBC 
Complete blood count 
CEA 
Carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CMP 
Comprehensive metabolic panel 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete response 
CRF 
Case report form 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450 
CQ 
Chloroquine 
DCF 
Docetaxel, Cisplatin, and 5-fluorouracil 
DILI 
Drug-Induced Liver Injury 
EAS 
Efficacy analysis set  
ECF 
Epirubicin, cisplatin and 5-fluorouracil 
EDC 
Electronic data capture 

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Abbreviation 
Definition/Explanation 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
ERK 
Extracellular signal-regulated kinase 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal junction 
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCQ 
Hydroxychloroquine 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRAS 
Harvey rat sarcoma virus 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IUD 
Intra-uterine device 
IUS 
Intra-uterine hormone-releasing system  
KRAS 
Kirsten rat sarcoma virus 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction  
MAPK 
Mitogen-activated protein kinase 
MEK 
MAPK kinase 
MMR 
Measle Mumps Rubella  
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NRAS 
Neuroblastoma RAS 
ORR 
Overall response rate  
PD 
Pharmacodynamic(s) 
PDAC 
Pancreatic ductal adenocarcinoma  
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 

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Abbreviation 
Definition/Explanation 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
RAF 
Rapidly accelerated fibrosarcoma 
RAS 
Rat sarcoma 
RECIST 
Response evaluation criteria in solid tumors 
RPPA 
Reverse-phase protein array 
SAE 
Serious adverse event 
SOA 
Schedule of Activities 
SD 
Stable disease 
SD-OCT 
Spectral-domain ocular coherence tomography 
t1/2 
Terminal elimination half-life 
TB 
Tuberculosis 
TdP 
Torsades de Pointes 
tmax 
Time of maximum observed concentration 
ULN 
The upper limit of normal 
VF 
Visual field 
V600E 
A mutation of the BRAF gene in which valine (V) is substituted by glutamic 
acid (E) at amino acid 600 
  
 

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3 
PROTOCOL SUMMARY 
3.1 
Synopsis 
Title: 
A phase 2 basket trial of ulixertinib (BVD-523) in combination with 
hydroxychloroquine in patients with advanced gastrointestinal 
malignancies harboring MAPK pathway mutations (BVD-523-HCQ) 
Study Description: 
This is an open-label, prospective phase 2 basket trial assessing the 
efficacy of ulixertinib in combination with hydroxychloroquine in 
patients with advanced gastrointestinal malignancies. All patients 
enrolled must have a MAPK activating mutation to be deemed 
eligible for trial participation. Each disease-based basket will open to 
enrollment in two stages. The opening of stage two will be 
dependent on the observed responses in the patients enrolled in the 
first stage. 
Objectives: 
 
Primary Objectives:  
• 
To assess the safety and tolerability of ulixertinib and 
hydroxychloroquine in patients with advanced, RAS, non-
V600 BRAF, MEK1/2, or ERK1/2 mutated gastrointestinal 
(GI) malignancies. 
• 
To assess the efficacy of ulixertinib and hydroxychloroquine 
in patients with advanced, RAS, non-V600 BRAF, ERK1/2, or 
MEK1/2 mutated gastrointestinal malignancies. 
 
Secondary Objective: 
• 
To assess the duration of efficacy of ulixertinib and 
hydroxychloroquine in patients with advanced RAS, non-
V600 BRAF, MEK1/2, or ERK1/2 mutated gastrointestinal 
malignancies. 
Exploratory Objective: 
• 
To evaluate the bioactivity of ulixertinib and 
hydroxychloroquine against ERK1/2, autophagy pathways, 
and pharmacodynamic biomarkers. 

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Endpoints: 
Primary Endpoints: 
• 
The incidence and frequency of adverse events (AEs) and 
serious adverse events (SAEs) characterized by type, 
severity (as defined by the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE, 
version 5.0), seriousness, duration, and relationship to study 
treatment. 
• 
Overall response rate as defined by the proportion of 
patients achieving a confirmed PR and CR (defined by 
RECIST 1.1) as evaluated by the local treating investigator. 
 
Secondary Endpoint: 
• 
Progression-free survival (PFS) as defined as the time from 
study drug initiation to the time of documented disease 
progression (as assessed by RECIST 1.1) or death from any 
cause. 
Exploratory Endpoint:  
• 
Pharmacokinetics (PK) of ulixertinib and hydroxychloroquine. 
• 
Blood and/or tissue samples used to assess biomarkers 
(RPPA, Nanostring, circulating tumor (ctDNA) examples of 
assays planned but not limited to only these). 
 
Study Population: 
Key Inclusion Criteria: 
• 
Patient with histologically confirmed advanced 
gastrointestinal malignancy harboring a MAPK-mutated GI 
malignancy: KRAS, NRAS, HRAS, BRAF non-V600, MEK1/2 
(MAP2K1/2), and ERK1/2 (MAPK3/1). 
• 
Patients must have been previously treated with one or more 
lines of anti-cancer therapy and have documented disease 
progression during or after their most recent line of anti-
cancer treatment subject to the restrictions below (variations 
of standard of care may exist and are acceptable). Patients 
with cholangiocarcinoma, esophageal, GEJ cancer and 
gastric cancer who are stable on second-line regimens or 
beyond are eligible for trial participation if current treatment 
becomes intolerable.  
• 
Measurable disease per RECIST 1.1 criteria. 

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• 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status ≤ 1. 
Key Exclusion Criteria: 
• 
Prior therapy washout: 
o Systemic antineoplastic therapy including 
investigational: ≤ 14 days or within five half-lives prior 
to starting study treatment, whichever is shorter. 
o Radiotherapy ≤ 14 days prior to the first dose of study 
treatment. 
• 
Known uncontrolled brain metastases or cranial epidural 
disease. 
Phase: 
2 
Description of Study 
Intervention: 
Ulixertinib 450 mg orally twice daily  
Hydroxychloroquine 600 mg orally twice daily. 
Study Duration: 
Approximately 35 months from when study opens to enrollment until 
completion of data analyses 
Patient Duration: 
Each patient will continue on study treatment until documented 
disease progression, intolerable toxicity, study closure, or until other 
treatment discontinuation criteria is met. Patients who discontinue 
study treatment prior to disease progression, will continue to be 
followed for progression. It is estimated that patients will be on study 
for up to two years. 

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3.2 
Schema 
 
Figure 1: Study Schema 
Abbreviations: ECOG = Eastern Cooperative Oncology Group; GI = Gastrointestinal; ORR= Overall Response Rate; RECIST = response evaluation criteria in 
solid tumors. Note: The numbers given under stage 1 and 2 represent the numbers of patients in each cohort. 
 
 

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3.3 
Schedule of Activities  
The Schedule of Activities table (Table 1) provides an overview of the protocol visits and procedures. Refer to Section 9 and 
Section 10 for detailed information on each assessment required for compliance with the protocol. The Investigator may schedule 
visits (unplanned visits) in addition to those listed in the Schedule of Activities (SOA) table to conduct evaluations or assessments 
required to protect the well-being of the patient. Every effort should be made to follow the SOA for the entire study. 
Table 1: Schedule of Assessments and Procedures 
Protocol Activities 
Screening1 
On-Treatment Period: One Cycle = 28 days 
Post-Treatment Period 
Cycle 1 
Cycle 2 
Cycle 3+ 
EOT2 
Safety 
Follow-Up3 
Follow-Up 
 
Day of Cycle 
(Visit Window) 
(≤ -28 days) 
14 
8 
(± 2 days) 
15 
(± 2 days) 
1 
(± 2 days) 
15 
(± 2 days) 
1 
(± 2 days) 
(+7 days) 
(± 7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Cancer History5 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
X 
X 
X 
 
 
X 
 
 
Echocardiogram 
X 
ACI 
 
 
 
Ophthalmologic Exam8 
X 
 
 
 
X 
 
X 
 
 
 
Adverse event collection 
X 
X 
Concomitant medications 
X 
X 
 
 
Laboratory Studies9 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Protocol Activities 
Screening1 
On-Treatment Period: One Cycle = 28 days 
Post-Treatment Period 
Cycle 1 
Cycle 2 
Cycle 3+ 
EOT2 
Safety 
Follow-Up3 
Follow-Up 
 
Day of Cycle 
(Visit Window) 
(≤ -28 days) 
14 
8 
(± 2 days) 
15 
(± 2 days) 
1 
(± 2 days) 
15 
(± 2 days) 
1 
(± 2 days) 
(+7 days) 
(± 7 days) 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Creatine kinase10 
X 
ACI 
 
 
 
LDH and Phosphorus 
X 
X 
X 
X 
X 
ACI 
 
 
 
Coagulation 
X 
ACI 
 
 
 
Urinalysis 
X 
ACI 
 
 
 
Tumor Marker11 
 
X 
 
 
X 
 
X 
X 
 
 
Pregnancy Test12 
X 
ACI 
 
 
 
Disease Assessments 
CT Scans or MRI13 
X 
 
 
 
 
 
X 
X 
 
X14 
RECIST 1.1 Assessment 
X 
 
 
 
 
 
X 
X 
 
X 
Treatment Compliance and Distribution 
Hydroxychloroquine 
 
X 
 
 
X 
 
X 
 
 
 
Ulixertinib 
 
X 
 
 
X 
 
X 
 
 
 
Treatment administration 
on site 
 
 
 
X15 
 
 
X 
 
 
 
Meal provided by site 
 
 
 
X 
 
 
X16 
 
 
 
Abbreviations: ACI = as clinically indicated; LDH = lactate dehydrogenase; CT = computed tomography; MRI = magnetic resonance imaging; ECG = 
electrocardiogram; EOT = end of treatment 
 
1 Screening procedures must be completed ≤ 28 days prior to C1D1 unless noted otherwise. 
2 The end of treatment visit should occur when the decision to discontinue treatment is made. If this visit overlaps with a regularly scheduled visit, only the 
procedures listed in the calendar for the EOT visit will be performed. All end of treatment procedures should be completed within 7 days after the decision to 
discontinue treatment has been made.  
3 Patients will have a safety follow-up visit 60 days (± 7 days) after last dose of study drug. 
4 C1D1 procedures do not need to be repeated if screening procedures were performed ≤ 7 days of the start of treatment. 
 

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5 Oncologic history of the malignancy under study including prior regimens (duration of therapy, best response on therapy, date of discontinuation, and reason 
for discontinuation), surgery, and radiation therapy.  
6 Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, pulse oximetry, weight, and body temperature. Height will be captured at 
screening only. 
7 If necessary to facilitate scheduling, the physical exam may occur one day prior to study treatment. 
8 A standard ophthalmologic exam must be completed at screening, C2D1, and every 3 cycles thereafter (i.e. C5D1, C8D1, etc.) and as clinically indicated to 
assess for retinopathies. All assessments must be conducted up to 7 days prior to the clinic visit to enable timely results review.  
9 Labs may be performed ≤ 3 days prior to a scheduled day one visit except for C1D1 labs which may be completed ≤ 7 days prior to C1D1. 
10 After screening, creatine kinase should only be drawn if creatinine is elevated. 
11 Tumor marker should be drawn on day one of each cycle. Tumor markers will be disease specific: pancreatic adenocarcinoma only CA 19-9; colorectal 
carcinoma only CEA; cholangiocarcinoma only CEA and CA 19-9. Tumor markers are not required for patients with esophageal or stomach cancers. 
12 Pregnancy test (serum or urine) must be obtained at screening ≤ 7 days prior to C1D1 for all women of childbearing potential and as clinically indicated while 
on treatment. 
13 Disease assessment will be repeated every 8 weeks (± 7 days) regardless of dose holds or delays. Patients who discontinue treatment for reasons other than 
progression will have computed tomography (CT) scans at the EOT visit (unless their previous restaging was performed within 6 weeks).  
14 Patients that discontinue study treatment for any reason other than disease progression, must continue to have disease assessments every 8 weeks (± 7 days) 
until disease progression or initiation of subsequent anticancer therapy. 
15 Patient should be instructed to not take their study treatment before arriving at clinic. Study treatment and meal should be provided after the pre-dose PK draw. 
16 Meal is only required to be given at C3D1, i.e., at the time of drug administration for ctDNA and tumor biopsy for stage 1.

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Table 2: Schedule of Correlative Sample Collection 
Correlative 
Test 
Screening 
C1D1 
C1D15 
C3D1 
EOT 
Pre-
Dose 
Post-Dose 
Time Point 
(hour) 
 
0.5 
1 
2 
4 
6 
8 
12 
± 7 
days 
 
Window (min) 
≤ 60 
±2 
±3 
±6 
±12 
±18 
±24 
±36 
STAGE 1 
PK Blood1 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ctDNA 
 
X 
 
 
 
 
 
 
 
 
X2 
X3 
Biopsy4 
X 
 
 
 
 
 
 
 
 
 
X 
X 
STAGE 2 
PK Blood 
 
 
X 
 
 
 
 
 
 
 
 
 
Abbreviations: C = cycle; ctDNA = circulating tumor DNA; D = day; EOT = end of treatment; PK = 
pharmacokinetics.
 
1 To accommodate PK blood draws, patients should be instructed not to take their morning doses of both 
medications until told to do so in the clinic. A meal should be provided by the site when taking the medications in 
the clinic. Pre-dose PK sample should be collected prior to the administration of study drugs. Post-dose PK samples 
should be collected at the appropriate time points following administration of study drugs. PK samples should be 
drawn while patients are at steady state, which is 5 days, or 10 consecutive doses. 
2 To be drawn at the time of the tumor biopsy. 
3 Required blood draw at EOT. If optional biopsy is collected at EOT, ctDNA should be drawn at the time of the 
tumor biopsy.   
4 Biopsies at screening and C3D1 (± 7 days) are required. When blood is being drawn at D3D1, site will provide a 
meal when study drugs are taken. An optional biopsy will be offered at the time when the decision to discontinue 
treatment is made (+ 7 days). 

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4 
INTRODUCTION 
4.1 
Study Rationale 
The mitogen-activated protein kinase (MAPK) pathway is a second messenger system that 
plays a key role in the regulation of the cell cycle. However, mutations in key kinases within the 
pathway leads to a loss of regulation and oncogenesis. Many targeted inhibitors have been 
developed to stop the persistent downstream signaling created by driver mutations at RAS, 
RAF, MEK, and ERK1. Yet, resistance mechanisms arise that skirt the inhibition imposed by 
these targeted therapies.2-4 Increased levels of autophagy, or self-consumption, have been 
found to correlate with pharmacologic resistance.5 Pre-clinical data has shown that blockade of 
MAP kinase pathway leads to upregulation of autophagy.6 Pre-clinical data has also 
demonstrated that targeted kinase inhibition in combination with autophagy inhibition has a 
synergistic antitumor effect.7 Therefore, we propose to combine hydroxychloroquine, an 
autophagy inhibitor, with ulixertinib, an ERK inhibitor, in MAPK-mutated gastrointestinal 
malignancies.  
4.2 
Gastrointestinal Malignancies 
Gastrointestinal malignancies are the second leading cause of death in the United States 
despite the downward trend of incidence and mortality in recent years. In 2019, an estimated 
165,460 deaths and 328,030 new cases will occur. 8 Regardless of recent advances in 
oncology, the relative 5-year survival rate for patients diagnosed with a gastrointestinal 
malignancy remains low: esophageal (21%), cholangiocarcinoma (19%), pancreatic (9%), and 
stomach (32%).  
Empowered by Next Generation Sequencing, precision pharmacology has sought to identify 
and target disease-driver mutations. While targeted therapies have seen much success in other 
malignancies (such as melanoma and non-small cell lung), gastrointestinal malignancies have 
demonstrated little efficacy and only a few are approved by the Food and Drug Administration 
(FDA) for use in this patient population.  
4.3 
MAPK-Mutated Gastrointestinal Malignancies 
The MAPK pathway is a second messenger system transmitting signals from extracellular 
stimuli, such as growth factors, to the nucleus. The extracellular signal is propagated through a 
series of downstream phosphorylation events cumulating in the regulation of genes responsible 
for cell survival and proliferation.1 However, genetic mutations that alter the function of the 
protein kinases along the pathway have been linked to oncogenesis and the promotion of cell 
migration and metastasis in a variety of cancers.2,3 Common sites for mutations leading to 
persistent pathway activation are often described in the RAS, RAF, MEK, and ERK protein 
families. 
The RAS proteins, HRAS, NRAS, and KRAS, are GTPases that activate the RAF proteins in the 
signaling cascade. About one-third of malignancies contain an activating mutation in a RAS 
protein generating continual downstream signaling in the absence of extracellular stimuli.10 The 

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most common of these mutations is KRAS with the highest reported frequency among 
pancreatic cancer and right-sided colorectal patients. 11 Table 3 lists the frequency of RAS 
mutations by cancer type.  
Table 3: Frequency of RAS mutations by cancer type11 
 
KRAS (%) 
NRAS 
(%) 
HRAS (%) 
Colorectal cancer 
27 – 56 
1-7 
< 1 
Stomach cancer 
2.85 – 9.4 
1.9 
< 1 
Pancreatic cancer 
90 
< 1 
< 1 
Cholangiocarcinoma 
16 – 38 
Limited 
Data 
< 1 
RAS proteins activate kinases of the RAF family: ARAF, BRAF, and CRAF. BRAF mutations are 
well documented as drivers of malignancy, primarily in melanoma and non-small cell lung 
cancers.6,7 BRAFV600E mutation allele is the most common oncogenic variant and is standardly 
treated with a targeted inhibitor (vemurafenib or dabrafenib). However, BRAFnon-V600E mutations 
occur in about 18% of advanced malignancies and have demonstrated lower efficacy to these 
approved agents.14 
RAF proteins phosphorylate MEK1 and MEK2 and in turn, MEK proteins activate ERK1 and 
ERK2. While MEK and ERK mutations are rare, they can propagate the signal leading to 
oncogenesis.  
4.4 
MAP Kinase Inhibition 
Due to the multiple kinases involved in the MAPK phosphorylation cascade, multiple 
opportunities for pharmacologic inhibition exist. It was noted that BRAF mutations are common 
in melanoma and so the race to target BRAF began. The first BRAF inhibitor, sorafenib, was a 
dirty kinase inhibitor with poor specificity which led to poor tolerance at therapeutic doses.9-11 
These off-target effects motivated the development of a more specific BRAF inhibitor, 
vemurafenib. Clinical trials quickly demonstrated improved objective response rates, 
progression-free survival (PFS), and overall survival (OS) which led to FDA approval in 2011.12 
Later, dabrafenib followed after demonstrating similar efficacy.19 
Similar to BRAF, KRAS mutations were commonly described as drivers of oncogenesis. 
However, after many attempts to develop an inhibitor, KRAS was deemed “undruggable”20 and 
pharmacologic development turned its attention downstream to MEK. As the kinase 
downstream of RAS and RAF, MEK appeared to be a great opportunity for stopping pathway 
over-activation originating from RAS, RAF, and MEK mutations. This led to the eventual 
development and approval of trametinib.21 

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Despite the clinical success of these inhibitors, experience quickly demonstrated that resistance 
persistently develops 6 – 8 months after the start of BRAF and MEK therapies.16,17 Combining 
MEK and BRAF inhibitors seemed to delay the development of secondary resistance and 
generated approval for multiple BRAF and MEK inhibitor combinations.16-19 Combined inhibition 
of the MAPK pathway has demonstrated improved efficacy and delayed the development of 
resistance in melanoma20,21 and non-small cell lung cancer.22,23 Yet even with inhibition at two 
points in the MAPK pathway, patients that initially demonstrate a response acquire resistance 
and disease progression soon after starting therapy.  
4.4.1 Mechanisms of Resistance  
The secondary or acquired mechanisms of resistance that arise from MAPK pathway inhibition 
are classified into pathway-dependent and pathway independent. Pathway-dependent based 
resistance arises as an “escape” from pathway inhibition. By this mechanism, BRAF and MEK 
kinases develop alternative mutations that block the binding pocket used by inhibitors.16,17,24 
Pathway independent resistance is characterized by overexpression of regulating tyrosine 
kinases to compensate for pathway inhibition or increased cross-talk from the AKT pathway 
which activates ERK. 3 However, either mechanism of resistance leads to ERK reactivation. 
However, a new understanding of the connection between the autophagy and the MAPK 
pathways is developing. Cytoprotective autophagy is a catabolic pathway that includes the 
lysosomal degradation of proteins to support cellular metabolism during times of cellular stress. 
28 By recycling cellular components, the cancer cell manages to continue to fuel its high 
metabolic needs despite the potentially cytotoxic effects of pathway inhibition. Not only do 
MAPK-mutated cells rely on a higher level of baseline autophagy26, but it has also been 
demonstrated that cells with higher levels of resistance also have increased levels of 
autophagy. 27 Kinsey et al. have shown that inhibition of KRAS→RAF→MEK→ERK signaling in 
pancreatic ductal adenocarcinoma cell lines elicits autophagy, a process of cellular self-
consumption. 28  
Ojha et al. have described a process by which ERK reactivation and autophagy arise when 
MEK or BRAF inhibitors are introduced.30 They demonstrated that with the introduction of MEK 
and BRAF inhibitors, the MAPK pathway is translocated into the endoplasmic reticulum (ER). 
Within the ER, the accumulation of proteins produces ER stress and initiates the Unfolded 
Protein Response (UPR) in an effort to restore ER proteostasis. 28 UPR initiation causes GRP78 
to disassociate from Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK). PERK, in 
turn, upregulates the transcription of ATF4 and phosphorylates ERK.25,29 In turn, pERK 
phosphorylates ATF4 which increases cellular autophagy and cell survival. 
Therefore, as the last master kinase in the MAPK pathway and a key to acquired resistance, 
ERK plays a large role in oncogenesis and is an appealing target for pharmacologic inhibition.  
4.4.2 Pre-Clinical Experience 
Due to the complex interaction between the autophagy pathway and ERK, the combination of 
pathway inhibition and an autophagy inhibitor should have complementary effects. Combined 

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inhibition of MEK1/2 and autophagy with chloroquine (CQ) has displayed synergistic anti-
proliferative effects against pancreatic ductal adenocarcinoma (PDAC) cell lines in vitro. 28 Most 
strikingly, whereas single-agent therapy had modest effects, combined treatment of xenografted 
patient-derived PDAC tumors with trametinib plus chloroquine/ hydroxychloroquine elicited 
striking tumor regression. In these experiments, the regression elicited by trametinib plus 
chloroquine/hydroxychloroquine was superior to gemcitabine/ nab-paclitaxel, standard of care 
chemotherapy. Similar effects have been seen in BRAF inhibitor-resistant melanoma. 27  
Bryant et al. combined ERK (ulixertinib) and autophagy inhibition (chloroquine) in KRAS 
mutated PDAC cells.30 They demonstrated that ERK inhibition and suppression of KRAS 
increased cellular dependence on autophagy for survival. When chloroquine was added as an 
autophagy inhibitor, synergistic antitumor activity was observed in organoid and PDX models.  
4.5 
Investigational Intervention 
4.5.1 Ulixertinib 
Ulixertinib is a highly potent small-molecule inhibitor of extracellular signal-regulated kinase, 
ERK1 and ERK2. It competitively and reversibly binds to the adenosine triphosphate (ATP) 
binding site in a dose-dependent manner. It effectively binds with ERK in its phosphorylated and 
de-phosphorylated state thereby inhibiting phosphorylation of ERK substrates. Ultimately, this 
inhibition of downstream signaling leads to inhibition of cell proliferation and survival.) 
Following administration, ulixertinib plasma concentration reaches maximum observed 
concentration (Cmax) in 3 to 4 hours (tmax) and remains sustained for about 2 to 4 hours. After 
reaching Cmax, plasma concentrations slowly decline with a half-life (t1/2) ranging from 4 to 
6 hours. Ulixertinib is primarily metabolized by CYP3A4 and to a lesser extent CYP2D6 and 
CYP1A2 by oxidation and de-alkylation. No significant cytochrome P450 (CYP) induction was 
observed after up to 14 days of drug treatment in rats. In vitro, human liver microsome studies 
do demonstrate ulixertinib to induce CYP1A2, CYP2B6, and CYP3A4 mRNA expression, whilst 
also directly inhibiting CYP2C8 and CYP3A4/5. These data suggest limited potential for drug-
drug interactions. Fecal excretion is the primary route of elimination around 82% with about 15% 
excreted renally. 
The most commonly reported treatment-related AEs are consistent with other drugs that inhibit 
the MAPK pathway: fatigue, diarrhea, nausea, dermatitis acneiform, and vomiting. However, 
phototoxicity, hematologic, hepatic, ophthalmologic, and cardiac effects have been noted in a 
small proportion of patients. Refer to the most recent Investigator’s Brochure (IB) for more 
information. 
4.5.2 Previous Human Experience 
Ulixertinib has been administered to humans in 5 commercially sponsored clinical studies, 4 
Investigator sponsored trials and 3 NCI sponsored trials to date:  

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Table 4: Previous Human Experience with Ulixertinib 
Study Type 
Study Identifiers 
Status/Results 
Commercial 
sponsored 
NCT01781429  
BVD-523-01 
Phase 1 Dose-Escalation, 
Safety, Pharmacokinetic and 
Pharmacodynamic Study of 
BVD-523 in Patients with 
Advanced Malignancies.  
In the first in human, phase I study of ulixertinib a total of 
135 patients were enrolled in the dose escalation and dose 
expansion phases of the study. Twenty-seven patients were 
enrolled in the dose escalation phase (10-900 mg b.i.d.). The 
maximum tolerated dose (MTD) and recommended phase 2 
dose (RP2D) was determined to be 600 mg twice daily given 
continuously. Dose-limiting toxicities (DLT) included rash, 
diarrhea, elevated AST, and elevated creatinine. Drug 
exposure was dose proportional up to the RP2D, which 
provided near-complete inhibition of ERK activity in whole 
blood. In the expansion cohort (108 patients), there were no 
drug-related deaths; however, 32% of patients required a 
dose reduction. The most common adverse events (AEs) at 
RP2D, regardless of attribution, were diarrhea (50%), fatigue 
(50%), nausea (45%), decreased appetite (31%), and 
dermatitis acneiform (31%). In addition to 3 patients with 
partial responses during escalation (11%), an additional 11 of 
81 (14%) evaluable patients at expansion had a partial 
response: 1 BRAFV600E mutant melanoma patient refractory 
to prior BRAF/MEK inhibitor treatment, 3 NRAS mutant 
melanoma patients, 3 patients with BRAF mutant lung 
cancers including response in brain metastases, 1 with 
BRAFV600E mutant glioblastoma multiforme, 1 with BRAFG469A 
head & neck cancer, 1 with BRAFG469A small-bowel cancer, 
and 1 with BRAFL485W gallbladder cancer. The duration of 
response ranged from 2 to 24+ months (82, 98). A total of 
28 evaluable patients whose BRAF mutations were not at 
amino acid V600 were included in the BVD-523-01 solid 
tumor study of ulixertinib. 
Commercial 
sponsored 
NCT00296242 
BVD-523-02  
Phase 1/2 Dose-Escalation, 
Safety, Clinical Activity, 
Pharmacokinetic and 
Pharmacodynamic Study of the 
ERK 1/2 Inhibitor BVD-523 in 
Patients with Acute Myelogenous 
Leukemia or Myelodysplastic 
Syndromes 
An open-label, multicenter Phase I/II study to determine the 
safety, tolerability, and pharmacokinetic profile of ulixertinib in 
patients with acute myelogenous leukemia (AML) or 
myelodysplastic syndromes (MDS), as well as to assess 
clinical response, progression-free survival (PFS), and 
duration of response in those patients. The study consisted of 
2 parts: Part 1 was a dose-escalation phase to investigate 
safety and determine the MTD and the RP2D, and Part 2 was 
a cohort-expansion phase using the RP2D to examine safety, 
and to identify early indications of clinical effects. Patients 
received continuous twice-daily oral dosing with ulixertinib in 
21-day cycles. A total of 18 patients received at least one 
dose of ulixertinib in the dose-escalation phase (300-750mg 
b.i.d.). In Part 1, the MTD and RP2D were determined to be 
600 mg b.i.d., and this is the dose that was tested in the 
cohort-expansion phase (Part 2) of the study. A total of 
35 patients received at least one dose of ulixertinib in the 
cohort-expansion phase of the study. Of the 35 patients in 
Part 2, 14 patients (40%) were RAS mutant positive, and 
21 patients (60%) were RAS mutant negative. The most 
frequently reported study drug-related events at RP2D were 
diarrhea (31%), nausea (20%), increased creatinine (17%), 
vomiting (9%), and rash (5%). All bone marrow biopsies in 
Part 1 showed less than partial response. In Part 2, one 
patient with RAS (+) AML, had complete remission with 

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Study Type 
Study Identifiers 
Status/Results 
incomplete platelet recovery (CRp) at two sequential visits. A 
second patient with RAS (-) AML, had a complete response 
(CR) on cycle 2, day 1. All other evaluations in Part 2 AML 
patients showed less than partial response (PR). A third 
patient with RAS (+) MDS had a PR on cycle 2, day 1. All 
other bone marrow evaluations in Part 2 MDS patients 
showed less than PR. 
Commercial 
sponsored 
NCT02994732 
BVD-523HV001 
A Phase 1 Study to Investigate 
the Absorption, Metabolism, and 
Excretion of [14C] BVD-523 
Following Single Oral Dose 
Administration in Healthy Male 
Subjects 
The purpose of study BVD-523HV001 was to evaluate the 
absorption and excretion characteristics as well as relevant 
pharmacokinetic properties of ulixertinib; and to characterize 
and, where possible, identify the metabolites present in 
plasma, urine, and feces in healthy male subjects following a 
single dose of 600mg (approximately 200 μCi) of [14C]-
ulixertinib. The secondary objective of this study was to 
evaluate the safety and tolerability of a single oral dose of 
[14C]-labeled ulixertinib in healthy male subjects. A total of 
6 subjects were enrolled. The absorption of ulixertinib (BVD-
523) was moderate and after reaching Cmax, concentrations 
of ulixertinib (BVD-523) in plasma appeared to decline in a 
generally biphasic manner. Ulixertinib (BVD-523) undergoes 
moderate metabolism to produce 13 identified/characterized 
metabolites in plasma and excreta. The metabolites BVD-
502+BVD503 and BVD-513 were formed moderately rapidly 
and their plasma concentration-time profiles generally 
mirrored that of parent drug, suggesting formation rate limited 
elimination. The metabolite BVD-506 was found to be present 
and disproportionate levels compared to levels measured in 
pre-clinical in vivo studies. The primary route of elimination 
was through fecal excretion. No clinically significant findings 
with respect to clinical laboratory, vital signs, 
electrocardiogram (ECG), or physical examinations. Fatigue 
and diarrhea were reported for 2 subjects (33%) and were 
possibly related to study drug. All treatment-emergent AEs 
(TEAEs) were of mild severity and there were no moderate or 
severe events reported. 
Commercial 
sponsored 
BVD-523A-FE 
A Randomized, Open-Label, 
Single-Dose, 2-Way Crossover 
Study to Evaluate the Effect of 
Food on the Pharmacokinetics, 
Safety and Tolerability of Orally 
Administered BVD-523 in 
Healthy Volunteers 
A Phase I, randomized, open-label, single-dose, 2-way 
crossover study to assess the safety and PK in 14 healthy 
male and female subjects. Subjects received a single oral 
dose of BVD-523A (an investigational formulated blend of 
ulixertinib) in 2 different treatment periods; once after an 
overnight fast of at least 10 hours and once after 
consumption of an FDA-defined high-fat breakfast. There 
was a washout period of 5 days between dosing in one 
period and dosing in the next period. Subjects were 
randomized equally to receive 1 of 2 treatments sequences 
(fasted/fed or fed/fasted), with 7 subjects assigned to each 
sequence. Each subject received both treatments. 
Pharmacokinetic (PK) concentrations achieved in the fed 
group were considerably higher than observed in the fasted 
group. However, fasting and fed conditions were extreme. 
Collective experience in patients and healthy volunteers 
shows that best exposure and variability is achieved when 
ulixertinib is taken with food. There were no clinically 
significant findings with respect to clinical laboratory, vital 
signs, ECG, or physical examination. Headache in 2 subjects 
(14%) under fed conditions and diarrhea in 1 subject (7%) 

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Study Type 
Study Identifiers 
Status/Results 
under fasted conditions were considered by the investigators 
to be possibly related to the study drug. All TEAEs were of 
mild severity, and there were no moderate or severe events 
reported. 
Commercial 
sponsored 
BVD-523-FC 
A Randomized, Open-Label, 
Single-Dose, 2-Way Crossover 
Study Evaluating the 
Pharmacokinetics, Safety, and 
Tolerability of two oral 
formulations of Ulixertinib (BVD-
523) in Healthy Volunteers 
A Phase I, randomized, open-label, single-dose, 2-way 
crossover study to assess the effect of two oral formulations 
of ulixertinib on the PK, safety, and tolerability of a single oral 
dose of 600mg ulixertinib in 14 healthy male and female 
subjects. The oral formulations included a single dose of 
600mg powder in capsule (PIC) formulation and a single oral 
dose of 600mg formulated blend formulation of ulixertinib. 
Subjects were randomized equally to receive 1 of the 2 
treatment sequences with 7 subjects assigned to each 
sequence and a washout period of 5 days separated the 
treatments. The formulated blend formulation produced peak 
and total systemic exposures which were slightly lower than 
PIC formulation. Additionally, the AUClast and AUCinf of the 
formulated blend formulation were approximately 25% lower 
than compared to PIC formulation. No clinically significant 
findings with respect to clinical laboratory, vital signs, ECGs, 
or physical examinations. Headaches were reported in 
4 subjects (29%) and were possibly related to study drug. All 
other possibly related TEAEs were only reported by 1 subject 
(7%). All events were of mild severity, except for 1 event of 
urticaria, which was of moderate severity. 
Commercial 
sponsored 
NCT04488003 
BVD-523-ABC 
A Two-Part, Phase II, Multi-
center Study of the ERK Inhibitor 
Ulixertinib (BVD-523) for Patients 
with Advanced Malignancies 
Harboring MEK or Atypical BRAF 
Alterations 
Ongoing 
Investigator 
sponsored 
NCT02608229 
Phase Ib Study of BVD-523 Plus 
Nab-Paclitaxel and Gemcitabine 
in Patients with Metastatic 
Pancreatic Cancer 
Study was stopped after part 1 (dose escalation) due to 
tolerability issues experienced from the triple combination 
treatment. 
Investigator 
sponsored 
NCT03454035 
A Phase I Trial of Ulixertinib 
(BVD-523) in Combination with 
Palbociclib in Patients with 
Advanced Solid Tumors with 
Expansion Cohort in Previously 
Treated Metastatic Pancreatic 
Cancer 
Ongoing 
Investigator 
sponsored 
NCT04145297 
Phase 1 study of ulixertinib and 
hydroxychloroquine in patients 
with advanced MAPK-mutated 
Ongoing 

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Study Type 
Study Identifiers 
Status/Results 
gastrointestinal 
adenocarcinomas 
Investigator 
sponsored 
NCT03417739 
A Phase II Study of BVD-523 in 
Metastatic Uveal Melanoma 
In interim analysis of 13 patients, 4 patients had best 
response of stable disease (SD) (31%), 7 had best response 
of progressive disease (54%), and 2 were unevaluable for 
response (15%). According to the Simon design, the trial 
stopped recruitment at this point due to lack of responders in 
the first stage. 
Investigator 
sponsored 
NCT04566393 
Expanded Access to Ulixertinib 
(BVD-523) in Patients with 
Advanced MAPK Pathway-
Altered Malignancies 
Ongoing 
NCI 
sponsored 
NCT03155620 
Targeted Therapy Directed by 
Genetic Testing in Treating 
Pediatric Patients with Relapsed 
or Refractory Advanced Solid 
Tumors, Non-Hodgkin 
Lymphomas, or Histiocytic 
Disorders (The Pediatric MATCH 
Screening Trial) 
Ongoing 
  
NCI 
sponsored 
NCT02465060 
Targeted Therapy Directed by 
Genetic Testing in Treating 
Patients with Advanced 
Refractory Solid Tumors, 
Lymphomas, or Multiple 
Myeloma (The MATCH 
Screening Trial) 
Ongoing 
 
NCI 
sponsored 
NCT03698994 
Ulixertinib in Treating Patients 
with Advanced Solid Tumors, 
Non-Hodgkin Lymphoma, or 
Histiocytic Disorders with MAPK 
Pathway Mutations (A Pediatric 
MATCH Treatment Trial) 
Ongoing 
 
4.5.3 Hydroxychloroquine 
Hydroxychloroquine is an old drug originally approved for the treatment and prevention of 
malaria. While the exact mechanism of action is still not well understood, it has been shown to 
inhibit lysosomal acidification and prevent the degradation of autophagosomes. This inhibition 
suppresses the process of autophagy, the cellular survival mechanism.  
Due to extensive distribution and protein binding after absorption, hydroxychloroquine has a 
long half-life ranging from 40-50 days. 40-50% of the drug is excreted renally and 24-25% 
eliminated through the feces.  

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Hydroxychloroquine has a known risk for QT interval corrected (QTc) prolongation and 
Torsades de Pointes (TdP). Therefore, caution should be used when administering other 
medications of TdP risk. Refer to the package insert for more information.  
4.5.4 Dose Rationale  
Hydroxychloroquine has been FDA approved for the treatment of malaria, lupus erythematosus, 
and rheumatoid arthritis at doses ranging from 200 mg to 600 mg daily. Due to the increased 
risk of retinopathies, it is recommended not to exceed 600 mg daily for long term maintenance. 
However, it is only with chronic exposure that retinopathies are observed. The rate of 
retinopathies dramatically increases after 5 years of hydroxychloroquine use and a cumulative 
dose of over 1000 g (total).31 Multiple trials have conducted investigations of 600 mg twice-daily 
dosing for the treatment of cancers and have found the dose safe and tolerable. 32-34 Wolpin et 
al. found similar adverse event profiles between 400 mg and 600 mg twice-daily dosing of 
single-agent hydroxychloroquine in pancreatic cancer patients.34 At this dose level, it would take 
approximately 2.25 years to reach a total accumulated dose of 1000 g. It is not anticipated that 
patients will exceed 12 months of treatment while on this trial. Therefore, due to the relatively 
short-term use of hydroxychloroquine and the similar adverse event profile, 600 mg twice-daily 
dosing will be utilized for the study combination.  
Ulixertinib (first-in-class ERK1/2 inhibitor) has been tested in a rapid phase I dose-escalation 
and expansion study that enrolled 135 patients. Doses from 10 to 900 mg twice daily were 
explored and the recommended phase 2 dose of 600 mg twice daily was found. It was well 
tolerated, and all toxicities were manageable and reversible. The most common treatment-
related AEs were diarrhea, fatigue, nausea, and dermatitis acneiform. In this monotherapy 
setting including a diverse patient population, about 14% of the response evaluable patients 
dosed at or above the MTD experienced a partial response (PR). Patients demonstrating a 
response included NRAS, BRAFV600, and BRAFnon-V600 mutant solid tumors. 35  
In an expanded access protocol, ulixertinib is used to treat patients with advanced MAPK 
pathway-altered malignancies (NCT04566393). At the time of this protocol submission, 
9 patients have received the combination of ulixertinib (dose ranges of 300 – 450 mg BID) and 
hydroxychloroquine (dose ranges of 200 – 600 mg BID). The dose of ulixertinib 450 mg BID 
combined with hydroxycholorquine 600 mg BID has been used to treat 4 of those patients with 
2 of those patients on treatment for 21 and 39 days. The safety profile observed in these 
patients receiving this combination has been similar to the safety profile of the individual agents. 
In the phase I, dose-escalation trial ulixertinib was safely combined with hydroxychloroquine 
(NCT04145297) in a 6-patient cohort at 450 mg BID and 600 mg BID, respectively. There were 
6 AEs, but only 2 were considered related to ulixertinib and no SAEs were reported. One patient 
experienced grade 1 fatigue and another patient experienced grade 3 QT prolongation. The 
event of QT prolongation was considered probably related to both hydroxychloroquine and 
ulixertinib, and the patient had both drugs held until resolution. The patient was subsequently 
restarted on full dose ulixertinib and hydroxychloroquine at a reduced dose level of 800mg QD. 

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4.5.5 Drug-Drug Interaction Assessment 
Based on the characteristics of each ulixertinib and hydroxychloroquine, drug-drug interaction 
(DDI) potential among ulixertinib and hydroxychloroquine exists for the following reasons:  
• 
In vitro, human liver microsome studies demonstrate ulixertinib to induce CYP1A2, 
CYP2B6, and CYP3A4 mRNA expression, whilst also directly inhibiting CYP2C8 and 
CYP3A4/5.   
• 
Hydroxychloroquine is metabolized by CYP3A4.  
However, the DDI potential may be limited for the following reasons: 
• 
No significant CYP induction was observed after up to 14 days of ulixertinib treatment in 
rats.  
• 
The drugs do not share metabolic or elimination pathways except for CYP3A4:  
o Ulixertinib is metabolized by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A4 and extensively eliminated in feces. 
o Hydroxychloroquine is metabolized by CYP3A4 and is primarily excreted renally. 
While both medications are metabolized by CYP3A4, ulixertinib has the option for metabolism 
by multiple alternative CYP enzymes. Ultimately DDI potential will be defined by 
pharmacokinetic evaluations of ulixertinib and hydroxychloroquine administered at a tolerated 
combination dose in treated patients. 
4.5.6 Clinical Experience 
Hydroxychloroquine, the most widely used autophagy inhibitor, has been safely combined with 
multiple anti-cancer therapies in the past and these trials have generated preliminary data to 
support the theory that an autophagy inhibitor could overcome acquired therapeutic resistance. 
32,33,36,37 Hydroxychloroquine is also currently under investigation in combination with the MEK 
inhibitor, trametinib, and has been well tolerated (NCT03825289). 
In the phase 1b dose-escalation portion of the ulixertinib combined with palbociclib trial 
(NCT03454035), an MTD was achieved at the doses of ulixertinib 450mg BID combined with 
palbociclib 125 mg daily. This combination dose demonstrated SD in 3 patients, one of which 
with metastatic pancreatic cancer remained on study for over 12 months. The PK analysis for 
ulixertinib and palbociclib was linear and consistent with previously published data. One grade 3 
hyponatremia was reported in this dose combination and three patients demonstrated stable 
disease with one patient remaining on study for over 12 cycles. 

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5 
OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objectives 
• 
To assess the safety and tolerability of ulixertinib and hydroxychloroquine in patients 
with advanced, RAS, non-V600 BRAF, MEK1/2 (MAP2K1/2), or ERK1/2 (MAPK3/1) 
mutated gastrointestinal malignancies. 
Primary endpoint: The incidence and frequency of adverse events (AEs) and 
serious adverse events (SAEs) characterized by type, severity (as defined by the 
NCI CTCAE, version 5.0), seriousness, duration, and relationship to study 
treatment. 
• 
To assess the efficacy of ulixertinib and hydroxychloroquine in patients with advanced, 
RAS, non-V600 BRAF, MEK1/2 (MAP2K1/2), or ERK1/2 (MAPK3/1) mutated 
gastrointestinal malignancies. 
Primary Endpoint: Overall response rate as defined by the proportion of patients 
achieving a confirmed partial response or complete response (CR) [defined by 
RECIST 1.1] as evaluated by the local treating investigator. 
5.2 
Secondary Objective 
• 
To assess the duration of efficacy of ulixertinib and hydroxychloroquine in patients with 
advanced, RAS, non-V600 BRAF, MEK1/2 (MAP2K1/2), or ERK1/2 (MAPK3/1) mutated 
gastrointestinal malignancies. 
Secondary Endpoint: Progression-free survival (PFS) as defined as the time from 
study drug initiation to the time of documented disease progression (as assessed 
by RECIST 1.1) or death from any cause.  
5.3 
Exploratory Objective 
• 
To evaluate the bioactivity of ulixertinib and hydroxychloroquine against ERK1/2 
(MAPK3/1), autophagy pathways, and pharmacodynamic biomarkers. 
Exploratory Endpoint:  
o Pharmacokinetics of ulixertinib and hydroxychloroquine 
o Blood and/or tissue samples used to assess biomarkers (RPPA, Nanostring, 
ctDNA are assays planned but not limited to only these) 

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6 
STUDY DESIGN 
6.1 
Overall Design 
This is an open-label, multicenter, phase 2 basket study of ulixertinib in combination with 
hydroxychloroquine in patients with advanced gastrointestinal malignancies harboring RAS, 
non-V600 BRAF, MEK1/2, or ERK1/2 mutations. The trial will have five baskets based on 
disease primary as listed below. 
• 
Basket 1: Cholangiocarcinoma including intrahepatic cholangiocarcinoma, perihilar 
cholangiocarcinoma, or extrahepatic cholangiocarcinoma; 
• 
Basket 2: Pancreatic adenocarcinoma; 
• 
Basket 3: Colorectal adenocarcinoma; 
• 
Basket 4: Esophageal adenocarcinoma, esophageal squamous cell carcinoma, or 
gastroesophageal junction (GEJ) adenocarcinoma; 
• 
Basket 5: Gastric adenocarcinoma. 
To assess eligibility, cancer mutational status must be confirmed through patient medical 
records by treating physician. Once deemed eligible, ulixertinib and hydroxychloroquine will be 
orally administered twice daily on 28-day cycles. Safety will be assessed regularly through the 
monitoring of AEs, laboratory values, physical exams, vital signs, echocardiogram, eye exams, 
and ECGs. Disease assessments will be performed regularly as well to assess treatment 
efficacy. Upon disease progression, patients will be followed for safety.  
While the overall trial is a basket design, each individual basket will operate using a Simon two-
stage design independently of the other baskets.  
The first stage in each basket will open to enrollment and remain open until 13 patients are 
declared evaluable for response, at which time enrollment will be placed on hold for the 
evaluation of efficacy. To be evaluable for this stage 1 efficacy analysis, a patient must have 
completed at least one cycle of therapy and must have at least 75% of the prescribed doses of 
ulixertinib and hydroxychloroquine during cycle 1. Non-evaluable patients may remain on study 
treatment if deemed to be clinically benefiting by the treating Investigator.  
The stage 1 efficacy analysis will occur when all evaluable patients have had at least one post-
treatment disease evaluation or have discontinued study treatment due to clinical progressive 
disease or drug-related AEs. Patients who have discontinued study treatment due to clinical 
progressive disease or drug-related AEs prior to the first efficacy evaluation will be considered 
non-responders. If a patient in the first 13 evaluable patients has an unconfirmed partial or 
complete response but has not yet had a confirmatory scan at the time of the stage 1 efficacy 
analysis, that patient may be counted as a responder for the purposes of the Stage 1 
evaluation. If ≥ 4 of the first 13 evaluable patients in stage 1 have a complete or partial 

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response, with permission of the Safety Monitoring Committee (SMC) the sponsor may open 
enrollment to stage 2 for that basket. Stage 2 will expand enrollment of each basket until a total 
of 43 patients, including those enrolled during stage 1, have been enrolled. Any patient deemed 
non-evaluable for the primary efficacy endpoint may be replaced.  
An internal SMC will be charged with assuring risk/benefit balance for patients involved in the 
study. They will make study conduct recommendations based on emerging safety and efficacy 
data. Stage 2 of enrollment on each basket will not open until data review and approval from the 
SMC.  
6.2 
Number of Patients 
Total enrollment for stage 1 is targeted at approximately 65 patients with 13 patients per group. 
Additional patients may be enrolled as appropriate. 
Total enrollment for stage 2 is targeted to approximately 150 patients with up to 30 patients per 
group. Additional patients may be enrolled as appropriate.  
6.3 
Number of Study Sites 
The study will take place at sites within the United States. Approximately 10 sites will be utilized, 
however, additional sites may be added. Clinical trial networks may be utilized. Each study site 
may enroll as many eligible patients as possible. 
6.4 
End of Study  
As the primary endpoint of the study is overall response, a patient is considered to have 
completed the study upon disease progression or death, whichever comes first.  
The study will end when the last patient remaining on study has disease progression per 
RECIST 1.1, initiates subsequent anti-cancer therapy, or dies, whichever occurs first. In 
addition, the sponsor may terminate the study at any time. If the sponsor terminates the study, 
all effort will be made to ensure continued access to study treatment for any patients receiving 
clinical benefit from the study intervention.  
7 
STUDY POPULATION 
Potential study participants must meet all inclusion criteria and no exclusion criteria to be 
deemed eligible for trial participation. To ensure patient safety, all patients must be deemed 
eligible at the time of study registration and must continue to meet eligibility criteria up to cycle 1 
day 1 dosing.  
7.1 
Inclusion Criteria 
1. Male or female patient aged ≥ 18 years. 

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2. Histologically confirmed esophageal adenocarcinoma, esophageal squamous cell 
carcinoma, GEJ adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, 
intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, extrahepatic 
cholangiocarcinoma, or colorectal adenocarcinoma harboring a MAPK-mutated GI 
malignancy: KRAS, NRAS, HRAS, BRAF non-V600, MEK1/2 (MAP2K1/2), or ERK1/2 
(MAPK3/1). 
3. Patients must have been previously treated with one or more lines of anti-cancer therapy 
and have documented disease progression during or after their most recent line of anti-
cancer treatment subject to the restrictions below (variations of standard of care may 
exist and are acceptable): 
• 
Patients with intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, 
or extrahepatic cholangiocarcinoma who have progressed during or after 
receiving a first-line regimen of gemcitabine/cisplatin unless deemed 
ineligible by the treating investigator to receive gemcitabine/cisplatin 
regimens due to prior comorbidities. Patients who are currently stable on 
second-line or beyond regimens but, in the opinion of the investigator have 
become intolerant to current treatment are also eligible for trial participation. 
• 
Patients with pancreatic adenocarcinoma must have progressed during or 
after first-line therapy of FOLFIRINOX/ mFOLFIRINOX, or gemcitabine/nab-
paclitaxel unless deemed ineligible by the treating investigator to receive 
chemotherapy-based regimens due to prior comorbidities. 
• 
Patients with colorectal adenocarcinoma must have progressed during or 
after two lines of therapy, including FOLFOX ± Avastin and FOLFIRI ± 
Avastin, unless deemed ineligible by the treating investigator to receive 
chemotherapy-based regimens due to prior comorbidities. 
• 
Patients with esophageal adenocarcinoma, esophageal squamous cell 
carcinoma, GEJ adenocarcinoma, or gastric adenocarcinoma who  have 
progressed during or after their first two lines of therapy. Patients who are 
currently stable on second-line or beyond regimens but, in the opinion of the 
investigator, have become intolerant to current treatment are also eligible for 
trial participation. 
o Acceptable first-line regimens: FOLFOX, 5-FU/Cisplatin, FOLFIRI, 
Paclitaxel/Cisplatin or Carboplatin, Docetaxel/Cisplatin, DCF (or 
modifications thereof), or ECF (or modifications thereof) unless 
deemed ineligible by the treating investigator to receive 
chemotherapy-based regimens due to prior comorbidities. 
o Acceptable second-line regimens: Ramucirumab/Paclitaxel, 
Docetaxel, Paclitaxel, Irinotecan, Trifluridine/Tipiracil, or FOLFIRI, 

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unless deemed ineligible by the treating investigator to receive 
chemotherapy-based regimens due to prior comorbidities. 
• 
Patients with dMMR/MSI-H tumors must have progressed during or after 
immunotherapy. 
4. Measurable disease by RECIST 1.1 criteria by CT or Magnetic resonance imaging 
(MRI). 
5. Willing to provide a biopsy at the time points indicated on the Schedule of Activities. 
6. ECOG Performance Status ≤ 1. 
7. Adequate organ function as defined as:  
• 
Hematologic: 
o Absolute neutrophil count (ANC) ≥ 1500/mm3 
o Platelet count ≥ 100,000/mm3 
o Hemoglobin ≥ 9 g/dL 
• 
Hepatic:  
o Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) 
o AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN 
▪ 
Patients with liver metastases will be allowed to enroll with 
AST and ALT levels ≤ 5 x ULN. 
• 
Renal:  
o Estimated creatinine clearance (CLcr)≥ 50 mL/min by Cockcroft-Gault 
formula:  
▪ 
Males: 
(140−𝑎𝑔𝑒) × 𝑤𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔]
𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔
𝑑𝐿] × 72 
▪ 
Females: (
(140−𝑎𝑔𝑒) × 𝑤𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔]
𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔
𝑑𝐿] × 72) × 0.85  
8. For female patients: Negative serum pregnancy test within 72 hours prior to first dose of 
study drugs for women of childbearing potential. The following definitions apply: 
• 
Women of childbearing potential, defined as a sexually mature woman: 

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o Has not been naturally post-menopausal for at least 12 consecutive 
months (i.e., who has had menses anytime in the preceding 12 
consecutive months).  
o Has not undergone menopause, surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
• 
Women not of childbearing potential: 
o Amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, if any.  
o Underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
9. Male and female patients of childbearing potential agree to use highly effective 
contraception throughout the study and at least 90 days after the last study treatment 
administration (see Section 7.3.1). 
10. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior 
cancer therapy, unless considered clinically not significant by the treating investigator. 
11.  Able to provide informed consent and willing to sign an approved consent form that 
conforms to federal and institutional guidelines. 
7.2 
Exclusion Criteria 
1. Received systemic antineoplastic therapy (including unconjugated therapeutic antibodies 
and toxin immunoconjugates) or any investigational therapy ≤ 14 days or within five half-
lives prior to starting study treatment, whichever is shorter. 
2. Received radiotherapy ≤ 14 days prior to the first dose of study treatment.  
Note: Localized radiation therapy for the treatment of symptomatic bone metastasis is 
allowed during that timeframe. 
3. Undergone major surgery ≤ 3 weeks prior to starting study drug or who have not fully 
recovered from major surgery. 
4. The diagnosis of another malignancy within ≤ 3 years before study enrollment, except for 
those considered to be adequately treated with no evidence of disease or symptoms 
and/or will not require therapy during the study duration (e.g., basal cell or squamous 
cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, or low-grade 
prostate cancer with Gleason Score ≤ 6).  
5. Known uncontrolled brain metastases or cranial epidural disease. 

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Note: Patients with stable brain metastases/cranial epidural disease either treated or 
being treated with a stable dose of steroids (<20 mg of prednisone daily or equivalent) or 
anticonvulsants, with no dose change within 4 weeks before the first study drug dose, 
and no anticipated dose change, are eligible. In the event of steroid taper post-radiation 
therapy, taper must be complete within 2 weeks before baseline.    
6. History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion 
(RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular 
hypertension, history of hyperviscosity).  
7. Current evidence of uncontrolled, significant intercurrent illness including, but not limited 
to, the following conditions: 
• 
Cardiovascular disorders: 
o Congestive heart failure (CHF) New York Heart Association Class 3 or 
4, unstable angina pectoris, serious cardiac arrhythmias.  
o Stroke (including transient ischemic attack [TIA]), myocardial 
infarction (MI), or other ischemic events, or thromboembolic event (eg, 
deep venous thrombosis, pulmonary embolism) within 3 months 
before the first dose.  
o QTc prolongation defined as a QTcF >470ms. 
o Known congenital long QT. 
o Left ventricular ejection fraction < 50%. 
• 
History of seizures. 
• 
Impairment of gastrointestinal function or gastrointestinal disease (e.g., 
ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption 
syndrome). 
• 
Any other condition that would, in the Investigator’s judgment, contraindicate 
the patient’s participation in the clinical study due to safety concerns or 
compliance with clinical study procedures (e.g., infection/inflammation, 
intestinal obstruction, unable to swallow medication, [patients may not receive 
the drug through a feeding tube], social/ psychological issues, etc.) 
8. Prior stomach or duodenal resection that in the opinion of the Principal Investigator and 
Medical Monitor would affect the breakdown and absorption of the study medications. A 
patient with a feeding tube should also be excluded, as ulixertinib capsules cannot be 
taken apart.  

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Note: Ulixertinib is primarily absorbed in the duodenum and therefore patients with any 
prior stomach or duodenal resection should be discussed with the Medical Monitor. 
9. Known Human immunodeficiency virus (HIV) infection with a detectable viral load within 
6 months of the anticipated start of treatment. 
Note: Patients on effective antiretroviral therapy with an undetectable viral load within 6 
months of the anticipated start of treatment are eligible for this trial. 
10. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination, radiographic findings, and TB testing in line with local practice), 
hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.  
Note: Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients 
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is 
negative for HCV RNA. 
11. Medical, psychiatric, cognitive or other conditions that may compromise the patient's 
ability to understand the patient information, give informed consent, comply with the 
study protocol or complete the study. 
12. Known prior severe hypersensitivity to investigational product (IP) or any component in 
its formulations (NCI CTCAE v5.0 Grade ≥ 3). 
13. Patients taking prohibited medications as described in Section 8.7.2. A washout period 
of prohibited medications for a period of at least 5 half-lives or as clinically indicated 
should occur before the start of treatment. 
7.3 
Lifestyle Considerations 
7.3.1 Contraception 
Ulixertinib has not undergone testing in pregnant women, but because of known embryotoxic 
and abortifacient risk associated with MAPK inhibition, women of childbearing potential and men 
with partners of childbearing potential must exercise appropriate contraception to avoid 
pregnancy. Highly effective contraception must be used for the duration of study treatment and 
90 days after the last dose of study drug.  
Male patients must agree to use a condom (even after vasectomy) during treatment and for 90 
days after the last dose of study treatment. In addition, female partners of childbearing potential 
should also use a highly effective contraceptive method during the same time period.  
Acceptable highly effective contraceptive methods include: 
• 
Bilateral tubal occlusion 

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• 
Vasectomized partner 
• 
Intra-uterine device (IUD) or hormone-releasing system (IUS) 
• 
Any hormonal (estrogen combined with progesterone or progesterone alone) 
contraception associated with inhibition of ovulation: implanted, oral, intravaginal, 
transdermal, or injectable 
• 
The combination of spermicide with a compatible barrier method (i.e. diaphragm, 
sponge, or male or female condoms) 
• 
Abstinence from heterosexual intercourse 
7.4 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but who do 
not meet one or more criteria required for participation in the trial during the screening 
procedures. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure patients, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened (up to a maximum of 1 time for the same individual). Rescreened patients will be 
assigned a new patient identification number. Labs can be retested within the screening window 
and not count as a rescreen. 
7.5 
Strategies for Recruitment 
Patients will be recruited at sites around the United States. Site Principal Investigators will be 
responsible for the recruitment of eligible patients from their local clinics and communities.  
8 
STUDY DRUGS 
8.1 
Dosing and Administration 
Ulixertinib and hydroxychloroquine will be administered twice-daily on a 28-day cycle starting 
with cycle 1 day 1. Ulixertinib and hydroxychloroquine will be administered orally twice daily 
(every 12 hours ± 2 hours) together with food. Patients will be instructed to take the medications 
at approximately the same time every day.    
Patients should be instructed to swallow the study drug whole and not chew the capsule before 
swallowing. No capsule should be ingested if it is broken, cracked, or otherwise not intact. 
Patients should not take extra medication for any reason. A patient that is observed to vomit an 
intact capsule after dosing in the clinic during the PK measurements may receive a substitute 
dose of drug. However, patients should be instructed NOT to take a substitute capsule if 

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vomiting occurs after self-dosing at home. Missed doses should be skipped and not taken as a 
double dose at the next dosing timepoint.  
Patients will be provided enough ulixertinib and hydroxychloroquine for a full cycle to self-
administer at home. 
8.1.1 Study Drug Compliance 
The Investigator will dispense the study drugs only for use by patients enrolled in the study as 
described in this protocol in the SOA (Table 1). The study drugs are not to be used for reasons 
other than those described in this protocol. 
The Investigator or other study staff will supervise study drug treatment given in the clinic and 
instruct the patient on study drug self-administration. Patients will be asked to bring their study 
drug containers with them at the start of each cycle and compliance with protocol-defined study 
drug intake will be checked by pill count. In case of non-compliance, the patients will be 
instructed again on how to appropriately take study drug. 
Information pertaining to study drug compliance (i.e., date time, and dose) will be recorded in 
the electronic case report form (eCRF) by the study team. A member of the study team will 
review patient drug compliance at the end of each cycle and provide patient re-education as 
required. Any reason for non-compliance will be clearly documented in the patient’s research 
chart and the corresponding eCRF. At the discretion of the Principal Investigator, a patient may 
be discontinued from the trial for non-compliance with study visits or study drug. 
Patients will be required to return any unused medication or empty bottles at the end of every 
cycle. Unless prohibited by investigational site’s SOP, used study drug is to be retained until the 
monitor has verified drug accountability. Once the site monitor has verified drug accountability at 
the site, any drug remaining in opened dispensing containers will be destroyed. Unused and 
unopened study drug will be returned to the Sponsor. 
The total number of capsules dispensed, returned, and documented as taken will be reconciled 
to support drug accountability. Treatment compliance will be calculated and recorded separately 
for each drug. It will be recorded as a percentage defined as the number of doses taken divided 
by the expected number of doses taken multiplied by 100%. 
8.2 
Investigational Product Supplies 
BioMed Valley Discoveries, Inc. will provide both investigational products, ulixertinib and 
hydroxychloroquine. Product labeling and packaging will be in accordance with Good 
Manufacturing Practice (GMP) and applicable regulatory requirements. The investigator or 
appropriately trained and delegated personnel shall ensure appropriate accounting is 
maintained demonstrating receipt, distribution, and destruction of both investigational products. 
They should also ensure appropriate storage, handling, and distribution of the investigational 
products according to the protocol and any applicable laws and regulations.  

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8.2.1 Preparation and Dispensing 
The investigator or appropriately trained and delegated personnel will prepare and dispense all 
investigational supplies. The investigational products will be supplied only to patients deem 
eligible for study treatment. IP may not be dispensed to patients who have not been enrolled in 
the trial.  
8.2.2 Ulixertinib 
Ulixertinib drug substance is manufactured according to cGMP as a monohydrochloride salt and 
is supplied as a formulated powder blend comprised of standard excipients to support the 
manufacturing processes that is encapsulated in a hard gelatin capsule. Capsules (white) 
contain 150 mg of ulixertinib calculated on free base content and are packaged in white high-
density polyethylene (HDPE) bottles.  
8.2.3 Hydroxychloroquine 
Hydroxychloroquine will be supplied as sulfate tablets which are white, to off-white, film-coated 
tablets. Each tablet contains 200 mg hydroxychloroquine sulfate (equivalent to 155 mg base). 
Each bottle will contain 100 tablets and will be appropriately labeled according to regulations. 
8.2.4 
Product Storage and Stability 
Information will be provided in the pharmacy manual. 
8.3 
Dose Interruptions 
Dose interruptions for study treatment-related AEs are allowed as per the dose modification 
recommendations (Table 5). Doses of any investigational product that were not administered 
due to toxicity will not be replaced within the same cycle. In addition to dose interruption, the 
need for a dose reduction at the time of treatment resumption should also be considered based 
on the dose modifications recommendations. If toxicities require dose hold, both study drugs 
should be held and resumed concurrently. If a patient experiences a dose interruption, the SOA 
remains fixed according to cycle 1 day 1 (note that assessments that require a patient to be at 
steady-state and safety evaluations that are dose-dependent (ECG)), should be performed 
following the resumption of therapy). 
If a toxicity-related dose delay lasts for > 21 days, treatment will be discontinued permanently, 
and the patient should be removed from study treatment. If a patient requires a dose hold for > 
21 days for a non-treatment related adverse event or situation (i.e. radiation therapy) the patient 
may continue on study only after approval and discussion with the Sponsor and Medical 
Monitor. 
8.4 
Dose Reductions 
Following dosing interruption due to treatment-related toxicity, the offending agent may need to 
be resumed at a reduced dose as per the dose modification recommendations. Ulixertinib and 
hydroxychloroquine may be independently modified as necessary to address the emergence of 

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treatment-related toxicities. Dose reduction should proceed by decreasing the administered 
dose of the offending agent by one dose level per Table 5. 
Once the study treatment has been reduced for a given patient, all subsequent cycles will be 
administered at that dose level. Intra-patient dose re-escalation is not allowed except as 
described in the toxicity management guidelines, Table 6. 
Table 5: Ulixertinib and Hydroxychloroquine Dose Levels 
Dose Level  
Ulixertinib 
 
Dose Level 
Hydroxychloroquine 
Dose Level 0  
450 mg twice daily 
 
Dose Level 0 
600 mg twice daily 
Dose Level -1 
300 mg twice daily 
 
Dose Level -1 
800 mg daily  
Dose Level -2 
150 mg twice daily 
 
 
 
 
8.5 
Dose Modifications Guidelines 
Patients experiencing AEs attributed to either study drug may undergo dose modifications for 
toxicity management; however, the ultimate decision is up to the investigator’s discretion. Dose 
modification guidelines are provided below for AEs considered to be related to either study drug. 
If either ulixertinib or hydroxychloroquine requires a reduction below Dose Level -2 or Dose 
Level -1, respectively, for toxicity management, study treatment will be discontinued.  
 

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Table 6: Treatment-related adverse event management guidelines 
Adverse Event 
Severity 
Adverse Event Management 
Hematologic Toxicities 
Anemia 
Grade ≥ 3 
• 
Hold study treatment and monitor weekly. 
• 
Once resolved to grade ≤ 1, resume study treatment. 
• 
The doses of ulixertinib and hydroxychloroquine may be 
reduced by one dose level. 
Neutropenia with or without fever 
Grade ≥ 3 
• 
Hold study treatment and monitor weekly. 
• 
Once resolved to grade ≤ 1, resume study treatment. 
• 
The doses of ulixertinib and hydroxychloroquine may be 
reduced by one dose level. 
Thrombocytopenia  
Grade ≥ 3 
• 
Hold study treatment and monitor weekly. 
• 
Once resolved to grade ≤ 1, resume study treatment.  
• 
The doses of ulixertinib and hydroxychloroquine may be 
reduced by one dose level. 
Non-Hematologic Laboratory Toxicities 
Any clinically significant non-hematologic 
laboratory abnormality. 
Grade ≥ 3 
• 
Hold study treatment. 
• 
Resume once resolved to grade ≤ 1 or baseline. Reduce the 
offending agent(s) (as assessed by the treating investigator) 
by one dose level upon the continuation of therapy. 
Grade ≥ 4 
• 
 Consider permanently discontinuing, after discussion with 
medical monitor. 
Cutaneous Reactions 
Rash 
(maculopapular or acneiform) 
Grade 1 
• 
Continue study treatment and closely monitor. 
• 
Consider topical steroid cream BID, clindamycin gel, oral 
antihistamine. 
• 
Reassess after 2 weeks.  

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Grade 2 
• Continue study treatment and closely monitor. 
• 
Consider oral antihistamine and/or oral steroids (prednisone 
0.5mg/kg or equivalent) for maculopapular rash. 
• 
Consider doxycycline. 
• Reassess after 2 weeks. If no improvement, interrupt dosing 
until grade ≤ 1. Once resolved, resume ulixertinib at a 
reduced dose level or same dose with close observation. 
Grade ≥ 3 
• Hold study treatment, initiate treatment, and maintain close 
monitoring. 
• Use moderate strength topical steroids PLUS oral steroids 
(prednisone 0.5mg/kg or equivalent); consider adding oral 
antibiotics as described for Grade 2.  
• Consider dermatologist consult. 
• If rash resolves to grade ≤ 1, restart study drugs, with 
ulixertinib reduced by one dose level.  
• Escalation of ulixertinib to the previous dose level may be 
permitted following discussion with the medical monitor.  
• If no recovery to grade ≤ 1 within 3 weeks, consider 
discontinuation of ulixertinib and hydroxychloroquine 
permanently. 
 Photosensitivity  
Grade ≥ 3 lasting > 7 
consecutive days despite 
treatment (as per local 
practice) 
• Hold study treatment. 
• Continue study treatment upon resolution to grade ≤ 1. 
Reduce hydroxychloroquine by one dose level upon 
resolution. 
Stevens-Johnson syndrome or toxic 
epidermal necrolysis 
Any 
• 
Hold study drugs. 
• 
Obtain dermatology consult. 
• Consider permanent discontinuation of study treatment after 
discussion with medical monitor. 
Gastrointestinal Toxicities 
Diarrhea 
Grade ≤ 2 
• 
Continue study treatment. 

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• 
Initiate symptom management and supportive care (i.e. 
loperamide and hydration). 
Grade ≥ 3 
• 
Hold study treatment. 
• 
Initiate symptom management and supportive care (i.e. 
loperamide and hydration).  
• 
Upon resolution to grade ≤ 1 or baseline for > 24 hours, restart 
study treatment and reduce ulixertinib and hydroxychloroquine 
by one dose level.  
• 
Escalation of ulixertinib to the previous dose level is allowed in 
the absence of another episode of grade ≥ 3 diarrhea in the 4 
weeks after dose reduction. 
Nausea or vomiting lasting ≥ 7 days 
despite optimal medicinal therapy. 
Grade ≥ 3 
• 
Hold study treatment and monitor until resolution to grade ≤ 1. 
• 
Resume once resolved to grade ≤ 1.  
• 
The dose of ulixertinib and hydroxychloroquine may be 
reduced by one dose level.   
Hepato-biliary Toxicities 
ALT/AST increase 
Grade 2 
 
• 
Hold study treatment and evaluate for other causes.  
• 
Upon resolution to grade <1 ulixertinib and hydroxychloroquine 
may be resumed at a reduced level.  
Grade 3 or 4  
 
• 
Hold study treatment and evaluate for other causes. 
• 
Consider GI consult. 
• 
Upon resolution to grade < 1 continued study treatment should 
be discussed with the medical monitor. 
• 
If study treatment is resumed (grade must have resolved to 
<1) ulixertinib and hydroxychloroquine should be resumed at a 
reduced level. 
 
Ophthalmological Toxicities 

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Retinal vein occlusion, retinal 
detachment, vitreal detachment, cataract 
or clinically relevant ocular event  
Any 
• 
Hold study treatment. 
• 
Obtain ophthalmology consult and follow up until 
resolution/stabilization. 
• 
Upon resolution to baseline, discuss with medical monitor 
regarding re-initiation of study treatment; decrease dosing of 
ulixertinib and hydroxychloroquine by one dose level. 
Cardiac Toxicity 
QTc interval prolongation 
Grade 3  
(mean from triplicate ECG) 
• 
Hold study treatment.  
• 
Upon resolution to grade ≤ 1, resume study treatment and 
decrease the dose of hydroxychloroquine. 
• 
If reoccurs, discontinue study treatment. 
Symptomatic congestive heart failure 
Any 
• 
Consider permanently discontinuation of study treatment after 
discussion with medical monitor. 
All Other AEs 
All other clinically significant AEs except: 
• 
Nausea, vomiting, or diarrhea lasting 
≤ 72 hours;  
• 
Fatigue lasting < 5 days;  
• 
Hypertension controlled with medical 
therapy. 
Grade ≥ 3 or unacceptable 
toxicity 
• 
Hold study treatment.  
• 
Monitor AE until resolution to Grade ≤ 1.  
• 
Resume study treatment upon resolution and reduce the dose of 
the offending agent (as assessed by the treating investigator) by 
one dose level.  
Abbreviations: AE = adverse event; BID = bis in die (twice daily); ECG = electrocardiogram; GI = gastrointestinal.   
 
 

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8.6 
Supportive Care 
All supportive measures consistent with optimal patient care may be given throughout the study 
as deemed necessary by the treating investigator. Granulocyte-colony stimulating factors may 
be used at any time according to the current American Society of Clinical Oncology (ASCO) 
guidelines for the management of treatment-emergent neutropenia. The use of hematopoietic 
growth factors is at the discretion of the treating physician and according to local institutional 
standards. 
Patients who enter the study on stable doses of erythropoietin or darbepoetin may continue this 
treatment, and patients may start either drug during the study at the discretion of the treating 
physician. 
8.7 
Concomitant Medications and Therapies 
All administered concomitant medications (including herbal supplements) and non-medicinal 
therapies (including transfusions) used 28 days prior to cycle 1 day 1, and until 30 days after the 
last dose of study treatment will be recorded in the patient’s research chart and corresponding 
eCRF. All medications, including those used to treat AEs, chronic conditions or diseases, or as 
supportive therapy should be documented in the eCRF.  
8.7.1 Radiotherapy  
If deemed necessary by the treating investigator and reviewed by the medical monitor, palliative 
radiation therapy for a single site (e.g., bone or brain metastasis) is allowed provided that it is 
the only site of disease progression. The radiation field must not affect any of the target lesions 
designated for disease assessment. Protocol treatment will be held during radiation therapy and 
will be restarted after any acute toxicities have resolved following the conclusion of therapy.  
8.7.2 Prohibited Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the active treatment period. Patients are prohibited from receiving the following therapies 
during the treatment phase of this trial:  
• 
Anti-cancer systemic chemotherapy or biological therapy;  
• 
Other investigational agents;  
• 
Radiation therapy (with the exception noted above); 
• 
Any live-attenuated vaccine therapies for the prevention of infectious disease (e.g. MMR, 
nasal flu, or rotavirus); 
• 
Herbal remedies known to potentially interfere with major organ function (e.g. hypericin);  
• 
Medicinal products known to prolong the QTc interval (see Appendix 2 for a list of 
medications known to cause QTc prolongation); 

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• 
Strong inhibitors of CYP1A2, CYP2D6, and CYP3A4 listed in Appendix 3; 
• 
Strong inducers of CYP3A4 listed in Appendix 3; 
• 
Antimalarial agents, other than hydroxychloroquine (HCQ); 
• 
Dapsone;  
• 
Cyclosporin. 
If a patient requires treatment with one or more of the listed prohibited medications, the patient 
may need to be taken off study treatment. Each individual case will be considered and if 
possible, the investigator should discuss with the Sponsor and Medical Monitor prior to initiating 
prohibited therapy. 
8.7.3 Cautionary Therapy 
The following medications should be used with caution and only when there is not another 
therapy option: 
• 
Digoxin; 
• 
Insulin or antidiabetic drugs; 
• 
Beta-blockers; 
• 
Monoamine oxidase inhibitors; 
• 
Selective serotonin reuptake inhibitors; 
• 
Medications with the possible risk for QTc prolongation.  
In addition, antacids or kaolin should not be administered with hydroxychloroquine but may be 
administered 4 hours before or after hydroxychloroquine.  
Should an investigator deem treatment with a listed cautionary medication necessary, 
monitoring should be increased as deemed appropriate by the treating investigator to ensure 
patient safety. 
8.8 
Duration of Therapy 
Patients will receive combined treatment until treatment discontinuation criteria is met. Upon 
meeting treatment discontinuation criteria, patients will continue on the study in follow-up until 
study discontinuation criteria is met.  

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If the sponsor prematurely terminates the study, patients receiving clinical benefit from the study 
treatment will roll over to an expanded access protocol to ensure continued access to the study 
drug.  
8.8.1 Criteria for the Discontinuation of Treatment 
Discontinuation from the study drug does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. If a 
clinically significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in patient 
management is needed. Any new clinically relevant finding will be reported as an AE.  
Patients may withdraw from treatment or the study overall at any time at their request, or they 
may be withdrawn at the discretion of the Investigator or Sponsor for safety, behavioral reasons, 
or the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures. In addition to the drug-specific discontinuation criteria listed in Table 6, the following 
will result in treatment discontinuation: 
• 
The patient or legally authorized representative withdraws consent from the study 
treatment and/or study procedures;  
• 
Clinical deterioration that, in the opinion of the investigator, increases the risk to the 
patient; 
• 
Confirmed disease progression based on radiographic progression per RECIST 1.1; 
except as permitted for radiation treatment of single site (e.g., bone/brain) metastasis as 
per Section 8.7.1. Also, in rare cases of radiographic progression, treatment may be 
continued for a patient who has met the criteria for radiographic progression but, in the 
Investigator’s opinion, is receiving benefit, after discussion with MM; 
• 
AEs or intercurrent illness that in the opinion of the investigator warrants the patient’s 
withdrawal from study treatment; 
• 
Significant non-compliance with the protocol schedule or treatment administration in the 
opinion of the investigator; 
• 
Unacceptable toxicity; 
• 
Pregnancy; 
• 
Death. 
8.8.2 Criteria for the Discontinuation of Study  
Patients may withdraw from the study overall at any time at their request, or they may be 
withdrawn at the discretion of the Investigator or Sponsor for safety, behavioral reasons, or the 

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inability of the patient to comply with the protocol-required schedule of study visits or 
procedures. Patients must be withdrawn from the study for any of the following reasons: 
• 
Completed study follow-up period; 
• 
Patient or legally authorized representative requests to be fully withdrawn from the 
study;  
• 
If, in the investigator's opinion, the continuation of the trial would be harmful to the 
patient's well-being; 
• 
The patient is lost to follow-up;  
• 
Patient non-compliance (at the discretion of the Principal Investigator); 
• 
Screen failure; 
• 
Death. 
Patients will also be withdrawn at any time if the Investigator concludes that it would be in the 
patient’s best interest for any reason. Protocol violations do not lead to patient withdrawal 
unless they constitute a significant risk to the patient’s safety. 
If the investigator withdraws the patient due to a reason not related to safety (i.e. patient 
compliance, ability to make appointments) and the patient has not reached the first assessment 
period (end of cycle 2) then the patient may be replaced. 
The Investigator must determine the primary reason for a patient’s withdrawal from the study 
and record this information on the eCRF. 
8.8.3 Withdrawal of Consent 
Patients are free to withdraw from the study at any time without prejudice to further treatment. 
They are to be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, became lost to follow-up for any reason, or if any of the following occurs: 
• 
Discovery of patient ineligibility 
• 
Missed / unscheduled / off-schedule / incomplete / incorrect assessments that result in 
patients being put at risk. 
Patients who withdraw consent for further participation in the study will not receive any further 
study drugs or further study observation. 
If a patient withdraws prior to the first assessment period (end of cycle 2) for reasons not related 
to safety, then this patient may be replaced. 

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8.8.4 Lost to Follow-Up 
Patients will be considered lost to follow-up only if no contact has been established by the time 
the study is completed, such that there is insufficient information to determine the patient’s 
status at that time. Patients who refuse to continue participation in the study, including 
telephone contact, should be documented as “withdrawal of consent” rather than “lost to follow-
up.” Investigators should document attempts to re-establish contact with missing patients 
throughout the study period. If contact with a missing patient is re-established, the patient 
should not be considered lost to follow-up and evaluations should resume according to the 
protocol. 
9 
STUDY PROCEDURES 
9.1 
Screening 
For screening procedures; see the SOA (Table 1) and Section 10. Screening activities may only 
begin after a patient has signed consent. Tests conducted for the standard of care monitoring 
and disease assessment may be used to prove eligibility if performed within the screening 
period. All screening activities must take place within 28 days before cycle 1 day 1 unless 
otherwise noted. 
9.2 
Treatment Period  
Once a patient has completed screening, has been found to be eligible, and has been 
registered, treatment procedures may begin. See the SOA (Table 1) and Section 10 for 
treatment period procedures.  
9.3 
End of Treatment 
Once treatment discontinuation criteria have been met, the End of Treatment (EOT) visit will 
occur. The EOT visit should occur when the decision to discontinue treatment is made. If this 
visit overlaps with a regularly scheduled visit, only the procedures listed in the calendar for the 
EOT visit will be performed. For EOT procedures see the SOA (Table 1) and Section 10. 
9.4 Safety Follow-Up 
Patients will return to the clinic or will be contacted for a safety follow-up assessment 60 ± 7 
days after the last dose of study drug was taken; or earlier if subsequent therapy for advanced 
malignancy is initiated prior to 60 ± 7 days. Only information about AEs and SAEs will be 
collected at this visit.  
9.5 
Follow-Up 
Patients that discontinue study treatment for any reason other than disease progression, must 
continue to have disease assessments every 8 weeks (± 7 days) until disease progression, the 
initiation of subsequent anti-cancer therapy, or death. 

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10 STUDY ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that there may be circumstances outside of 
the control of the Investigator that may make it unfeasible to perform the test. In these cases, 
the Investigator will take all steps necessary to ensure the safety and well-being of the patient. 
When a protocol-required test cannot be performed, the Investigator will document the reason 
for this and any corrective and preventive actions that he or she has taken to ensure that normal 
processes are adhered to as soon as possible. 
10.1 General Assessments 
10.1.1 Patient Consent 
Prior to the initiation of any study procedures, all potential patients or their legal representative 
must be fully informed of the risks and potential benefits of trial participation and demonstrate 
understanding. An informed consent document must be signed and dated by the patient or their 
legal representative indicating that they understand the risks and consent to participation and 
treatment on the study. The Principal Investigator or their appropriately trained and delegated 
study personnel conducting the informed consent discussion must also sign and date the 
document. A copy of the signed document should be provided to the patient. 
Standard of care procedures performed prior to patient consent may contribute to the 
assessment of eligibility and/or screening procedures if performed within ±7 days prior to 
signing informed consent.   
10.1.2 Medical History 
The investigator or appropriately trained and delegated study personnel will collect medical 
history to the extent that supports the assessment of eligibility. Medical history will include any 
active conditions and any conditions deemed to be clinically significant by the treating 
investigator. The use of symptom terms should be discouraged; if possible, terms describing the 
principal condition or syndrome should be used. Special attention should be given to prior 
cancers (other than the one under study), prior anti-cancer therapies and/or surgeries, current 
smoking status, and smoking history. Additionally, female patients of childbearing potential 
should have the date of last menstrual cycle noted.  
10.1.3 Prior and Concomitant Medications 
All medications currently being used by a study participant, regularly or as needed, must be 
reviewed and documented by the investigator or qualified designee. Specific attention should be 
given to medications with a protocol-required washout as described in the exclusion criteria and 
any medication taken 28 days prior to cycle 1 day 1. The last dose of any prohibited 
medications requiring a washout as described in the exclusion criteria and Section 8.7.2 must 
be clearly documented in the patient’s research chart.  

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Prior medications are considered those medications which are taken from signing of informed 
consent but stopped prior to the first day of study drug administration. Concomitant medications 
are any medications ongoing from signing informed consent through the first day of study drug 
or started after the first day of study drug.   
During protocol therapy, any medications taken by the patient or used to treat an adverse event 
will be documented in the patient’s research chart and the corresponding eCRF. If a new anti-
cancer therapy is initiated during study follow-up, the new therapy should also be recorded in 
the patient’s research chart and corresponding eCRF.  
10.1.4 Tumor Mutation Testing 
It is required that all patients have histological confirmation and documentation of the necessary 
MAPK mutation. To assess eligibility, cancer mutational status must be confirmed through 
patient medical records and recorded in the eCRF.  
10.2 Safety Assessments 
10.2.1 Physical Examinations and Vital Signs 
Patients will have physical examinations to include major body systems, vital signs, assessment 
of ECOG performance status (see Appendix 1), weight and height at the time points described 
in the SOA (Table 1). Vital signs include systolic/diastolic blood pressure (BP), heart rate (HR), 
respiration rate (RR), pulse oximetry, weight, and body temperature. Height will be measured at 
screening only. If necessary, to facilitate scheduling, the physical exam may occur one day prior 
to study treatment.  
10.2.2 Adverse Events 
AEs experienced during trial participation will be collected per the SOA (Table 1) and Section 
11. Each study participant will be questioned about the occurrence of AEs in a non-leading 
manner. Should the treating investigator feel that the adverse event is attributed to study 
treatment, dose modification guidelines in Section 8.5 should be followed using the 
investigator’s discretion.  
10.2.3 Laboratory Assessments 
Samples for all laboratory assessments will be drawn at the time points indicated in the SOA 
(Table 1) and when clinically indicated. Laboratory tests may be performed up to 3 days prior to 
the scheduled clinic visit (7 days for cycle 1 day 1). All safety laboratory analyses will be 
performed by the local laboratory for each study center. When applicable, all safety laboratory 
assessments must be reviewed by the treating investigator prior to study drug administration. 
When applicable, results from the pregnancy test must also be available for review prior to 
dosing.  

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Table 7: Laboratory Assessments 
Laboratory Assessments 
Complete Blood Count 
(CBC) with Platelet Count 
and Differential 
• 
White Blood Cell Count 
• 
Hematocrit/Hemoglobin 
• 
Platelets 
• 
Absolute Neutrophil Count 
• 
Absolute Lymphocytes 
 Chemistry 
• 
Comprehensive Metabolic Panel 
o Sodium 
o Potassium 
o Chloride 
o Carbon Dioxide 
o Alkaline Phosphatase 
o Aspartate Aminotransferase 
o Alanine Aminotransferase 
o Urea Nitrogen 
o Glucose 
o Creatinine 
o Calcium 
o Protein 
o Albumin 
o Bilirubin 
• 
Uric Acid 
• 
Lactate Dehydrogenase 
• 
Creatine Kinaseϯ 
• 
Inorganic Phosphorus 
Coagulation 
• 
PT (prothrombin time) 
• 
INR (international normalized ratio) 
• 
PTT (partial thromboplastin time) 
Urinalysis  
• 
Specific gravity  
• 
Protein  
• 
Glucose  
• 
Occult blood 
• 
Microscopic examination as clinically indicated 
Pregnancy 
• 
Beta-human chorionic gonadotropin (β-hCG) 
Qualitative Urine or Serum 
Tumor Marker# 
• 
Pancreatic adenocarcinoma only CA 19-9 
• 
Colorectal carcinoma only CEA 
• 
Cholangiocarcinoma only CEA and CA 19-9 
Ϯ After screening, creatine kinase should only be drawn if creatinine is elevated. 
# Tumor markers are not required for patients with esophageal or stomach cancers. 

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10.2.4 12-Lead Electrocardiograms (ECG) 
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs. All patients 
will require single 12-lead ECG measurements according to the SOA (Table 1). The parameters 
to be recorded are HR, RR, QT, PR, and QRS. All ECGs should be conducted pre-dose and 
Fridericia's formula will be used for all QT correction calculations. Decisions for dose 
modifications for QTc prolongation will be made based on QTcF values. 
If at any time after screening the QTcF > 500 ms, a triplicate ECG will be performed with 
tracings approximately one-minute apart. The mean QTcF from these ECGs should be used 
when following the dose modification guidelines.  
10.2.5 Echocardiogram  
A transthoracic echocardiogram will be used to assess left ventricular ejection fraction (LVEF) at 
screening and as clinically indicated during study treatment. Should a decline in LVEF occur, 
the dose modification guidelines should be followed.  
10.2.6 Ophthalmologic Exam  
A full ophthalmic examination (performed by an ophthalmologist or optometrist) will be 
performed at the time points described in the SOA (Table 1) and will include: 
• 
Best-corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of 
the central 10 degrees (with retesting if an abnormality is noted); 
• 
Slit-lamp examination;  
• 
Intraocular pressure; 
• 
Dilated fundoscopy with attention to retinal abnormalities; 
• 
Spectral-domain ocular coherence tomography (SD-OCT).  
In patients of Asian descent, it is recommended that visual field testing be performed in the 
central 24 degrees instead of the central 10 degrees.  
It is recommended that hydroxychloroquine be discontinued if ocular toxicity is suspected, and 
the patient should be closely observed given that retinal changes (and visual disturbances) may 
progress even after cessation of therapy.  
All ophthalmology assessments must be conducted up to 7 days prior to the clinic visit to enable 
timely results review. 

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10.3 Efficacy Assessments 
10.3.1 Disease Assessment 
Disease assessments must include all known or suspected sites of disease; therefore, the 
decision for body areas to be scanned will depend on the extent of disease. The minimum 
recommended body areas to be scanned is chest, abdomen, and pelvis. Local treating 
investigators will evaluate disease assessments and define response per RECIST 1.138. All 
treatment decisions will be based on the local treating investigator’s assessment.  
Disease assessments will be evaluated radiologically and conducted at baseline (within 28 days 
prior to the first dose of study treatment) and then every 8 weeks thereafter ≤ 7 days prior to the 
start of the following cycle (e.g., prior to cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc.). If a 
response is observed (CR or PR), confirmation of response is required ≥ 4 weeks from the first 
documentation of response (note: a confirmation of response does not have to occur at the next 
scan. It can occur any time ≥ 4 weeks to 8 weeks). Disease assessments will continue until 
disease progression, the initiation of subsequent anti-cancer therapy, or death. In addition, 
radiological tumor assessments will be conducted whenever disease progression is suspected 
(e.g., symptomatic deterioration) or when clinically indicated. The schedule of tumor 
assessments should be fixed according to the calendar, starting with cycle 1 day 1, regardless 
of treatment delays or interruptions due to toxicity. 
Brain CT or MRI scans are required at baseline for all patients with stable brain lesions and for 
those for whom Central Nervous System (CNS) involvement is suspected. If stable brain 
metastases are present at baseline, brain imaging should be repeated at each tumor 
assessment. Otherwise, brain imaging will be conducted post-baseline only when clinically 
indicated. 
The CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons. Consistent imaging modality should be used for all disease assessments.  
If a single site of metastasis (e.g., bone or brain) requires palliative radiation as described in 
Section 8.7.1, it will not necessarily be considered progressive disease and the patient will be 
allowed to continue study treatment after discussion with the Medical Monitor. 
10.3.2 Correlative Studies 
Correlative studies will focus on exploring the pharmacokinetics, pharmacodynamics, and 
biomarkers for response and/or resistance. To support these studies, de-identified 
biospecimens (blood and tissue) samples will be collected at the time points indicated on the 
SOA (Table 1). Any blood or tissue remaining after the completion of the correlative studies will 
be stored for use in future research. All correlative study samples need to be drawn when 
patients are at steady state. 

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10.3.2.1 Pharmacodynamics  
To assess the extent of pharmacologic inhibition the study drugs produce, blood and tissue 
samples will be drawn in stage one only as indicated on the Schedule of Correlative Sample 
Collection (Table 2). Assays to investigate pharmacodynamic markers, including p62 and pRSK, 
will be deployed. These may include but are not limited to RPPA, Nanostring, and RNA-exome.  
Refer to the lab manual for sample collection and processing instructions. 
10.3.2.2 Pharmacokinetics 
Pharmacokinetic studies will be conducted at the time points indicated in the Schedule of 
Correlative Sample Collection (Table 2). Patients enrolled in stage one will have blood drawn for 
the support of pharmacokinetic studies pre- and post-dose. However, patients enrolled in stage 
two will have blood drawn only pre-dose. 
On the day of blood collection for the support of pharmacokinetic studies, patients will be 
instructed not to take their morning doses, but to wait to take them in the clinic. When taking the 
study drugs, a meal will be provided by the site. After pre-dose samples have been collected (≤ 
1 hour prior to the morning dose), patients will be instructed to take their study drug, and post-
dose blood will be drawn at 0.5 (±2 minutes), 1 (±3 minutes), 2 (±6 minutes), 4 (±12 minutes), 6 
(±18 minutes), 8 (±24 minutes), and 12 hours (±36 minutes). Patients should not have cycle 1 
day 15 PK blood draws if not at steady state. Steady state is reached after 5 days or 10 
consecutive doses. 
Refer to the lab manual for sample collection and processing instructions. 
10.3.3 Tissue 
Stage 1 patients will undergo a mandatory biopsy at the time points indicated in the Schedule of 
Correlative Sample Collection (Table 2). If a patient has undergone a biopsy ≤ 6 months prior to 
the planned cycle 1 day 1 and has not received any anti-cancer treatment since undergoing the 
biopsy, archival tissue from this biopsy may be used to fulfill screening tissue requirements. An 
optional biopsy will be offered to patients at the time of treatment discontinuation as noted in the 
SOA (Table 1). These tissues will be used to determine if observed responses are due to on-
target effects of study treatment. Samples may also be used to explore possible biomarkers 
predictive of treatment efficacy. Tissue should be taken when patients are at steady state during 
treatment. 
Testing may include, but is not limited to: 
• 
DNA/RNA sequencing.  
• 
Reverse-phase protein arrays. 
• 
Immunohistochemistry. 

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• 
RNA-exome. 
Instructions for collection and processing will be detailed in the lab manual. 
11 ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the study (investigational) product. This includes an exacerbation of 
pre-existing conditions or events, intercurrent illnesses, drug interaction, or the significant 
worsening of the indication under investigation that is not recorded elsewhere in the eCRF 
under specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, 
including the disease under study that does not represent a clinically significant exacerbation or 
worsening, need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study. AE 
information will be elicited by asking the patient a non-leading question, for example, “Have you 
experienced any new or changed symptoms since we last asked/since your last visit?”. AEs 
should be reported on the appropriate page of the eCRF. 
11.1.2 Serious Adverse Events 
 A Serious Adverse Event (SAE) is any untoward medical occurrence that occurs at any dose 
(including after the informed consent form (ICF) is signed and prior to dosing) that: 
• 
Results in death 
• 
Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• 
Requires in-patient hospitalization (formal admission to a hospital for medical reasons) 
or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital anomaly/birth defect 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 

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convulsions that do not result in in-patient hospitalization, or the development of drug 
dependency or drug abuse. 
Hospitalizations for elective surgery or other medical procedures that are not related to a 
treatment-emergent AE are not considered SAEs. 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal during the study or within the 
safety reporting period (see below). If the malignancy has a fatal outcome during the study or 
within the safety reporting period, then the event should be reported using the term “disease 
progression” with a CTCAE severity of grade 5. 
11.2 Adverse Event Reporting 
The investigator and qualified designees are responsible for the detection, documentation, 
reporting, and follow-up of all AEs experienced by patients during trial participation. AEs and 
SAEs will be recorded from the signing of the consent until 60 days after the last dose of study 
drug or until initiation of subsequent anti-cancer therapy, whichever is earliest. The following 
information will be required for each adverse event: 
• 
Event description, including severity as graded by the CTCAE v.5;  
• 
The causality assessment to either study drug per the below definitions; 
• 
Event duration; 
• 
Any action taken to treat or manage the event; 
• 
Event outcome. 
11.2.1 Severity Assessment 
The severity of AEs should be assessed by CTCAE v.5. If an event is not listed in CTCAE v.5, 
then the assessment of severity should follow the general guidelines listed in Table 8. 
Table 8: Severity assessment 
Grade 
Severity Description 
1 
Mild event that generally does not require intervention. 
2 
Moderate event that may require intervention. 
3 
Severe event that requires intervention. 
4 
Life-threatening event that requires urgent intervention. 
5 
Death. 

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Events meeting grade 4 or 5 severity description should be reported promptly as SAEs unless 
otherwise indicated in Section 11.1.2. 
11.2.2 Relationship to Study Drug 
The Investigator will make a judgment regarding whether or not the AE was related to either 
study drug, as outlined below, and in accordance with FDA guidance of 2012. 
Unrelated 
The AE is unlikely to have been caused by 
study drug. 
Possibly related 
It is unclear whether the AE may have been 
caused by study drug. 
Related 
The AE is likely to have been caused by study 
drug. 
11.2.3 Action Taken and Outcome 
Start and stop dates will be required for all AEs and SAEs. The action taken in response to the 
event should also be recorded in the patient’s research chart and corresponding eCRF. Event 
action terms include none, medication administered, non-drug therapy administered, surgery, 
hospitalization, or other with the option to specify. If a new medication is added the medication 
should also be added to the concomitant medications log. 
All AEs should be followed until stabilization or resolution. Event outcomes may be classified as 
resolved, resolved with sequelae, ongoing, or death.  
11.2.4 Reporting Serious Adverse Events 
ALL SAEs must be entered into the eCRF within 24 hours of first knowledge of the event by 
study personnel. It is important that the investigator provide his/her assessment of 
relationship to study drug at the time of the initial report. Follow-up information must also be 
reported within 24 hours of first knowledge. Entry of an SAE (or updated SAE information) into 
the eCRF will trigger an automatic alert to the designated CRO Safety team. Timely notification 
of an event supersedes the requirement to have all information at the time of the initial report.    
If the electronic data capture (EDC) system is not available, the Investigator must send a 
completed paper SAE Report Form to the CRO Safety team via email or fax as follows, within 
24 hours. If no acknowledgement is received within one working day, the report should be re-
submitted. 
Safety Report Email Address: sae@cmedresearch.com   
Safety Report Fax No.: 866.240.8830 (US) or +44 1403 330459 (international)  

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The SAE data must be entered into the eCRF as soon as it becomes available.  
The following information must be reported on the eCRF SAE report form:  
• 
Protocol number  
• 
Site and/or Investigator number 
• 
Patient number 
• 
Demographic data  
• 
Brief description of the event  
• 
Onset date and time 
• 
Resolution date and time, if the event resolved  
• 
Current status, if event not yet resolved  
• 
Any concomitant treatment and medication  
• 
Investigator’s assessment of whether the SAE was related to Investigative product or 
not  
• 
Outcome of the event if available  
The CRO Safety team will contact the site for clarification of data entered onto the eCRF, or to 
obtain missing information. In the event of questions regarding SAE reporting, the 
site may contact Cmed Drug Safety and Pharmacovigilance via 
email sae@cmedresearch.com.   
Unexpected serious suspected adverse reactions are subject to expedited 
reporting to FDA. The CRO Safety team is responsible for submitting reports of AEs associated 
with the use of the drug that are both serious and unexpected to the FDA and to investigators 
participating in ongoing clinical studies with the study drug, according to 21 CFR 312.32 and 
the applicable guidance documents. All investigators participating in ongoing clinical studies 
with the study drug are responsible for prompt submission of these reports to their Institutional 
Review Board (IRB) or Ethics Committee (EC).  
11.3 Special Situations 
11.3.1 Pregnancy or Breastfeeding  
Although pregnancy is not considered an adverse event, any exposure to the investigational 
products during pregnancy or breastfeeding must be reported to the sponsor promptly. 
Exposure may occur by a woman actively receiving study treatment or the partner of a male 

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patient actively receiving study treatment becoming pregnant. Any possible pregnancy or 
breastfeeding exposure during study treatment and up to 90 days after the last dose of study 
treatment or up to the start of subsequent anti-cancer therapy (whichever happens first) must be 
reported within 24 hours of awareness regardless of the occurrence of an SAE. Should a 
woman on study treatment become pregnant, she should immediately discontinue study 
treatment. 
Women exposed to IP during pregnancy or while breastfeeding will be followed for pregnancy 
outcome and neonate health. Pregnancy outcomes may meet criteria as an SAE if ectopic 
pregnancy, spontaneous abortion, intra-uterine fetal demise, neonatal death, or congenital 
anomaly occurs. Congenital anomalies that occur in a live-born baby, a terminated fetus, an 
intra-uterine fetal demise, or a neonatal death should be reported as an SAE. Any neonatal 
deaths that occur up to 30 days after birth or breastfeeding exposure should be reported as an 
SAE. Further follow-up on birth outcomes and neonate health will be handled on a case-by-case 
base. 
11.3.2 Hy’s Law Cases 
It is important to identify possible cases of Drug-Induced Liver Injury (DILI) early. Total bilirubin, 
Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) should be regularly 
monitored for elevations indicative of liver damage. Patients who experience a transaminase 
elevation above three times the ULN should be monitored frequently to determine if the 
elevation is transient. Transient elevations are an indication of adaption, and these patients may 
be identified as “adaptors.” However, should a transaminase elevation be followed by total 
bilirubin (TBili) increase, a DILI could be occurring. Any laboratory abnormalities meeting the 
following criteria should be reported into the EDC system within 24 hours of awareness: 
• 
AST or ALT elevation > 3 x ULN; and 
• 
Total bilirubin > 2 x ULN; and 
• 
Absence of cholestasis; and  
• 
No alternative explanation for the elevations. 
Investigators should conduct reasonable investigations to rule out other possible etiologies. 
Investigators should take into consideration the patient's use of ethanol, acetaminophen, 
recreational drugs, herbal supplements, and medical history. A potential Hy’s Law case will not 
be considered a confirmed case until all results and considerations have excluded alternative 
etiologies. 
Patients who experience possible DILI should be managed per the Dose Modification 
Guidelines.  
These events will not be collected by the CRO Safety Team unless they meet the criteria of an 
SAE. 

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11.3.3 Medication Error 
The sponsor should be notified immediately (via an email from the clinical research associate) if 
a medication error occurs. Medication errors include: 
• 
Patient dosing errors such as taking more medication than instructed; 
• 
Medication uses outside of what is anticipated in the protocol; 
• 
Medication errors that do not involve a trial patient. 
Any medication errors resulting in an AE should be reported per AE/SAE reporting 
requirements.  
Medication errors will not be collected by the CRO Safety Team unless they meet the criteria of 
an SAE. 
11.4 Safety Oversight 
An internal Safety Monitoring Committee (SMC) will be set up to review the safety of patients 
undergoing study treatment as the study progresses. The SMC will consist of a few Clinical 
Investigators, the Medical Monitor, and Sponsor representatives. The SMC will review any SAE 
that occurs during the study and will examine the safety of ulixertinib in combination with 
hydroxychloroquine, including toleration of the starting dose, dose interruptions, dose 
reductions, and toxicities that may occur in later cycles of treatment.  
An assessment of dose tolerability will be determined by conducting an early safety review of 
the first 3 patients. The sponsor, CRO medical team, and the specific patients’ Principal 
Investigators will do an extensive review of all AEs from the first 3 patients through a minimum 
of 1 cycle to ensure tolerability of the starting dose combination. 
Before the expansion of any basket, the SMC will review the available safety and efficacy data 
of all patients enrolled in the specific basket. If necessary, the Medical Monitor can call ad-hoc 
meetings to review ongoing events and data.  
Based on emerging safety data, the SMC may make study conduct recommendations including 
but not limited to: open a basket expansion cohort, discontinue enrollment to a basket, continue 
the study per protocol, protocol amendment, add safety procedures, perform additional 
analyses, hold enrollment or close the study. 

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12 STATISTICAL CONSIDERATIONS 
12.1 General Considerations 
The detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP) covering all baskets. This section 
is a summary of the planned statistical analyses at the time of protocol development. 
The safety and efficacy reviews to be conducted by the SMC will be addressed in the overall 
study SAP. 
12.2 Sample Size Determination 
Under Simon's optimal two-stage design39 with a 5% significance level and 80% power, 
assuming a null hypothesis for ORR ≤ 20% versus the alternate hypothesis of ORR ≥ 40%, a 
total of 43 evaluable patients are required for the evaluation of the primary endpoint; 13 in stage 
1 and an additional 30 in stage 2, for each basket. 
In the first stage, if there are 3 or fewer patients achieving a response in the 13 evaluable 
patients, the study will be stopped for this basket. Otherwise, 30 additional patients will be 
accrued for a total of 43.  
Then, if there are 12 or fewer responses in the 43 patients, the null hypothesis will not be 
rejected and any further investigation of the study drug in this basket will not be warranted. 
However, should at least 13 of the 43 evaluable patients achieve a response then the null 
hypothesis will be rejected, and it will be concluded that the study drug demonstrates activity for 
this basket to allow further investigation. 
12.3 Population for Analyses 
The full analysis set (FAS) will consist of all patients who received at least one dose of study 
drug. This analysis set will be used for all safety analyses. 
The stage 1 analysis set (S1AS) will consist of the first 13 patients who have completed at least 
one cycle of therapy and who have received a minimum of 75% of prescribed study treatment 
during cycle 1. This analysis set will be used only for the purpose of the stage 1 efficacy 
analysis.   
The evaluable analysis set (EAS) will consist of all patients who received at least one dose of 
study drug and have at least one post-treatment study evaluation or who have discontinued 
therapy prior to the first post-treatment study evaluation due to clinical progressive disease or 
drug-related AEs. This analysis set will be used for the evaluation of the primary efficacy 
endpoint, i.e., ORR. 

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The PK analysis set will consist of all patients who have received at least one dose of study 
drug and have at least one post-dose PK measurement. This analysis set will be used for PK 
analyses. 
12.4 Data Analysis 
Descriptive statistics for continuous variables will include the number of patients, mean, 
standard deviation, median, minimum, maximum; frequencies and percentages will be displayed 
for categorical data. No formal hypothesis testing will be performed. 
Summary data will be provided by basket and overall. 
Data will be analyzed using the SAS system software version 9.4 (or later). 
12.4.1 
Demographic and Baseline Characteristics 
Demographics, medical history and other baseline data will be listed and summarized using 
descriptive statistics.  
12.4.2 
Prior and Concomitant Medications 
The number and percentage of patients taking prior and concomitant medications will be 
summarized by therapeutic class and preferred term using descriptive statistics. All data will be 
recorded as follows: 
• 
Prior medication: ended before the first day of study drug administration. 
• 
Concomitant medication: ongoing at first day of study drug or started after first day of 
study drug. 
12.4.3 Study Drugs 
Exposure to ulixertinib and hydroxychloroquine will be summarized with descriptive statistics, 
including the duration of study drug exposure (in days), cumulative dose, dose intensity and 
relative dose intensity. The number of patients with dose reductions and interruptions will be 
presented by basket and overall, along with reasons for the dose modification. Exposure data 
will be listed. 
12.5 Primary Endpoint Analysis  
12.5.1 Safety and Tolerability 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). System 
Organ Class (SOC), High-Level Group Term (HLGT), High-Level Term (HLT), Preferred Term 
(PT), and Lower-Level Term (LLT) will be attached to the clinical database. 
AEs will be summarized based on the date of onset for the event. Summaries (number and 
percentage of patients) of treatment-emergent AEs will be provided by SOC and PT, by basket 
and overall. 

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Treatment-emergent adverse event (TEAE) is defined as any AE that emerges during treatment 
having been absent pre-treatment or worsens relative to the pre-treatment state. 
The severity of the AEs will be graded according to the CTCAE v5.0.  
The detailed information collected for each AE will be listed, including a description of the event, 
duration, severity, relatedness to study drugs, action taken, and clinical outcome.  
AEs analysis will be conducted on the FAS. 
12.5.2 Confirmed Overall Response Rate 
Confirmed overall response rate will be calculated as the number of patients achieving a 
confirmed complete response or confirmed partial response (as per RECIST v1.1) divided by 
the total number of patients in the EAS. Patients without a confirmed response or a missing 
baseline/screening tumor assessment will be considered non-responders.  
ORR will be reported along with a 95% exact binomial confidence interval (Clopper-Pearson 
method).  
ORR analysis will be conducted on the EAS and replicated on the FAS. 
12.6 Secondary Endpoints Analysis 
12.6.1 Progression-Free Survival  
Progression-free survival (PFS) will be defined as the time from study drug initiation until 
disease progression as per RECIST v1.1, or death from any cause. Patients with no event will 
be censored at the last available tumor assessment.  
Kaplan-Meier estimates and curves, median PFS and its respective 95% confidence intervals 
(CIs) will be used to analyze PFS.  
PFS analysis will be conducted on the EAS and replicated on the FAS. 
12.7 Other Endpoints Analysis 
12.7.1 Pharmacokinetics 
For patients enrolled in stage 1 of each basket, PK concentrations of ulixertinib and 
hydroxychloroquine will be determined pre-dose and post-dose in plasma at cycle 1 day 15. 
Summary parameters such as AUC, Cmax, Cmin, t1/2, tmax will be calculated. 
PK parameters in plasma will be listed and summarized, by basket, using descriptive statistics 
(e.g., sample size, arithmetic and geometric mean, % coefficient of variation, standard deviation, 
median, minimum, and maximum).  

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For patients enrolled in stage 2 of each basket, PK parameters of ulixertinib will be measured on 
cycle 1 day 15. This will be a single timepoint collection prior to taking study drug on this day.    
Pharmacokinetic values will be presented in by-patient listings. 
PK analysis will be conducted on the PK analysis set. 
12.7.2 Pharmacodynamics 
Pharmacodynamic markers, including p62, will be explored and listed as appropriate. These 
may include but are not limited to RPPA, Nanostring, and RNA-exome. 
PD analysis will be conducted on the FAS. 
12.7.3 Laboratory Evaluations 
The parameters associated with the clinical laboratory tests (hematology, clinical chemistry, and 
urinalysis) will be summarized with descriptive statistics by visit and for the change from 
baseline to each planned post-baseline visit, by basket and overall. Listings of all laboratory 
results and reference ranges will be provided.  
Graded laboratory abnormalities will be defined using the grading scheme based on NCI 
CTCAE (v5.0) and summarized by basket and overall. Shift tables will also be produced for 
gradable parameters based on the baseline CTCAE grade and the maximum CTCAE grade. 
Only abnormal laboratory values deemed to be clinically significant by the investigator should be 
reported as AEs. 
Analysis of laboratory evaluations will be conducted on the FAS. 
12.7.4 Other Safety Evaluations 
Changes in the patient’s physical examination findings, vital sign parameters, and ECG will be 
summarized by basket and overall, and any abnormal values will be tabulated.  
Listings of all data related to the patient’s physical examination findings, vital signs and ECG will 
be provided. 
Analysis of other safety evaluations will be conducted on the FAS. 
13 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
13.1 Regulatory, Ethical, and Study Oversight Considerations 
13.1.1 Informed Consent Process 
13.1.1.1  Consent And Other Informational Documents Provided to Patients 
Consent forms describing in detail the study drug, study procedures, and risks are given to the 
patient and written documentation of informed consent is required prior to performing any study-

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related assessment which is not standard of care. Consent forms will be reviewed and approved 
by the appropriate IRB/EC prior to being given to potential participants. 
13.1.1.2 
 Consent procedures and documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
approved by an Institutional Review Board (IRB) and the patient will be asked to read and 
review the document. The investigator or designee will explain the research study to the patient 
and answer any questions that may arise. A verbal explanation will be provided in terms suited 
to the patient’s comprehension of the purposes, procedures, and potential risks of the study and 
of their rights as research patients. Patients will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The patients should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The patient will sign the informed consent document prior to any procedures 
being done specifically for the study. Patients must be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the patients for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the 
form signed before the patient undergoes any study-specific procedures. The rights and welfare 
of the patients will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in the study. 
13.1.2 Study Discontinuation and Closure 
It is agreed that for reasonable cause, either the Investigator or the Sponsor may temporarily 
suspend or prematurely terminate this study or the Investigator’s participation in this study, 
provided a written notice is submitted at a reasonable time in advance of intended suspension 
or termination. If discontinuation is by the investigator, notice is to be submitted to BioMed 
Valley Discoveries, Inc. If discontinuation is by the Sponsor, notice will be provided to each 
investigator. If the study is suspended or prematurely terminated, the Investigator will promptly 
inform the study patients, IRB, and the Sponsor will provide the reason(s) for the suspension or 
termination. Study patients will be contacted, as applicable, and be informed of changes to the 
study visit schedule. 
If a severe local reaction or drug-related SAE occurs at any time during the study, the Safety 
Monitoring Committee will review the case immediately. 
If one or more patients at any dose level develop any of the following AEs deemed to be 
possibly, probably or definitely related to ulixertinib by the Investigator and/or Medical Monitor, 
based upon close temporal relationship or other factors, the study will be immediately 
suspended and no additional ulixertinib doses will be administered pending review and 
discussion of all appropriate study data by the SMC: 

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• 
Death 
• 
Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia, or respiratory 
distress) 
 The study will not be restarted until all parties have agreed to the course of action to be taken 
and the Institutional Review Board/Ethics Committee (IRB/EC) (s) has/have been notified. 
13.1.3 Confidentiality and Privacy 
Patient confidentiality and privacy is strictly held in trust by the participating Investigators, their 
staff, and the Sponsor and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to patients. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
or regulatory agencies may inspect all documents and records required to be maintained by the 
Investigator, including but not limited to, medical records and pharmacy records for the patients 
in this study. The clinical study site will permit access to such records. 
The study patient’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or Sponsor 
requirements. 
Patient’s data collected on eCRFs during the trial will be documented in a de-identified fashion 
and the patient will only be identified by the patient number, and/or by the patient’s initials, if 
also required. The study data entry and study management systems used will be secured and 
password protected. If, as an exception, it is necessary for safety or regulatory reasons to 
identify the patient, all parties are bound to keep this information confidential. 
The investigator will guarantee that all persons involved will respect the confidentiality of any 
information concerning the trial patients. All parties involved in the study will maintain strict 
confidentiality to assure that neither the person nor the family privacy of a patient participating in 
the trial is violated. Likewise, appropriate measures shall be taken to prevent access of non-
authorized persons to the trial data. 
13.1.4 Future Use of Stored Specimens and Data 
With the patient’s approval and as approved by local IRBs, de-identified biological samples will 
be stored for future analysis as warranted by the rapidly advancing understanding in this field. 
During the conduct of the study, an individual patient can choose to withdraw consent to have 

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biological specimens stored for future research. However, withdrawal of consent with regard to 
biological specimens’ storage may not be possible after the study is completed. 
Collected samples may be transferred for analysis to the Sponsor, or to other laboratories 
working for the Sponsor. 
Biological samples will be stored for the time established by regulatory requirements or 
destroyed after the final clinical study report has been finalized if storage is not required. There 
might be a new request for these samples to be used for purposes related to the quality 
assurance of the laboratory tests described in this protocol, in which case they will be used for 
this purpose. This may include the assessment of the quality of current tests, the maintenance 
or improvement of these tests, the development of new test methods for the markers described 
in this protocol, as well as making sure that new tests are comparable to previous methods and 
work reliably. 
If study results suggest that further investigations using stored biological samples are 
warranted, these tests might be carried out on an exploratory basis. In addition, biological 
samples may be used by the Sponsor or their research partners for further research that is not 
related to the disease or the product under study. This testing will be done on de-identified 
samples (meaning that any identification linking the patient to the sample is destroyed). Patients 
will be asked to sign an additional, separate consent form for this optional testing and refusal of 
consent will not affect their possibility of participating in the study. 
13.1.5 Key Roles and Study Governance 
13.1.5.1 
Safety Oversight 
An internal Safety Monitoring Committee (SMC) will be set up to review the safety of study 
treatment as the study progresses. The SMC will consist of a few Clinical Investigators, the 
Medical Monitor, and Sponsor representatives. The SMC will review any SAE that occurs during 
the study and will examine the safety of ulixertinib in combination with hydroxychloroquine, 
including toleration of the starting dose, dose interruptions, dose reductions, and toxicities that 
may occur in later cycles of treatment. 
The safety review will be performed at regular intervals, at least semi-annually to access safety 
and efficacy data. 
The entire study or treatment of individual patients may be stopped under defined 
circumstances as outlined in Section 8.8. 
13.1.5.2 
 Clinical Monitoring 
Site monitoring is conducted to ensure that the rights and well-being of trial patients are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
ICH GCP, and with applicable regulatory requirements. 

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Monitoring standards require full verification for the presence of informed consent, adherence to 
the inclusion/exclusion criteria, documentation of SAEs, and the recording of primary efficacy 
and safety variables. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
A clinical monitoring plan will be developed by the Sponsor’s CRO. 
During the course of the study, a site monitor will conduct routine site visits to review protocol 
compliance, compare eCRF entries with individual patient’s original source documents 
(accessed by the Investigator), assess product accountability and ensure the study is conducted 
according to applicable regulatory requirements. The review of the patient’s original medical 
records shall be performed in a manner which ensures patient confidentiality is maintained. 
The Investigator shall permit the site monitor to review study data as frequently as deemed 
necessary to ensure that data are recorded in an adequate manner and that protocol adherence 
is satisfactory. 
The Investigator may not enroll patients into the study until such time that an initiation visit, or 
with the agreement of the Sponsor, attendance at the Investigator meeting, has been performed 
by the site monitor to conduct a detailed training of the protocol and eCRF. 
13.1.5.3  Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted, data are 
generated, biological specimens are collected, documented (recorded), and reported in 
compliance with the protocol, ICH GCP, and applicable regulatory requirements.  
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/sponsor’s designee, and inspection by local and regulatory authorities. Key trial 
personnel must be available to assist monitors during visits. 
13.1.5.4  Auditing Procedure 
In addition to the routine monitoring procedures, the Sponsor or the regulatory authority can 
conduct an audit or an inspection (during the study or after its completion) to evaluate 
compliance with the protocol and the principles of GCP. 

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The investigator agrees that representatives of the Sponsor and regulatory authorities will have 
direct access, both during and after the course of this study, to audit and review all study-
relevant medical records. 
13.1.6 Data Handling and Record Keeping 
13.1.6.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Data recorded in the eCRF derived from source documents should be consistent with the data 
recorded on the source documents. All information on CRFs (case report form) must be 
traceable to source documents in the patient's file. Data without a written or electronic record 
will be defined before trial start and will be recorded directly on the CRFs, which will be 
documented as being the source data. All data requested on the eCRF must be entered and all 
missing data must be accounted for. 
Clinical data and clinical laboratory data will be entered into a 21 CFR Part 11 compliant 
electronic data capture system. The data system includes password protection and internal 
quality checks to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data 
will be entered directly from the source documents. 
13.1.6.2 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be retained 
for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the Sponsor, if applicable. It is the responsibility of the Sponsor to 
inform the Investigator when these documents no longer need to be retained.  
Study documents include:  
• 
IRB/EC approvals for the study protocol and all amendments 
• 
All source documents and laboratory records 
• 
CRF copies (electronic copies on a CDROM) 
• 
Patients' informed consent forms (with study number and title of trial) 
• 
FDA form 1572 
• 
Any other pertinent study document 

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13.1.7 Protocol Deviations 
A protocol deviation is any non-compliance with the clinical trial protocol, ICH GCP, or study 
manual requirements. The non-compliance may be either on the part of the patient, Investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly. 
It is the responsibility of the Investigator to use continuous vigilance to identify and report 
deviations. All deviations must be addressed in study source documents. Protocol deviations 
must be sent to the reviewing IRB per their policies. The Investigator is responsible for knowing 
and adhering to the review IRB requirements. Further details about the handling of protocol 
deviations will be included in the study manual. 
13.1.8 Publication and Data Sharing Policy 
An ICH-compliant integrated clinical and statistical report will be prepared upon completion of 
the study and data analysis. The results of the study may be published in a relevant peer-
reviewed journal, with authorship status and ranking designated according to the acknowledged 
contributions of participating investigators, institutions, and the Sponsor. 
All information provided to the investigator by BioMed Valley Discoveries, Inc., or their designee, 
will be kept strictly confidential. No disclosure shall be made except in accordance with a right of 
publication granted to the investigator. 
No information about this study or its progress will be provided to anyone not involved in the 
study other than by BioMed Valley Discoveries, Inc., or its authorized representatives, or in 
confidence to the IRB, or similar committee, except if required by law. 
13.1.9 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence is critical. Therefore, any 
actual conflict of interest of person who has a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, person who have a 
perceived conflict of interest will be required to have such conflicts managed in such a way that 
is appropriate to their participation in the design and conduct of this trial. 
13.1.10 
Insurance 
The Sponsor has established an insurance policy for the total anticipated duration of the study, 
covering the patients with respect to the risks involved in taking part in this study in accordance 
with this protocol. In the case of injury or disability deriving from participation in the study, 
patients are requested to inform the Investigator or his/her staff responsible for the study at the 
institution without delay. 
 
 

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Sanchez JN, Wang T, Cohen MS: BRAF and MEK Inhibitors: Use and 
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Vogl DT, Stadtmauer EA, Tan K-S, et al: Combined autophagy and proteasome 
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Rangwala R, Leone R, Chang YC, et al: Phase I trial of hydroxychloroquine with 
dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 
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of Autophagy Inhibition Using Hydroxychloroquine in Patients With Metastatic Pancreatic 
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35. 
Sullivan RJ, Infante JR, Janku F, et al: First-in-Class ERK1/2 Inhibitor Ulixertinib 
(BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-
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Rosenfeld MR, Ye X, Supko JG, et al: A phase I/II trial of hydroxychloroquine in 
conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with 
newly diagnosed glioblastoma multiforme. Autophagy 10:1359-1368, 2014 
 
37. 
Rangwala R, Chang YC, Hu J, et al: Combined MTOR and autophagy inhibition. 
Autophagy 10:1391-1402, 2014 
 
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Appendix 1: ECOG Performance Status40 
 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hour 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
 
 
 

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Appendix 2: List of QTc Prolonging Agents 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 inhibitor 
Arsenic trioxide 
Trisenox 
Anti-cancer 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Chloroquine 
Aralen 
Antimalarial 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic / Antiemetic 
Cilostazol 
Pletal 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Disopyramide 
Norpace 
Antiarrhythmic 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Donepezil 
Aricept 
Cholinesterase inhibitor 
Dronedarone 
Multaq 
Antiarrhythmic 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Antipsychotic / Antiemetic 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, Ery-
Tab, Eryc Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate Filmtab, Erythrocot, 
E-Base, Erythroped, Ilosone, MY-E, 
Pediamycin, Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, Stiemycine, 
Acnasol, Tiloryth 
Antibiotic 
Escitalopram 
Cipralex, Lexapro, Nexito, Anxiset-E, 
Exodus, Esto, Seroplex, Elicea, Lexamil, 
Lexam, Entact, Losita, Reposil, 
Animaxen, Esitalo, Lexamil 
Antidepressant, SSRI 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine 
Antiarrhythmic 
Fluconazole 
Diflucan, Trican 
Antifungal 
Haloperidol 
Haldol, Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol, Einalon S, 
Eukystol, Halosten, Keselan, Linton, 
Peluces, Serenace, Serenase, 
Sigaperidol 
Antipsychotic 
Ibutilide 
Corvert 
Antiarrhythmic 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Methadone 
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, Heptadon 
Opioid agonist 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 

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Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, 
Emetron, Ondavell, Emeset, Ondisolv, 
Setronax 
Antiemetic 
Oxaliplatin 
Eloxatin 
Anti-cancer 
Papaverine HCl (Intra-coronary) 
Vasodilator, Coronary 
Pentamidine 
Pentam 
Antifungal 
Pimozide 
Orap 
Antipsychotic 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Propofol 
Diprivan, Propoven 
Anesthetic, general 
Quinidine 
Quinaglute, Duraquin, Quinact, Quinidex, 
Cin-Quin, Quinora 
Antiarrhythmic 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Vandetanib 
Caprelsa 
Anti-cancer 
 

 
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Appendix 3: Prohibited Concomitant Medications 
INHIBITORS 
CYP1A2 
CYP2D6 
CYP3A 
ciprofloxacin  
bupropion  
ceritinib 
fluvoxamine 
fluoxetine  
clarithromycin 
 
paroxetine  
cobicistat 
 
quinidine 
elvitegravir and ritonavir 
 
terbinafine 
idelalisib 
 
indinavir and ritonavir 
 
itraconazole 
INDUCERS 
ketoconazole 
CYP3A 
lopinavir and ritonavir 
apalutamide 
nefazodone 
carbamazepine 
nelfinavir 
enzalutamide 
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir) 
ivosidenib1 
posaconazole 
lumacaftor and ivacaftor 
ritonavir3,4,5 
mitotane 
saquinavir and ritonavir 
phenytoin 
tipranavir and ritonavir 
rifampin 
telithromycin 
St. John’s wort2 
voriconazole 
 
 
 
1: Based on PBPK 
simulation 
3: Ritonavir is approved for use in combination with 
other anti-HIV or anti-HCV drugs. Caution should be 
used when extrapolating the observed effect of 
ritonavir alone to the effect of anti-HIV or anti-HCV 
combination regimens on CYP3A activities. 
2: The effect of St John's 
wort varies widely and is 
preparation dependent 
4: Moderate inducer of CYP1A2 with dosage of 800 
mg/day ritonavir (not with other anti-HIV drugs). 
Effect on CYP1A2 at lower dosages of ritonavir is 
unknown. 
 
5: Weak inducer of CYP2B6, CYP2C9, and CYP2C19. 
Classification is based on studies conducted with 
ritonavir itself (not with other anti-HIV drugs) at 
dosages of 100-200 mg/day, although larger effects 
have been reported in literature for high dosages of 
ritonavir.  
 

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Strong inhibitors: ≥ 5-fold increase in AUC 
Strong inducers: ≥ 80% decrease in AUC 
Table 1 (CYP Enzyme- and Transporter System-Based Clinical Substrates, Inhibitors, or Inducers) 
https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-
interact-cyp-enzymes-and-transporter-systems, dated 06.05.2023; Accessed 08.30.2023