A Phase II Trial of Vemurafenib in Combination With Sorafenib to Treat Patients With Advanced KRAS Mutated Pancreatic Cancer: Targeting RAF Dimers to Suppress Oncogenic RAS Signaling (The Dr. Nate Nieto Study)
Phase: PHASE2
Conditions: Pancreas Cancer
Sponsor: HonorHealth Research Institute

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CONFIDENTIAL 
 
A Phase II Trial of Vemurafenib in Combination with Sorafenib to Treat Patients 
with Advanced KRAS Mutated Pancreatic Cancer. Targeting RAF Dimers to 
Suppress Oncogenic RAS Signaling  
(The Dr. Nate Nieto Study) 
 
Protocol #:  HRI-Vemurafenib-Sorafenib-001 
 
NCT05068752 
IND Exempt 
 
Sponsor 
HonorHealth Research Institute 
 
Principal Investigator 
Erkut H. Borazanci, MD, MS 
HonorHealth Research Institute 
10510 North 92nd Street 
Scottsdale, AZ 85258 
Phone: 480-323-1350 
Email: eborazanci@honorhealth.com 
 
Lead Scientific Investigator 
Haiyong Han, PhD 
Translational Genomics Research Institute (TGen) An Affiliate of City of Hope 
445 North Fifth Street 
Phoenix, AZ 85004 
Email: hhan@tgen.org 
 
Consulting Investigator 
Daniel D. Von Hoff, MD, FACP, FASCO, FAACR 
HonorHealth Research Institute 
10510 North 92nd Street 
Scottsdale, AZ 85258 
 
Translational Genomics Research Institute (TGen) An Affiliate of City of Hope 
445 North Fifth Street 
Phoenix, AZ 85004 
Phone: 602-343-8492 
Email: dvh@tgen.org 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the proprietary property 
of Sponsor. Any unauthorized use or disclosure of such information without the prior 
written authorization of the Sponsor is prohibited. 

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CONFIDENTIAL 
Consulting Investigator 
Talia Golan, MD 
Sheba Medical Center - Israel 
Pancreatic Cancer Center 
Phone: 972-77-997-2480 
Email: Talia.golan@sheba.health.gov.il 
 
Clinical Sub-Investigator 
Gayle S. Jameson, ACNP-BC, AOCN 
HonorHealth Research Institute 
10510 North 92nd Street 
Scottsdale, AZ 85258 
Phone: 480-323-1350 
Email: gjameson@honorhealth.com 
 
Clinical Sub-Investigator 
Lana Caldwell 
HonorHealth Research Institute 
10510 North 92nd Street 
Scottsdale, AZ 85258 
Email: lcaldwell@honorhealth.com 
Scientific Sub-Investigator 
Richard G. Posner, PhD 
Northern Arizona University 
Flagstaff AZ, 86011 
Phone: 928-606-2805 
Email: Richard.Posner@nau.edu 
 
Scientific Sub-Investigator 
William S. Hlavacek, PhD 
Theoretical Biology & Biophysics Group 
Los Alamos National Laboratory 
Los Alamos, NM 87545 
Phone: 505-665-1355 (office) 
Email: wish@lanl.gov 
 
Scientific Sub-Investigator 
Boris N. Kholodenko, PhD, D.Sc., MRIA 
University College Dublin - Belfield 
Dublin 4, Ireland 
Phone: +353-1-716-6304 
Email: boris.kholodenko@ucd.ie 
 
Scientific Sub-Investigator 
Walter Kolch, MD, FRSE, MRIS 
Systems Biology Ireland & Conway 
Institute 
University College Dublin, Ireland 
Phone: 00353-1-716 6303 
Email: walter.kolch@ucd.ie 
 
Scientific Sub-Investigator 
Oleksii S. Rukhlenko, PhD 
Systems Biology Ireland 
University College Dublin, Ireland 
Email: oleksii.rukhlenko@ucd.ie 
 
 
Biostatistician 
Denise J. Roe, DrPH. 
The University of Arizona Cancer Center 
1515 North Campbell Avenue 
Campus PO Box 245024 
Levy Building 1933 
Tucson, AZ 85724 
Phone: 520-626-2281 
Email: droe@email.arizona.edu 

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CONFIDENTIAL 
 
Funding Provided 
TGen Foundation 
 
Trial Drug Supply Provided 
Bayer 
(Bayer Ref #IRR-US-000177) 
 
Genentech 
(Genentech Ref #ML 42826) 
 
Version Dates 
Version 3 dated 28 Mar 2023 
Version 2 dated 14 Oct 2021 
 
 
 
 

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INVESTIGATOR’S PROTOCOL AGREEMENT 
 
 
Study Title: A Phase II Trial of Vemurafenib in Combination with Sorafenib to Treat 
Patients With Advanced KRAS Mutated Pancreatic Cancer. Targeting RAF Dimers to 
Suppress Oncogenic RAS Signaling (The Dr. Nate Nieto Study)  
Protocol No.: HRI-Vemurafenib-Sorafenib-001 
 
Version 3 dated 28 Mar 2023 
 
I confirm that my staff and I have carefully read and understand this protocol. I/we 
agree to comply with the procedures and terms of the study specified herein. In 
particular, I/we have agreed to: 
• Abide by all obligations stated on Form FDA 1572 and on other document(s) 
required by local regulatory authority. 
• Retain records and documents related to this trial for at least 7 years after the last 
approval of a marketing application in an International Conference on Harmonization 
(ICH) region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 7 years have elapsed since the formal discontinuation of 
clinical development of the investigational products. 
• Comply with Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 
• Maintain confidentiality and assure security of HonorHealth Research Institute (HRI) 
confidential documents. 
• Obtain Institutional Review Board (IRB) approval of the protocol, any amendments 
to the protocol, and periodic re-approval as required, and to keep the IRB informed 
of adverse events and periodically report the status of the study to them. 
• Not implement any deviations from or changes to the protocol without agreement 
from the sponsor and prior review and written approval from the IRB, except where 
necessary to eliminate an immediate hazard to the subjects or for administrative 
aspects of the study (where permitted by all applicable regulatory requirements). 
• Assure that each patient enrolled into the trial has read, understands, and has signed 
the Informed Consent. 
• Ensure that I and all persons assisting me with the study are adequately informed 
and trained about the investigational drug and of their study-related duties and 
functions as described in the protocol. 
• Make prompt reports of serious adverse events (SAEs), AESIs, pregnancies, and 
deaths (within 1 business day of becoming aware of the event) to HRI Oncology 
Drug Safety as indicated in Section 8 of the protocol. 
• Assure access to study monitors. 

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• Prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the investigation on each individual treated 
in the investigation. 
• Arrange for the transfer of appropriate data from case histories to case report forms 
for the collection and transmission of data to the Sponsor. 
• Cooperate fully with any study-related GCP audit as performed by quality assurance 
group specified by the sponsor. 
• Abide by the stipulations in the Disclosure of Data section and the manuscript 
preparation/authorship guidelines established at the outset of the study. 
 
 
Investigator’s Printed Name: _________________________________________ 
 
 
Investigator’s Signature and Date:  
 
 
 
 
 
  
 
 

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SAE REPORTING REQUIREMENTS 
 
All SAEs, AESI, and pregnancies must be reported on Medwatch Form 3500A within 24 
hours/ 1 business day of becoming aware of the event, to HonorHealth Oncology Drug 
Safety Team after the Investigator recognizes/classifies the event as a SAE, AESI, or 
pregnancy.  
 
The completed MedWatch Form 3500A with accompanying SAE Coversheet should be 
sent to the Oncology HRI Drug Safety, at the contacts as specified below.  Refer to 
Section 8 for more details. 
 
HonorHealth will be responsible for reporting SAEs, AESI, and pregnancies to Bayer and 
Genentech as per Section 8.12. 
 
 
HonorHealth Oncology Drug Safety Team 
Phone: 480-323-1350 
Fax: 480-323-1560 
Email: OncologyDrugSafety@honorhealth.com 
 
 

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List of Abbreviations 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BID 
Twice a day (from Latin “bis in die”) 
BRAF 
Proto-oncogene B-Raf 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CA-125 
Cancer antigen 125 
CA 19-9 
Carbohydrate antigen 19-9  
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
CO2 
Bicarbonate 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor Deoxyribonucleic Acid 
CTEP 
Cancer Therapy Evaluation Program 
DHHS 
Department of Health and Human Services 
DILI 
Drug Induce Liver Injury 
DNA 
Deoxyribonucleic Acid 
DTC 
Differentiated Thyroid Cancer 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ERK 
Extracellular Signal-Related Kinase 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FDAMA 
Food and Drug Administration Modernization Act 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HCC 
Hepatocellular Carcinoma   
HIPAA 
Health Insurance Portability and Accounting Act 
HRI 
HonorHealth Research Institute 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 

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KRAS 
KRAS gene 
LDH 
Lactate Dehydrogenase 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NS 
Normal Saline 
OS 
Overall Survival 
PD 
Progressive Disease 
PDA 
Pancreatic Ductal Adenocarcinoma 
PFS 
Progression free survival 
P-gp 
P-glycoprotein 
PO 
By mouth (from Latin “per os”) 
PR 
Partial Response 
pRBC 
Packed Red Blood Cells 
PT 
Prothrombin Time 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SPF 
Sun Protection Factor 
SD 
Stable Disease 
TGen 
Translation Genomics Research Institute 
ULN 
Upper Limit of Normal 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
WOCBP 
Women of Childbearing Potential 
 
 
 

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TRIAL SCHEM 
PaƟents with metastaƟc 
advanced RAS mutated 
refractory pancreaƟc 
cancer where the paƟent 
has progressed on ≥ 2 
prior chemotherapy 
regimens for their 
advanced disease. 
• must have QTC of 
≤500ms.
Vemurafenib
480 mg PO BID daily* 
+
Sorafenib
200 mg PO AM and 
200 mg PO PM 
daily** 
X 28 days
( 1 cycle)
Tumor Assessment 
every 8 weeks + CA19-
9 (or CA 125, or CEA if 
not expressers of CA 
19-9)
Key Study Endpoints:
•
Disease control rate (DCR) - CR+PR+SD at 16 weeks
•
Safety
•
Progression Free Survival (PFS) 
•
Overall Survival (OS)
•
Changes in plasma free DNA mutated KRAS – Blood 
collected at baseline and prior to each cycle ( X )
*Vemurafenib Dose level-1 will be 240 mg PO BID
** Sorafenib Dose level-1 will be 200 mg PO daily
0 8 weeks 16 weeks 24 weeks
X X X X X X X X X
DCR
Study treatment conƟnues unƟl disease progression or 
unacceptable toxicity 
< C1 > < C 2 > < C 3 > < C 4 > < C 5 > < C 6 > < C 7 > < C 8 > +

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TRIAL SYNOPSIS 
 
Title and Number: A Phase II Trial of Vemurafenib in Combination with Sorafenib to 
Treat Patients With Advanced KRAS Mutated Pancreatic Cancer. Targeting RAF 
Dimers to Suppress Oncogenic RAS Signaling (The Dr. Nate Nieto Study) 
Protocol No. HRI-Vemurafenib-Sorafenib-001 
Version 2.0 dated 14 Oct 2021 
Sponsor:  
HonorHealth Research Institute 
Principal Investigator:  
Erkut H. Borazanci, MD, MS – HonorHealth Research Institute, Scottsdale, AZ 
Consulting Investigator: 
Daniel D. Von Hoff, MD, FACP, FASCO, FAACR – HonorHealth Research Institute, 
Scottsdale, AZ and Translational Genomics Research Institute (TGen), an Affiliate of 
City of Hope 
 
Talia Golan, MD – Sheba Medical Center, Israel 
Clinical Phase: 
Phase II 
Objectives: 
 
Primary: To determine the efficacy by the disease control rate (CR+ PR +Stable at 
16 weeks) of the combination of the type I½ RAF inhibitor (RAFi) Vemurafenib in 
combination with the type II RAFi Sorafenib in patients with KRAS mutated refractory 
pancreatic cancer. 
Note: Type I inhibitors bind to the active protein kinase conformation (DFG-ASP “in” 
αC helix “in”). Type I½ inhibitors bind to a DFG-ASP “in” and αC helix “out” inactive 
conformation. Type II RAF inhibitors trap kinases in the DFG-ASP “out” αC helix “in” 
inactive conformation (Roskowski, 2016, Rukhlenko 2018). 
 
Secondary: 
1. To confirm the safety of giving Vemurafenib + Sorafenib to patients with 
advanced pancreatic cancer 
 
2. To determine the clinical activity of Vemurafenib + Sorafenib as defined 
progression free survival (PFS) and overall survival (OS) rate. 
 
3. To utilize circulating tumor DNA (ct DNA) in plasma to give qualitative 
(mutations) and to some extent quantitative (amount of ct DNA) information 
regarding BRAF and KRAS. This will be measure at baseline and just before 
each cycle.  
  
4. To measure phospho ERK and phospho AKT in plasma to determine if the 
treatment has hit the intended target (Takano et al. 2010, Petricoin 2009). This 
will be measure at baseline and just before each cycle 
 

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Exploratory: 
• To evaluate changes in phospho ERK and phospho AKT in tumor tissue. 
 
Trial Design:  
Open Label, Single Arm Trial 
Number of Patients:  
Between 7 and 12 evaluable patients 
 
In the first stage 7 evaluable patients will be accrued. If there are zero patients with 
disease control (CR+ PR +Stable at 16 weeks) in these first 7 evaluable patients, the 
study will be stopped. Otherwise, 5 additional evaluable patients will be accrued for a 
total of 12 evaluable patients. 
  
An evaluable patient is defined as one that receives any number of doses of both 
agents (Vemurafenib + Sorafenib) and has a scan after at least 2 cycles of treatment. 
Name & Dose of Drugs: 
• Vemurafenib will be given 480 mg PO BID daily x 28 days = 1 cycle Dose level 
-1 will be 240 mg PO BID 
 
• Sorafenib will be given 200 mg PO BID daily x 28 days = 1 cycle (Dose level -1 
will be 200 mg PO daily) 
 
Note: All doses are to be taken without food. Doses can only be taken one hour 
before or 2 hours after a meal. 
Patient Population: 
Patients with metastatic advanced KRAS mutated refractory pancreatic cancer where 
the patient has progressed on ≥ 2 prior chemotherapy regimens for their advanced 
disease. 
Endpoints: 
 
Primary: disease control rate (defined as CR + PR + Stable at 16 weeks) using 
RECIST 1.1 criteria. 
 
Secondary: 
• Safety of giving vemurafenib + sorafenib in this population of patients 
• Progression free survival (PFS) 
• Overall survival (OS) 
• Identify whether or not the drug combination resulted in changes in plasma free 
DNA mutated KRAS, BRAF, phospho ERK and phospho AKT 
 
Exploratory: 
• Changes in phospho ERK and phospho AKT in tumor tissue. 
Inclusion Criteria: 
1. Be able to understand and be willing to sign the written informed consent for 
the trial. A signed informed consent form must be appropriately obtained prior 
to the conduct of any trial-specific procedure. 

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2. Be ≥ 18 years of age on day of signing informed consent. 
3. Histologically confirmed cancer of the pancreas (KRAS mutated) with 
metastases and progression on at least ≥ 2 prior treatment regimens for their 
disease. 
4. Known mutation status of KRAS and BRAF kinases. For those patients in 
which this has not previously been determined, the patient must have an 
archival tumor specimen (primary or metastatic stie) available to submit to 
confirm KRAS and BRAF status.  
5. Have a performance status of 0 or 1 on the ECOG performance scale. 
6. Demonstrate adequate organ function as defined below: 
a. Absolute neutrophil count ≥1,500/mm3 
b. Platelet concentration ≥ 60 x 109/L 
c. Hemoglobin  ≥ 8.5 g/dL. Criteria must be met without erythropoietin 
dependency and without packed red blood cells (pRBC) transfusion 
within the last 2 weeks.  
d. Serum creatinine < 1.5 X institutional ULN.  
e. Total bilirubin ≤ 2.5 mg/dL  
f. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) 
< 5 × ULN  
g. Prothrombin time (PT) ≤ 60 seconds or International Normalized Ratio 
(INR) ≤ 2.3 
7. Female participants of childbearing potential must have a negative serum 
pregnancy test performed within 24 hours prior to receiving first dose of trial 
medication. Post-menopausal women (defined as no menses for at least 1 
year) and surgically sterilized women are not required to undergo a pregnancy 
test. 
8. A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) 
OR 
b. A WOCBP who agrees to follow the contraceptive guidance during the 
treatment period and for at least 30 days after the last dose of trial 
treatment. 
9. Male participants must agree to use contraception during the treatment period 
and for at least 30 days after the last dose of trial treatment and refrain from 
donating sperm during this period.  
10. Patient must have QTC of ≤500ms. 
11. Subject must be able to swallow and retain oral medication. 
12. Measurable disease per RECIST 1.1 
Exclusion Criteria: 
1. Is currently participating and receiving trial therapy or has participated in a trial 
of an investigational agent and received trial therapy or used an investigational 
device within 2 weeks of the first dose of this trials’ treatment. 
2. Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to Cycle 1/Day 1 or who has not recovered (i.e. 

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NCI-CTC AE Version 5.0 ≤ Grade 1 at the time of signing informed consent) 
from adverse events due to a previously administered agent(s). 
 
Note:  Patients with ≤ Grade 2 neuropathy and ≤ Grade 2 alopecia are an 
exception to this criterion and may qualify for the trial. 
 
3. Previous BRAF inhibitor use such as vemurafenib, GSK2118436 or sorafenib. 
4. If patient received major surgery, and has not yet recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
5. Previously untreated or concurrent cancer that is distinct in primary site or 
histology from pancreatic cancer except cervical cancer in-situ, treated basal 
cell carcinoma, or superficial bladder tumor.  Subjects surviving a cancer that 
was curatively treated and without evidence of disease for more than 3 years 
before study entry.  All cancer treatments must be completed at least 3 years 
prior to study entry (i.e., signature date of the informed consent form). 
6. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Patients with previously treated brain metastases 
may participate provided they are stable (without evidence of progression by 
imaging for at least four weeks prior to the first dose of trial treatment and any 
neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 7 days prior 
to trial treatment. This exception does not include carcinomatous meningitis, 
which is excluded regardless of clinical stability. 
7. Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure 
> 90 mm Hg [NCI-CTCAE v5.0] on repeated measurement) despite optimal 
medical management. 
8. Active of clinically significant cardiac disease including: 
a. Congestive heart failure New York Heart Association (NYHA) > Class II. 
(Appendix D) 
b. Active coronary artery disease (CAD)  
c. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin. 
d. Unstable angina (anginal symptoms at rest), new-onset angina within 3 
months before randomization, or myocardial infarction within 6 months 
before randomization. 
9. Has history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
10. Has an active infection requiring systemic therapy. 
11. Evidence or history of bleeding diathesis or coagulopathy 
12. Patient with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v5.0  ≥ 
Grade 2 within 4 weeks before initiating study treatment; any other 
hemorrhage/bleeding event of NCI-CTCAE v5.0   ≥ Grade 3 within 4 weeks 
before initiating study treatment. 

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13. Patient with thrombotic, embolic, venous, or arterial events, such as 
cerebrovascular accident (including transient ischemic attacks) within 6 months 
of informed consent. 
14. Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
15. History of organ allograft (including corneal transplant). 
16. Known or suspected allergy or hypersensitivity to any of the study drugs 
(sorafenib, and or vemurafenib) study drug classes, or excipients of the 
formulations given during the course of this trial. 
17. All patients with known diagnosis of Neurofibromatosis Type 1 or other known 
RAS-opathies  
18. Patients with uncontrolled seizures  
19. Treatment with medications that have known risk of QTc interval prolongation 
or Torsades de Pointe (TdP) within 14 days or 5 half-lives before dose of either 
drug is given in this study and for the duration of the study. Refer to Appendix 
E1 for medications with a known risk of TdP. 
20. Treatment with a strong or moderate CYP3A inducers (e.g, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort [hypericum perforatum], 
dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], 
and/or rifabutin) or inhibitors within 28 days before dose of either drug is given 
in this study and for the duration of the study. Refer to Appendix G. 
21. Malabsorption or other significant bowel or stomach resections 
22. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or is not in the best 
interest of the patient to participate, in the opinion of the treating 
investigator. 
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
24. Inability to comply with the protocol and/or not willing or not available for follow-
up assessments required to assess toxicity  
Statistical Methods: 
Between 7 and 12 evaluable patients total will be entered into this study. To obtain 
that number of evaluable patients we estimate up to 24 patients will possibly be 
enrolled. An evaluable patient is defined as one that receives at least one dose of 
doses of both agents (vemurafenib + sorafenib) and has a scan after at least 2 cycles 
of treatment.  
 
After the adjustment based upon the NTF from May 13, 2022, we will examine 5 more 
patients at a reduced dose. If at least one patient of the five demonstrated a partial 
response (overall response rate of ≥ 20%), we will proceed with enrolling 7 more 
patients.  Simon’s two-stage design (Simon, 1989) will be used. The null hypothesis 
that the true response rate is 0% will be tested against a one-sided alternative. In the 
first stage, n=5 patients will be accrued. If there are zero patients with a response 
(either a PR or CR) in these 5 patients, the study will be stopped. Otherwise, 7 
additional patients will be accrued for a total of 12. The null hypothesis will be rejected 
if 3 or more patients have a response (either PR or CR) in 12 patients.  

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Table of Contents 
1. 
BACKGROUND AND RATIONALE ........................................................................ 21 
1.1. 
Disease Background and Introduction ............................................................. 21 
1.2. 
Rationale of Clinical Trial ................................................................................. 22 
1.3. 
Study Agent(s) Background and Associated Known Toxicities ........................ 22 
 Vemurafenib .............................................................................................. 22 
 Sorafenib ................................................................................................... 23 
1.4. 
Clinical Experience with Reported Phase I Trial with Vemurafenib + Sorafenib
 
23 
2. 
HYPOTHESIS ........................................................................................................ 24 
3. 
STUDY OBJECTIVES ............................................................................................ 24 
3.1. 
Primary Objectives ........................................................................................... 24 
3.2. 
Secondary Objectives ...................................................................................... 24 
3.3. 
Exploratory Objectives ..................................................................................... 25 
3.4. 
Endpoints ......................................................................................................... 25 
 Primary Endpoint ....................................................................................... 25 
 Secondary Endpoint .................................................................................. 25 
 Exploratory Endpoint ................................................................................. 25 
4. 
STUDY POPULATION ........................................................................................... 25 
4.1. 
Inclusion Criteria .............................................................................................. 25 
4.2. 
Exclusion Criteria ............................................................................................. 26 
5. 
STUDY TREATMENT ............................................................................................ 28 
5.1. 
Treatment Dosage and Administration ............................................................. 28 
5.2. 
Administration of Vemurafenib + Sorafenib ...................................................... 28 
5.3. 
Toxicities and Dosing Delays / Dose Modifications .......................................... 29 
 Vemurafenib Dose Modifications ............................................................... 29 
 Sorafenib Dose Modifications ...................... Error! Bookmark not defined. 
5.4. 
Concomitant Medications / Treatments ............................................................ 32 
5.5. 
Concomitant Therapies Requiring Caution ...................................................... 33 
 Vemurafenib .............................................................................................. 33 
 Sorafenib ................................................................................................... 33 
5.6. 
Duration of Therapy ......................................................................................... 34 
5.7. 
Duration of Follow-up ....................................................................................... 34 

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5.8. 
Removal of Subjects from Protocol Therapy .................................................... 34 
5.9. 
Subject Replacement ....................................................................................... 34 
6. 
STUDY PROCEDURES ......................................................................................... 35 
6.1. 
Screening / Baseline Procedures ..................................................................... 35 
6.2. 
Optional Tissue Collection................................................................................ 36 
6.3. 
Procedures During Treatment (Cycle is 28 Days) ............................................ 36 
 Day 1 of Each Cycle .................................................................................. 36 
 Day 3 (Cycle 1 Only) ................................... Error! Bookmark not defined. 
 Days 8, 15 and 22 of Each Cycle .............................................................. 37 
 Tumor Assessments Every 2 Cycles (Every 8 Weeks) .............................. 37 
6.4. 
Off Treatment Visit – to be Completed 14-28 (+/-2) Days From the Last Dose of 
Study Treatment ........................................................................................................ 37 
6.5. 
Follow-up Procedures ...................................................................................... 38 
6.6. 
Study Treatment Discontinuation ..................................................................... 38 
7. 
MEASUREMENT OF EFFECT .............................................................................. 39 
7.1. 
Disease Control Rate ....................................................................................... 39 
7.2. 
Safety / Tolerability ........................................................................................... 39 
7.3. 
Progression Free Survival (PFS) ...................................................................... 39 
7.4. 
Survival ............................................................................................................ 40 
8. 
ADVERSE EVENTS ............................................................................................... 40 
8.1. 
Adverse Event Monitoring ................................................................................ 40 
8.2. 
Adverse Event Definition .................................................................................. 40 
 Serious Adverse Event Definition .............................................................. 41 
8.3. 
Adverse Event Reporting ................................................................................. 41 
8.4. 
Assessment of Adverse Events ........................................................................ 41 
 Causal Relationship ................................................................................... 41 
 Action Taken with Study Treatment ........................................................... 42 
 Outcome .................................................................................................... 43 
 Assessment of Severity of Adverse Events ............................................... 43 
8.5. 
Procedures for Eliciting, Recording and Reporting Adverse Events ................. 44 
 Eliciting Adverse Events ............................................................................ 44 
 Specific Instructions for Recording Adverse Events .................................. 44 
8.6. 
Pregnancy ........................................................................................................ 45 

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8.7. 
Adverse Events of Special Interest (AESIs) ..................................................... 46 
8.8. 
Other Special Situations Reports ..................................................................... 47 
8.9. 
Product Complaints .......................................................................................... 47 
8.10. 
Post-Study Adverse Events .......................................................................... 47 
8.11. 
Adverse Event Requiring Expedited Reporting ............................................. 47 
 
Medwatch 3500A Reporting Guidelines ................................................. 48 
 
Follow-up Information ............................................................................. 48 
8.12. 
HonorHealth Reporting to Genentech and Bayer ......................................... 49 
9. 
DRUG / TREATMENT INFORMATION .................................................................. 50 
9.1. 
Vemurafenib ..................................................................................................... 50 
9.2. 
Sorafenib .......................................................................................................... 52 
9.3. 
Return and Retention of Study Drug ................................................................ 54 
9.4. 
Drug Accountability .......................................................................................... 54 
10. 
CORRELATIVES / SPECIAL STUDIES .............................................................. 54 
10.1. 
Trial Specimens ............................................................................................ 54 
10.2. 
Assay Methodology ....................................................................................... 54 
10.3. 
Specimen Banking ........................................................................................ 55 
11. 
STATISTICAL CONSIDERATIONS .................................................................... 55 
11.1. 
Study Design / Study Endpoints ................................................................... 55 
11.2. 
Sample Size and Accrual .............................................................................. 55 
11.3. 
Data Analyses Plans ..................................................................................... 55 
 
Analysis of the Conduct of the Trial ........................................................ 55 
 
Patient Disposition .................................................................................. 56 
 
Analysis of Patient Characteristics ......................................................... 56 
 
Statistical Analysis .................................................................................. 56 
 
Safety and Tolerance Analysis ............................................................... 57 
11.4. 
Stopping Rules ............................................................................................. 57 
12. 
STUDY MANAGEMENT ...................................................................................... 57 
12.1. 
Ethics ............................................................................................................ 57 
12.2. 
Institutional Review Board (IRB) Approval .................................................... 57 
12.3. 
Informed Consent ......................................................................................... 58 
12.4. 
Trial Registration and Results Posting Requirements ................................... 58 

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12.5. 
Reporting to Regulatory Authorities, Ethics Committees and Investigators .. 58 
12.6. 
Annual Reports and Study Close-Out ........................................................... 59 
12.7. 
Investigator Obligations ................................................................................ 59 
 
Form FDA 1572 ...................................................................................... 59 
 
Curriculum Vitae ..................................................................................... 59 
 
Investigator Protocol Agreement ............................................................ 59 
 
Financial Disclosures ............................................................................. 59 
 
Laboratory Certifications and Normal Ranges ........................................ 59 
 
Confidentiality ......................................................................................... 60 
12.8. 
Source Documentation ................................................................................. 60 
12.9. 
Case Report Forms ....................................................................................... 60 
12.10. 
Data Management and Monitoring / Auditing ............................................. 61 
 
Data Safety and Monitoring ................................................................. 61 
12.11. 
Record Retention ....................................................................................... 61 
13. 
REFERENCES .................................................................................................... 62 
APPENDICES ............................................................................................................... 65 
Appendix A: Schedule of Events ................................................................................... 65 
Appendix B: ECOG Performance Status ....................................................................... 67 
Appendix C: Revised National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), version 5.0 ................................................................... 68 
Appendix D: New York Heart Association (NYHA) ........................................................ 69 
Appendix E: Medications with Risk of QT Prolongation and TdP (Torsades de Pointes)
 ...................................................................................................................................... 70 
Appendix F: Table 1.Compiled list CYP3A4 inhibitors [US FDA (2019);Flockhart (2007)]
 ...................................................................................................................................... 92 
Appendix G continued: Table 2. Compiled list of CYP3A4 inducers [US FDA (2019); 
Flockhart (2007)] ........................................................................................................... 93 
APPENDIX H.  Compiled list of CYP1A2 major substrates [US FDA (2019); Flockhart 
(2007)] ............................................................................. Error! Bookmark not defined. 
 
 
 
 
 
 

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Tables 
Table 1: Study Drugs ..................................................................................................... 28 
Table 2: Study Drug Dose Levels .................................................................................. 28 
Table 3: Adverse Reactions Requiring Dose Modification of Sorafenib ........................ 30 
Table 4: Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE ............................................................................................................. 43 
 
 

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1. BACKGROUND AND RATIONALE 
 
1.1. Disease Background and Introduction 
Pancreatic cancer continues to be a very lethal disease.  It was estimated that in 2021, 
60,430 Americans (31,950 men and 28,480 women) would be diagnosed with pancreatic 
ductal adenocarcinoma (PDA), and 48,220 will die from the disease.  Pancreatic cancer 
accounts for about 3% of all cancers in the US and about 8% of all cancer deaths (Siegel 
et al. 2021).   
 
Furthermore it is projected that by 2030, PDA will be the second leading cause of death 
from cancer in the US. Worldwide, PDA is the twelfth most common cancer, accounting 
for an estimate of > 300,000 deaths a year (Rahib 2014). 
 
Detection of pancreatic cancer has been notoriously very late in the disease and therefore 
the 5-year survival rate is only 9%. Right now, the only potential cure for pancreatic cancer 
is surgical resection (if the disease is caught early).  However only 10-20% of PDA 
patients are diagnosed with localized, surgically resectable disease.  Even with the 
advances made over the past decade in the surgical resection of PDA, the 5- year survival 
after resection and adjuvant chemotherapy approaches 30% (Strobel 2019), and 
unfortunately most (~ 80%) have reoccurrence of their cancer within 2 years of resection, 
and those reoccurrences are almost universally fatal (Kleef 2016).  
 
The prognosis for this disease is poor despite diagnostic progress and new 
chemotherapeutic regimens. Current treatment regimens for advanced PDA although 
offering modest improvements in progression-free survival (PFS) and overall survival 
(OS), are clearly inadequate in achieving long term survival in these patients.  
 
Additional treatment strategies are desperately needed.  In this study we propose a 
combination of two commercially available drugs a type I½ RAF inhibitor and a type II 
RAF inhibitor.  As will be seen below this approach is based on some very solid science.  
 
It has been established that 90% of pancreatic cancer patients harbor somatic oncogenic 
point mutations in KRAS (90%). The oncogenic KRAS mutation has been shown to be 
the major event in pancreatic cancer; it confers permanent activation of the KRAS protein, 
which acts as a molecular switch to activate various intracellular signaling pathways and 
transcription factors inducing cell proliferation, migration, transformation and survival.  
 
The presence of mutated KRAS correlates with a worse prognosis for patients with 
pancreatic cancer whether or not they undergo surgical resection. 
 
The RAS/RAF/MEK/extracellular signal-related kinase (ERK) pathway is pivotal for cell 
proliferation and survival and is frequently hyperactivated in tumors. Virtually all 
pancreatic cancers are KRAS mutated and therefore that pathway is a prime target for 

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drug development. Clinically used RAF inhibitors are ineffective in RAS mutant tumors 
because they enhance homo- and heterodimerization of RAF kinases, leading to 
paradoxical activation of ERK signaling. We built a next-generation mechanistic dynamic 
model to analyze combinations of structurally different RAF inhibitors, which can 
efficiently suppress MEK/ERK signaling (Kholodenko, 2015 and Rukhlenko 2018). This 
rule-based model of the RAS/ERK pathway integrates thermodynamics and kinetics of 
drug-protein interactions, structural elements, posttranslational modifications, and cell 
mutational status as model rules to predict RAF inhibitor combinations for inhibiting ERK 
activity in oncogenic RAS and/or BRAFV600E backgrounds. Predicted synergistic 
inhibition of ERK signaling was corroborated by experiments in mutant NRAS, HRAS, and 
BRAFV600E cells, and inhibition of oncogenic RAS signaling was associated with 
reduced cell proliferation and colony formation. 
 
1.2. Rationale of Clinical Trial 
We lost a dear friend, Dr. Nate Nieto, an incredible microbiologist to advanced pancreatic 
cancer at the young age of 44. Nate’s colleagues, caregivers and friends (some listed 
here as coinvestigators,) who are experts in Systems Biology and Advanced Analytics, 
have banded together to provide the best possible fresh, systems-based science to attack 
pancreatic cancer. 
 
As an overview, this study aims to combine two RAF inhibitors (RAFi) to suppress 
oncogenic RAS signaling to ERK and overcome the notorious resistance to RAFi caused 
by RAF dimerization (Kholodenko 2015; Rukhlenko et al., 2018). This is an entirely new 
approach against RAS mutated pancreatic cancer. 
 
1.3. Study Agent(s) Background and Associated Known Toxicities 
 
 
Vemurafenib 
Vemurafenib is a type I½ RAF inhibitor. Vemurafenib is also an orally available inhibitor 
of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. 
Vemurafenib inhibits other kinases in vitro such as; CRAF, ARAF, wild-type BRAF, 
SRMS, ACK1, MAP4K5, and FGR at similar concentrations. At steady state, Vemurafenib 
exhibits linear pharmacokinetic within the 240 mg to 960 mg dose range. 
 
There has been a tremendous amount of clinical experience with Vemurafenib. The most 
common adverse events include (≥30%): arthralgias, rash, alopecia, fatigue, 
photosensitivity reactions, nausea, pruritus and skin papillomas. Special precautions from 
the package insert include new primary cutaneous malignancies, new non-cutaneous 
squamous cell carcinomas, tumor promotion in BRAF wild-type melanoma patients, 
serious hypersensitivity reactions (anaphylaxis and Drug Reaction with Eosinophilia and 
Systemic Symptoms - DRESS syndrome), Stevens-Johnson syndrome and toxic 
epidermal necrolysis, QT prolongation, hepatotoxicity, photosensitivity (advise patients to 
avoid sun exposure), uveitis, harm to the fetus, radiation sensitization and recall, and 

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renal failure. Vemurafenib is currently approved for patients with BRAF V600E mutated 
melanoma as well as for patients with BRAF V600E mutated Erdheim-Chester disease. 
 
 
Sorafenib 
Sorafenib is a kinase inhibitor that inhibits multiple intracellular (CRAF, BRAF and mutant 
BRAF) and many surface kinases (KIT, FLT3, RET, RET/PTC, VEGFR-1, VEGFR-2, 
VEGFR-3 and PDGFR-β). It is currently FDA approved for the treatment of patients with 
hepatocellular carcinoma, advanced renal cell carcinoma and locally recurrent or 
metastatic, progressive differentiated thyroid carcinoma refractory to radioactive iodine 
treatment. Sorafenib is a type II BRAF kinase inhibitor (traps their target kinases in an 
inactive so-called DFG-out state occupying a hydrophobic pocket adjacent to the ATP 
binding site (Kufareva and Abagyan 2008). The agent has had very extensive clinical 
trials. No trials with Sorafenib as a single agent in patients with advanced pancreatic 
cancer 
have 
been 
reported. 
However, 
Sorafenib 
has 
been 
added 
to 
a 
gemcitabine+cisplatin combination in patients with advanced pancreatic cancer with no 
indication for improving the response rate or median progression free survival over what 
was achieved with chemotherapy alone. 
 
A single arm phase II trial by Kindler and colleagues (Kindler 2012) of 
gemcitabine+sorafenib also didn’t appear promising. However, the hypothesis to be 
tested in the present study is that the addition of this type II kinase inhibitor to the type I½ 
kinase inhibitor Vemurafenib will produce responses in patients. This type of design is 
based on the very solid science of Kholodenko (2015) and Rukhlenko et al (2018).  
 
Sorafenib’s most common adverse reactions include: diarrhea, fatigue, infection, 
alopecia, hand-foot syndrome, rash, weight loss, anorexia, nausea, gastrointestinal and 
abdominal pain, hypertension and hemorrhage. The most dangerous of these include: 
cardiac ischemia (2.7%), bleeding from varices (2.4%), and hypertension (9.4%) (need to 
take BP weekly for the first 6 weeks). The rash and hand-foot reactions are generally 
grade 1-2. Rare events include: gastrointestinal perforation, wound healing 
complications, QT interval prolongation, a 0.06% incidence of hepatic failure and death, 
and impairment of thyroid stimulating hormone suppression in patients with Differentiated 
Thyroid Carcinoma. Patients can experience a rise in amylase or lipase (without 
pancreatitis) and hypophosphatemia (13%), anemia (44%), thrombocytopenia (12%), 
hypocalcemia (12%) and hypokalemia (5%). 
 
1.4. Clinical Experience with Reported Phase I Trial with Vemurafenib + Sorafenib 
Preclinical experiments with Vemurafenib plus Sorafenib in a Vemurafenib resistant 
melanoma cell line demonstrated a synergistic effect of Sorafenib+Vemurafenib 
(Srivastava and Moorthy, 2019). The MD Anderson team (Kato et al, 2015) have reported 
an initial phase I clinical trial of Vemurafenib plus Sorafenib to overcome BRAF resistance 
(NCT0153136). They established the safe doses in this heavily treated population (76% 
had had prior BRAF or MEK inhibitors). Their MTD was 720mg PO BID of Vemurafenib 

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and for Sorafenib 400mg AM PO and 200mg PM PO (n=24 patients). Toxicities included: 
grade 3 hypertension (n=1), grade 3 headaches (n=1), grade 3 rash (n=2), and grade 3 
depression (n=1). Five responses were noted (some who had prior PanRAF ERK and 
MEK inhibitors): 1 melanoma, 1 adenocarcinoma of the lung and 2 ovarian cancers. Of 
note, patients had a change in the amount of BRAF mutant DNA corresponding with their 
clinical course. Again, the MTD for the regimen was Vemurafenib 720mg PO BID and 
Sorafenib 400mg AM and 200mg PM (Kato et al 2015 and Janku, personal 
communication). Their study documented that this combination can be given safely with 
substantial efficacy. Of note, in their study is that unfortunately there were no patients 
with adenocarcinoma of the pancreas on the study.  
Amendment 3 of this study adjusts the starting dose of vemurafenib to 480 mg po bid and 
sorafenib to 200 mg po bid based upon toxicity seen in the first 3 patients who have 
completed 1 cycle of therapy. Of the first 3  patients who completed cycle 1 dosing the 
exposure of the combination was 57%- both agents; 64% Vemurafenib and 53% 
sorafenib; and 80% both agents. The reason for dose holding was due to 2 instances of 
a grade 3 rash and 1 instance of a grade 3 hypertension. 
 
2. HYPOTHESIS 
The addition of a type I½ RAF inhibitor to a type II RAF inhibitor will have clinical activity 
against KRAS mutated advanced pancreatic cancer. 
 
3. STUDY OBJECTIVES 
 
3.1. Primary Objectives 
To determine the efficacy (disease control rate- CR+PR+ Stable at 16 weeks) of the 
combination of the type I½ RAF inhibitor (RAFi) Vemurafenib in combination with the type 
II RAFi Sorafenib in patients with advanced KRAS mutated refractory pancreatic cancer. 
 
[Note: Type I inhibitors bind to the active protein kinase conformation (DFG-ASP “in” αC 
helix “in”). Type I½ inhibitors bind to a DFG-ASP “in” and αC helix “out” inactive 
conformation. Type II RAF inhibitors trap kinases in the DFG-ASP “out” αC helix “in” 
inactive 
conformation 
(Roskowski, 
2016, 
Rukhlenko 
2018)]. 
 
3.2. Secondary Objectives 
• To confirm the safety of giving Vemurafenib + Sorafenib to patients with 
advanced pancreatic cancer. 
 
• To determine the clinical activity of Vemurafenib + Sorafenib as defined 
Progression free survival (PFS) and Overall survival (OS) rate.  
 
• To utilize circulating tumor DNA (ct DNA) in plasma to give qualitative 
(mutations) and to some extent quantitative (amount of ct DNA) information 

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regarding BRAF and KRAS. This will be measured at baseline and just before 
each cycle 
 
• To measure phospho ERK and phosphor AKT in plasma samples to determine 
if the treatment has hit the intended target (Takano et al. 2010, Petricoin 2009). 
This will be measured at baseline and just before each cycle. 
3.3. Exploratory Objectives 
• To evaluate changes in phospho ERK and phospho AKT in tumor tissue. 
 
3.4. Endpoints 
 
 
Primary Endpoint 
• Disease control rate (defined as CR+PR+SD x16 weeks) using RECIST 
criteria. 
 
 
Secondary Endpoint 
• Safety of giving Vemurafenib + Sorafenib in this population of patients 
• Progression free survival 
• Overall survival 
• Identify whether or not the drug combination resulted in changes in plasma free 
DNA 
mutated 
KRAS, 
BRAF, 
phospho 
ERK, 
phospho 
AK 
 
 
Exploratory Endpoint 
• Changes in phospho ERK and phospho AKT in tumor tissue 
 
4. STUDY POPULATION 
 
4.1. Inclusion Criteria 
1. Be able to understand and be willing to sign the written informed consent for the 
trial. A signed informed consent form must be appropriately obtained prior to the 
conduct of any trial-specific procedure. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Histologically confirmed cancer of the pancreas (KRAS mutated) with metastases 
and progression on at least ≥ 2 prior treatment regimens for their disease. 
4. Known mutation status of KRAS and BRAF kinases. For those patients in which 
this has not previously been determined, the patient must have an archival tumor 
specimen (primary or metastatic stie) available to submit to confirm KRAS and 
BRAF status.  
5. Have a performance status of 0 or 1 on the ECOG performance scale. 
6. Demonstrate adequate organ function as defined below: 
a. Absolute neutrophil count ≥1,500/mm3 
b. Platelet concentration ≥ 60 x 109/L 

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c. Hemoglobin  ≥ 8.5 g/dL. Criteria must be met without erythropoietin 
dependency and without packed red blood cells (pRBC) transfusion within 
the last 2 weeks.  
d. Serum creatinine < 1.5 X institutional ULN.  
e. Total bilirubin ≤ 2.5 mg/dL  
f. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) < 
5 × ULN  
g. Prothrombin time (PT) ≤ 60 seconds or International Normalized Ratio 
(INR) ≤ 2.3 
7. Female participants of childbearing potential must have a negative serum 
pregnancy test performed within 24 hours prior to receiving first dose of trial 
medication. Post-menopausal women (defined as no menses for at least 1 year) 
and surgically sterilized women are not required to undergo a pregnancy test. 
8. A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) 
OR 
b. A WOCBP who agrees to follow the contraceptive guidance during the 
treatment period and for at least 30 days after the last dose of trial 
treatment. 
9. Male participants must agree to use contraception during the treatment period 
and for at least 30 days after the last dose of trial treatment and refrain from 
donating sperm during this period.  
10. Patient must have QTC of ≤500ms. 
11. Subject must be able to swallow and retain oral medication. 
12. Measurable disease per RECIST 1.1 
 
4.2. Exclusion Criteria 
1. Is currently participating and receiving trial therapy or has participated in a trial of 
an investigational agent and received trial therapy or used an investigational 
device within 2 weeks of the first dose of this trials’ treatment. 
2. Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to Cycle 1/Day 1 or who has not recovered (i.e. NCI-
CTC AE Version 5.0 ≤ Grade 1 at the time of signing informed consent) from 
adverse events due to a previously administered agent(s). 
 
Note:  Patients with ≤ Grade 2 neuropathy and ≤ Grade 2 alopecia are an 
exception to this criterion and may qualify for the trial. 
 
3. Previous BRAF inhibitor use such as vemurafenib, GSK2118436 or sorafenib. 
4. If patient received major surgery, and has not yet recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.   
5. Previously untreated or concurrent cancer that is distinct in primary site or 
histology from pancreatic cancer except cervical cancer in-situ, treated basal cell 
carcinoma, or superficial bladder tumor.  Subjects surviving a cancer that was 
curatively treated and without evidence of disease for more than 3 years before 

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study entry.  All cancer treatments must be completed at least 3 years prior to 
study entry (i.e., signature date of the informed consent form). 
6. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Patients with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment. This exception does not include carcinomatous meningitis, which is 
excluded regardless of clinical stability. 
7. Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure 
> 90 mm Hg [NCI-CTCAE v5.0] on repeated measurement) despite optimal 
medical management. 
8. Active of clinically significant cardiac disease including: 
a. Congestive heart failure New York Heart Association (NYHA) > Class II. 
(Appendix D) 
b. Active coronary artery disease (CAD)  
c. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin. 
d. Unstable angina (anginal symptoms at rest), new-onset angina within 3 
months before randomization, or myocardial infarction within 6 months 
before randomization. 
9. Has history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
10. Has an active infection requiring systemic therapy. 
11. Evidence or history of bleeding diathesis or coagulopathy 
12. Patient with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v5.0  ≥ 
Grade 2 within 4 weeks before initiating study treatment; any other 
hemorrhage/bleeding event of NCI-CTCAE v5.0   ≥ Grade 3 within 4 weeks 
before initiating study treatment. 
13. Patient with thrombotic, embolic, venous, or arterial events, such as 
cerebrovascular accident (including transient ischemic attacks) within 6 months 
of informed consent. 
14. Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
15. History of organ allograft (including corneal transplant). 
16. Known or suspected allergy or hypersensitivity to any of the study drugs 
(sorafenib, and or vemurafenib) study drug classes, or excipients of the 
formulations given during the course of this trial. 
17. All patients with known diagnosis of Neurofibromatosis Type 1 or other known 
RAS-opathies  
18. Patients with uncontrolled seizures  
19. Treatment with medications that have known risk of QTc interval prolongation or 
Torsades de Pointe (TdP) within 14 days or 5 half-lives before dose of either 
drug is given in this study and for the duration of the study. Refer to Appendix E1 
for medications with a known risk of TdP. 

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20. Treatment with a strong or moderate CYP3A inducers (e.g, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort [hypericum perforatum], 
dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], 
and/or rifabutin) or inhibitors within 28 days before dose of either drug is given in 
this study and for the duration of the study. Refer to Appendix G. 
21. Malabsorption or other significant bowel or stomach resections 
22. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
patient’s participation for the full duration of the trial, or is not in the best 
interest of the patient to participate, in the opinion of the treating investigator. 
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
24. Inability to comply with the protocol and/or not willing or not available for follow-
up assessments required to assess toxicity  
 
5. STUDY TREATMENT 
 
5.1. Treatment Dosage and Administration 
The specific study drugs, formulation, dosage, administration, and schedule are detailed 
in Tables 1 and 2 and the sections that follow.  Study treatment will be administered on 
an outpatient basis.  Each treatment cycle will be 4 weeks (28 days in duration).   
 
The commercial product for each study drug will be supplied for this trial. Vemurafenib 
will be provided by Genentech, and Sofaranib will be provided by Bayer. Refer to Section 
9 for Drug Treatment Information and link to prescribing information (package inserts). 
 
Table 1: Study Drugs 
Agent 
Formulation 
Dose 
Route 
Schedule 
Cycle 
Length 
Vemurafenib 240 mg 
tablets 
480 mg    PO 
BID 
28 days 
Sorafenib 
200 mg 
tablets 
200 mg  
PO 
BID 
28 days 
 
Table 2: Study Drug Dose Levels 
 
Vemurafenib 
Sorafenib 
Dose level 1 (starting 
dose) 
480  mg PO BID 
200 mg po bid  
Dose level -1 
240 mg PO BID 
200 mg daily 
 
 
 
 
5.2. Administration of Vemurafenib + Sorafenib 

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Patients will be asked to take the specified number of tablets for their prescribed dose on 
an empty stomach at a regular time each day with water. Doses should be taken either 
one hour prior or two hours after a meal. Approximately 12 hours should elapse between 
doses. 
 
5.3. Toxicities and Dosing Delays / Dose Modifications 
Any patient who receives study treatment on this trial will be evaluable for toxicity.  Each 
patient will be assessed for the development of toxicity according to the Schedule of 
Events (Appendix A). Toxicity will be graded according to the NCI CTCAE, Version 5 
which is available at:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_5x7.pdf 
 
For any dose interruptions, re-initiation of study treatment may be delayed for a maximum 
of 28 days to allow recovery from any toxicity. In exceptional cases where subjects are 
responding, re-initiation of therapy after missing > 28 consecutive days of treatment may 
be considered on a case-by-case basis after confirmation with the Principal Investigator. 
 
Treatment related toxicities will be attributed by investigators, and causality will be 
assessed individually for each of the study drugs in the combination regimen, both 
Vemurafenib and Sorafenib (Refer to Section 8.4). 
 
Dose modifications and treatment delays based on observed drug-related toxicity will be 
performed as described in Sections 5.3.1. and 5.3.2 and will follow the prescribing 
information: 
 
Vemurafenib 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202429s019lbl.pdf) 
 
Sorafenib 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021923s020lbl.pdf) 
 
In the event that either Vemurafenib or Sorafenib is to be discontinued due to toxicity, 
both drugs are to be discontinued and the patient is to have off treatment procedures 
completed (Section 6.3).  The patient is to be followed for 30 days after withdrawal from 
study treatment for adverse events (Section 6.4), and every 3 months until study 
completion for survival status. 
 
 
Vemurafenib and Sorafenib Dose Modifications 
 
 

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Vemurafenib and sorafenib should be withheld for Grade 3 or greater adverse reactions 
due to study treatment.  Upon recovery to Grade 0-1, restart vemurafenib and sorafenib 
at a reduced dose (dose level -1) as follows: 
• Vemurafenib 240 mg twice daily plus sorafenib 200 mg daily for first appearance 
of Grade 3 or greater adverse reactions. 
• Stop therapy for second appearance of Grade 3 or greater 
 
If dose reductions below Vemurafenib 240 mg twice daily or sorafenib 200 mg po daily 
are indicated, the patient will be withdrawn. 
 
Vemurafenib should be discontinued for any of the following: 
• Grade 4 adverse reaction, first appearance (if clinically appropriate) or second 
appearance 
• QTc prolongation > 500ms and increased by > 60s from pre-treatment values. 
 
Temporary interruption of sorafenib is recommended in patient undergoing major surgical 
procedures. 
 
Table 3: Adverse Reactions Requiring Dose Modification of Sorafenib 
Adverse Reaction 
CTCAE Grade 
Action 
Dose reduce and 
resume sorafenib 
Cardiovascular 
Events 
 
 
 
Cardiac ischemia 
and/or infarction 
Grade 2 and above 
Permanently 
discontinue 
Do not resume 
Congestive heart 
failure 
Grade 3 
Interrupt a until ≤ 
Grade 1 
Decrease to 200mg 
daily 
Grade 4 
Permanently 
discontinue 
Do not resume 
Hemorrhage 
requiring medical 
intervention 
Grade 2 and above 
Permanently 
discontinue 
Do not resume 
Hypertension 
Grade 2 asymptomatic 
and diastolic pressure 
90-99mmHg 
Treat with anti-
hypertensive 
therapy 
Continue sorafenib 
dosing as scheduled 
and closely monitor 
blood pressure 
Grade 3 
Interrupt until 
symptoms resolve 
and diastolic blood 
pressure < 
90mmHg 
Treat with anti-
hypertensives. 
Decrease to 200 mg 
daily when resumed.  

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If further reduction is 
needed patient is to 
be withdrawn. 
Grade 4 
Permanently 
discontinue 
Do not resume 
Gastrointestinal 
Perforation 
Any grade 
Permanently 
discontinue 
Do not resume 
QT Prolongation 
Monitor electrolytes and 
ECG. If QTc is >500ms 
or for an increase from 
baseline of 60ms or 
greater 
Interrupt 
Correct electrolyte 
abnormalities 
(magnesium, 
potassium, 
calcium) 
Use medical 
judgement before 
restarting 
Severe DILI 
≥ Grade 3 ALT in the 
absence of another 
causec 
AST/ALT > 3xULN with 
bilirubin > 2x ULN in the 
absence of another 
causec 
Permanently 
discontinue 
Do not resume 
Non-hematological 
toxicities 
Grade 2 
Treat on time 
Decrease to 200 mg 
daily 
 
Grade 3 
1st occurrence 
Interrupt until ≤ 
Grade 2 
Decrease to 200 mg 
daily 
No improvement within 
7 days or 2ndoccurrence 
Interrupt until ≤ 
Grade 2 
do not resume 
3rd  occurrence 
Permanently 
discontinue 
Do not resume 
Dermatological 
toxicities 
Grade 2: Painful erythema and swelling of the hands of feet and/or 
discomfort affecting the patient’s normal activities 
1st occurrence 
Continue sorafenib 
and consider 
topical therapy for 
symptomatic relief 
If no improvement 
after 7 days follow 
steps below. 
No improvement within 
7 days at reduced dose 
or 2nd or 3rd occurrence 
Interrupt until 
toxicity resolves to 
Grade 0-1 
Decrease to 200 mg 
dailyd 
4th occurrence 
Permanently 
discontinue 
Do not resume 

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Grade 3: Moist desquamation, ulceration, blistering, or severe pain 
of the hands or feet, resulting in inability to work or perform activities 
or daily living 
1st occurrence 
Interrupt until 
toxicity resolves to 
Grade 0-1 
Decrease to 200 mg 
dailyd 
2nd occurrence 
Interrupt until 
toxicity resolves to 
Grade 0-1 
Do not resume d  
3rd occurrence 
Permanently 
discontinue 
Do not resume 
ULN – upper limit of normal; DILI – drug induced liver injury 
a. If no recovery after 28-day interruption, treatment will be discontinued unless the 
patient is deriving clinical benefit 
b. If more than two dose reductions are required, treatment will be discontinued 
c. In addition, any grade Alkaline phosphatase increase in the absence of known bone 
pathology and Grade 2 or worse Bilirubin increase; Any 1 of the following: INR ≥ 1.5, 
Ascites and/or encephalopathy in the absence of underlying cirrhosis or other organ 
failure considered to be due to DILI. 
d. When dose reduction is necessary for Grade 2 or 3 dermatologic toxicities, after at 
least 28 days of treatment on a reduced dose of sorafenib, the dose of sorafenib may 
be increased by one dose level from the reduced dose. Approximately 50% of patients 
requiring dose reduction for dermatologic toxicity are expected to meet the criteria for 
resumption of the higher dose and roughly 50% of patients resuming the previous dose 
are expected to tolerate the higher dose (that is, maintain the higher dose level with 
recurrent Grade 2 or higher dermatologic toxicity). 
 
5.4. Concomitant Medications / Treatments 
Necessary supportive measures for optimal medical care may be given throughout the 
study, including IV antibiotics to treat infections, blood components, and antiemetics. 
Additional care will be administered as indicated by the treating physician and the 
patient’s medical need. No concomitant cytotoxic therapy, whether conventional or 
investigational, will be allowed during this study. All concomitant medications and 
supportive therapy must be recorded on the appropriate CRF.  
 
The use of grapefruit or grapefruit juice and St. John’s Wort (hyperforin) is prohibited 
during study treatment.  The treating investigator is to discuss this with the patient prior 
to initiating study treatment and will review list of all medications and supplements during 
the course of the study.  
 
Medications with a known risk of TdP are prohibited during the course of the study. Refer 
to Appendix F1. Use caution with medications with a possible risk of TdP or a conditional 
risk of TdP. Refer to Appendix F2 and F3. 

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Radiotherapy may be allowed while the patient is enrolled in this study if given to help 
palliate a specific symptom (e.g. bone pain, brain metastases, etc.). 
 
5.5. Concomitant Therapies Requiring Caution 
 
 
Vemurafenib  
• Strong CYP3A4 inhibitors: Coadministration of a strong CYP3A4 inhibitor 
increased vemurafenib plasma concentration and may lead to increased 
toxicity. Avoid coadministration of vemurafenib with strong CYPA4 inhibitors, if 
this is unavoidable consider dose reduction of vemurafenib, if clinically 
indicated.  Refer to Appendix G, Table 1 for a compiled list of CYP3A4 
inhibitors. 
• Strong CYP3A4 inducers: Coadministration of vemurafenib with rifampin, a 
strong CYP3A4 inducer, decreased vemurafenib plasma concentration and 
may result in decrease efficacy. Avoid coadministration of vemurafenib with 
strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampin for the 
duration of the study.  Refer to Appendix G, Table 2 for a compiled list of 
CYP3A4 inducers. 
• CYP1A2 Substrates: Coadministration of vemurafenib with tizanidine, a 
sensitive CYP1A2 substrate, increased tizanidine systemic exposure by 4.7-
fold.  Avoid concomitant use of vemurafenib with drugs having a narrow 
therapeutic window that are primarily metabolized by CYP1A2. If 
coadministration cannot be avoided, monitor closely for toxicities, and consider 
a dose reduction of concomitant CYP1A2 substrates. Refer to Appendix H for 
a compiled list of CYP1A2 major substrates. 
• P-gp Substrates: Coadministration of vemurafenib with digoxin, a sensitive P-
glycoprotein (P-gp) substrate, increased digoxin systemic exposure by 1.8-fold. 
Avoid concurrent use of P-gp substrates known to have narrow therapeutic 
indices.  If use of these medications is unavoidable, consider dose reduction of 
P-gp substrate. 
• Warfarin: INR (International Normalization Ratio) monitoring should be 
considered 
when 
Vemurafenib 
is 
used 
concurrently 
with 
warfarin. 
 
 
Sorafenib 
• Strong CYP3A4 inhibitors: Ketoconazole, a strong inhibitor of CYP3A4 and 
P-glycoprotein, administered at a dose of 400mg once daily for 7 days did not 
alter the mean AUC of a single oral dose of sorafenib 50mg in healthy 
volunteers. Refer to Appendix G, Table 1 for a compiled list of CYP3A4 
inhibitors. 
• Strong CYP3A4 inducers: Rifampin, a strong CYP3A4 inducer, administered 
at a dose of 600mg once daily for 5 days with a single oral dose of sorafenib 
400mg in healthy volunteers resulted in a 37% decrease in the mean AUC of 

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sorafenib. Avoid concomitant use of strong CYP3A4 inducers (such as 
carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, 
St. John’s wort), when possible because these drugs can decrease the 
systemic exposure to sorafenib. Refer to Appendix G, Table 2 for a compiled 
list of CYP3A4 inducers. 
• Neomycin: Neomycin administered as an oral dose of 1g three times daily for 
5 days decreased the mean AUC of sorafenib by 54% in healthy volunteers 
administered a single oral dose of sorafenib 400mg. The effects of other 
antibiotics on the pharmacokinetics of sorafenib have not been studied. 
• Drugs that increase Gastric pH: The aqueous solubility of sorafenib is pH 
dependent, with higher pH resulting in lower solubility. However, omeprazole, 
a proton pump inhibitor, administered at a dose of 40mg once daily for 5 days 
did not result in a clinically meaningful change in sorafenib single dose 
exposure. No dose adjustment of sorafenib is considered necessary. 
• Effect of sorafenib on other drugs: Sorafenib 400mg twice daily for 28 days 
did not increase the systemic exposure of concomitantly administered 
midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and 
omeprazole (CYP2C19 substrate). 
 
5.6. Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until:  
• Disease progression 
• Inter-current illness that prevents further administration of treatment  
• Unacceptable adverse event(s)  
• Patient decides to withdraw from the study, OR 
• General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator 
 
5.7. Duration of Follow-up 
Patients will be followed for adverse events for 30 days following the last dose of study 
treatment.  Patients will be followed for survival status every 3 months until study 
completion (this may be completed through medical record review or follow up phone 
calls). 
 
5.8. Removal of Subjects from Protocol Therapy 
Patients will be removed from study treatment when any of the criteria listed in Section 
5.6 apply. The reason for study removal and the date the patient was removed will be 
documented in the Case Report Form. The patient should complete the end of treatment 
visit and followed-up per protocol (Sections 6.5, 6.5). 
 
5.9. Subject Replacement 
Patients who receive any number of doses of both agents (Vemurafenib + Sorafenib) 
and has a scan after at least 2 cycles of treatment will not be replaced. Therefore, any 

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patient that does not meet this criteria will be replaced in order to achieve 7 evaluable 
patients. 
 
6. STUDY PROCEDURES 
 
6.1. Screening / Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 28 days prior to initiated study 
treatment unless otherwise stated. The screening procedures include: 
• Informed Consent 
• Medical History -To include concurrent baseline conditions (using NCI CTCAE, 
version 5.0), prior cancer therapy (including documentation of prior surgery, 
adjuvant or neoadjuvant chemotherapy and radiotherapy). 
• ECOG Performance Status (Appendix B) 
• Review inclusion / exclusion criteria 
• Vital Signs (blood pressure, pulse, respiratory rate, and temperature) 
• Complete physical examination including height (cm) and weight (kg) 
• Concomitant medication notation to include all medications taken in the last 30 
days 
• Hematology: CBC with differential and platelet count 
• Serum chemistries: glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase, albumin, LDH, total protein, and electrolytes (sodium, potassium, 
chloride, CO2, magnesium, calcium). In patients with known Gilbert’s syndrome, it 
is recommended to perform a direct bilirubin and indirect bilirubin. Calculate 
creatinine clearance (the Cockcroft-Gault equation may be used to calculate the 
creatinine clearance at any of the time points in this protocol) 
• Coagulation: PT, INR 
• CA19-9 (or CA 125, or CEA if not expressers of CA 19-9) 
• Serum pregnancy test for WOCBP within 72 hours prior to the first dose of study 
treatment.  
• Electrocardiogram (ECG)   
• Computed tomography (CT) / magnetic resonance imaging (MRI) scan to 
document disease status (including chest, abdomen, pelvis, and other regions as 
clinically indicated. In addition, brain scan is required to exclude brain metastases 
if clinically indicated only. If a CT scan was taken within 28 days prior to first dose, 
a new scan is not necessary. (RECIST 1.1 criteria Section 7.1) 
• Blood for correlative analysis - 3 X 10 mL  

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• Confirm KRAS and BRAF mutation status by tissue biopsy.  For those patients in 
which the mutation status of KRAS and BRAF kinases has not previously been 
determined, the patient must have an archival tumor specimen (primary or 
metastatic site) available to submit to confirm KRAS and BRAF status.  The results 
of the mutation status are required for determining patient’s eligibility for this trial. 
 
6.2. Optional Tissue Collection 
As part of participation in this trial, subjects will be provided the option to consent to the 
collection of tumor tissue for Reverse Phase Protein Array (RPPA) analysis. 
 
For those patients that consent to the optional tissue collection for RPPA analysis, tissue 
will be collected from a newly obtained core or excisional biopsy of a tumor lesion if 
performed recently (within 30 days prior to study treatment on Day 1) and during their 
participation in the study should they be scheduled for a biopsy as part of their routine 
care through the follow-up period. 
 
Tissue samples will be centrally analyzed by Theralink. Details for processing and 
shipping of the tissue will be provided in the Trial Lab Manual. 
 
6.3. Procedures During Treatment (Cycle is 28 Days) 
Patients must begin Cycle 1 within 28 days of signing the informed consent document 
and after the screening assessments. All assessments should be performed within 72 
hours of each specified time parameter, with the exception of Cycle 1 in which 
assessments must be conducted within 24 hours (except those noted), or if medical or 
scheduling conditions require a delay. 
 
 
Day 1 of Each Cycle 
• Inclusion/exclusion review (Cycle 1 only)  
• Directed Physical exam  
• Vital Signs (blood pressure, pulse, respiratory rate, and temperature) 
• Measurement of weight (kg) and BSA calculation prior to dosing   
• ECOG Performance Status   
• Hematology: CBC with differential and platelet count  
• Serum chemistries: glucose, creatinine, BUN, total bilirubin, AST, ALT, 
alkaline phosphatase albumin, LDH, total protein, and electrolytes (sodium, 
potassium, phosphorus, chloride, CO2, magnesium, calcium). In patients with 
known Gilbert’s syndrome, it is recommended to perform a direct bilirubin and 
indirect bilirubin.  Calculate creatinine clearance (Cockcroft-Gault equation) 
• Coagulation: PT, INR – only required for patients on warfarin 
• Serum Pregnancy Test  
• ECG (Cycles 1 through 3, then every 3 cycles 6, 9, 12 etc.)  
• Blood for correlative analysis- 3 X 10 mL (cycle 2 and beyond) 
• AEs using the NCI CTCAE 5.0 

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• Concomitant medication notation 
• Distribute study medications to the patient and provide the Patient Study Drug 
Diary (Appendix E) and provide instructions to the patient to return on day 1 
of each cycle.   
• Cycle 2 and beyond: Complete Drug Accountability (Per Section 9.4): Collect 
previous cycle study medications and review the completed Patient Study 
Drug Diary with the patient and address any discrepancies with the patient. 
 
 
 
Days 8, 15 and 22 of Cycle 1 
• Directed physical exam  
• Vital Signs (blood pressure, pulse, respiratory rate, and temperature) 
• ECOG Performance Status   
• Hematology: CBC with differential and platelet count  
• Serum chemistries: glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase albumin, LDH, total protein, and electrolytes (sodium, potassium, 
phosphorus, chloride, CO2, magnesium, calcium). In patients with known 
Gilbert’s syndrome, it is recommended to perform a direct bilirubin and indirect 
bilirubin.  Calculate creatinine clearance (Cockcroft-Gault equation) 
• ECG (Cycle 1/ Day 15 only) 
• AEs using the NCI CTCAE 5.0 
• Concomitant medication notation 
 
 
Tumor Assessments Every 2 Cycles (Every 8 Weeks) 
• Tumor measurements per RECIST 1.1 (before C3, C5, C7 etc.). Tumor 
measurements may be obtained at the discretion of the principal investigator if 
clinically indicated.  
• CA19-9 (or CA 125, or CEA if not expressers of CA 19-9) before C3, C5, C7 
etc.) 
 
In order to more precisely determine time to progression, the investigator is encouraged 
to obtain radiological assessments earlier if there is a strong clinical suspicion of disease 
progression, in order to either confirm or refute the clinical impression. 
 
Reassessment of the extent of tumor should be made by the same imaging methods used 
to establish baseline tumor measurements. 
 
6.4. Off Treatment Visit – to be Completed 14-28 (+/-2) Days From the Last Dose of 
Study Treatment 
• Directed physical exam, if deemed necessary 
• Weight (kg) 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature) 

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• ECOG Performance status 
• Hematology: CBC with differential and platelet count 
• Serum chemistries: glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase albumin, LDH, total protein, and electrolytes (sodium, potassium, 
phosphorus, chloride, CO2, magnesium, calcium).   In patients with known 
Gilbert’s syndrome, it is recommended to perform a direct bilirubin and indirect 
bilirubin. Calculate creatinine clearance (Cockcroft-Gault equation). 
• Coagulation: PT, INR– only required for patients on warfarin 
• CA19-9 (or CA 125, or CEA if not expressers of CA 19-9)  
• Serum pregnancy if applicable 
• Blood for correlative analysis- 3 X 10 mL  
• AEs using the NCI CTCAE 5.0 
• Concomitant medication notation 
• Complete Drug Accountability (Per Section 9.4): Collect all previously 
distributed study medications and review the completed Patient Study Drug 
Diary with the patient and address any discrepancies with the patient. 
• Confirm contact information for patient and a designated family member, and 
primary care physician and remind patient of follow-up telephone contact that 
will be conducted 30 days after the last dose of study treatment and then every 
3 months for survival status. 
 
6.5. Follow-up Procedures 
Patients will be followed for 30 days after completion of (or early withdrawal from) study 
treatment for adverse events.  
 
Patients will be followed for survival end points every 3 months until study completion 
(may be done through medical record review or follow up phone calls).  Receipt of second 
line therapy will be recorded. 
 
6.6. Study Treatment Discontinuation 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The patient should complete the end of treatment 
visit and required followed-up per protocol (Sections 6.3, 6.4) when possible. 
 
The reason(s) for discontinuation will be documented and may include: 
• Patient voluntarily withdraws from treatment (follow-up permitted); 
• Patient withdraws consent (termination of treatment and follow-up); 
• Patient is unable to comply with protocol requirements; 
• Patient demonstrates disease progression (unless continued treatment with study 
drug/treatment is deemed appropriate at the discretion of the investigator and 
approval by PI); 

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• Patient experiences toxicity that makes continuation in the protocol unsafe; 
• Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
• Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
• Lost to follow-up. If a research patient cannot be located to document survival after 
a period of 1 year, the subject may be considered “lost to follow-up.” All attempts 
to contact the patient during the one year must be documented. 
 
7. MEASUREMENT OF EFFECT 
 
7.1. Disease Control Rate 
Disease control rate (defined as CR + PR + Stable x16 weeks) will be evaluated using 
the RECIST criteria (version 1.1, 2009) proposed by the RECIST committee. 
 
These response criteria are widely recognized and accepted as the standard criteria for 
determining response in patients with solid tumors.  
 
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 
 
All patients who have measurable disease according to the RECIST criteria and who have 
their disease re-evaluated will be evaluable for response.  
 
For the purposes of this study, patients should be reevaluated for response approximately 
every 2 cycles. 
 
7.2. Safety / Tolerability 
Analyses will be performed for all subjects having received at least one dose of study 
therapy. The study will use the CTCAE version 5.0 for reporting of non-hematologic 
adverse events. 
 
The incidence of all AEs (regardless of causality) and all treatment-related AEs (those 
AEs thought to be suspected related to study drug) will be summarized by NCI CTCAE 
version 5.0 term and maximum grade. The incidence of AEs that lead to discontinuation 
of study drug will also be summarized. Listings of patients who discontinue study drug 
due to an AE and patients with SAEs and deaths will be presented.  
 
Vemurafenib + Sorafenib dose administration data will be listed and any dose 
interruptions and dose reductions will be summarized. 
 
7.3. Progression Free Survival (PFS) 
Progression-free survival (PFS) is defined as the time from study treatment initiation 
(C1/D1) to first documentation of objective tumor progression or to death due to any 

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cause. In the absence of previous documentation of objective tumor progression will be 
censored at the last date the patient was known to be progression-free in those who do 
not have objective tumor progression and who are: 1) still on study at the time of an 
analysis; 2) are given anti-tumor treatment other than the study treatment; or 3) are 
removed from study follow-up prior to documentation of objective tumor progression. 
 
7.4. Survival 
Survival is defined as the time from initiation of study treatment (C1/D1) to date of death. 
In the absence of confirmation of death, survival time will be censored at the last date the 
patient is known to be alive. 
 
8. ADVERSE EVENTS 
 
8.1. Adverse Event Monitoring 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) per protocol. This includes all events of death, and any 
study specific issue of concern. 
 
Investigators should refer to the Safety Information section of the current Investigator 
Brochures for sorafenib and vemurafenib, for the expected side effects of the study drugs.  
 
Therapeutic monitoring should be performed following dose selection or modification of  
study drug in a manner consistent with the local clinical standard of care.  In general, 
subjects should be closely monitored for side effects of all concomitant medications 
regardless of the path of drug elimination. 
All concomitant medications must be recorded in the subject’s source documentation. 
 
Subjects must be carefully monitored for AEs.  This monitoring also includes clinical 
laboratory tests.  Adverse events should be assessed in terms of their seriousness, 
intensity, and relationship to the study drug, or other chemotherapy/treatment. 
 
8.2. Adverse Event Definition 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal 
product (IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period (Section 8.3), including signs or symptoms 
associated with pancreatic cancer that were not present prior to the AE reporting 
period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations) 

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• If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• Preexisting medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
 
 
Serious Adverse Event Definition 
An AE should be classified as an SAE if any of the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the subject 
at immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization (see section 8.5.2.5). 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the study drugs. 
• It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
8.3. Adverse Event Reporting 
The study period during which AEs and SAEs as described in Section 8.2 where the 
patient has been exposed to study treatment must be reported.  Reporting period begins 
at the time of initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is 
earlier. After this period, investigators should only report SAEs that are attributed to prior 
study treatment. 
 
8.4. Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the study drug (assessed for each Sorafenib and Vemurafenib separately, 
see Section 8.4.1), and actions taken to study drug (8.4.2). 
 
 
Causal Relationship 
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information. 
 
The causality assessment should be done separately for each study treatment. 
 

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The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. 
 
Possible answers are “yes” or “no”. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guidelines to the attributions and causal relationship: 
 
Attribution 
Causal Relationship 
Possibly Related 
Yes- Related 
Probably Related 
 
Definitely Related 
 
Not Related 
No- Not Related 
Unlikely Related 
 
 
Yes (Possibly, Probably, Definitely) 
There is a plausible temporal relationship between the onset of the AE and administration 
of the study treatment (assessed for each Sorafenib and Vemurafenib separately) and 
the AE cannot be readily explained by the subject’s clinical state, intercurrent illness, or 
concomitant therapies; and/or the AE follows a known pattern of response to the study 
treatment or with similar treatments; and/or the AE abates or resolves upon 
discontinuation of the study treatment or dose reduction and, if applicable, reappears 
upon re- challenge. 
 
No (Not related, Unlikely) 
Evidence exists that the AE has an etiology other than the Sorafenib and Vemurafenib 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to study 
treatment (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Inserts (Refer to Section 9).  
 
Unexpected adverse events are those not listed in the Package Inserts or not identified. 
This includes adverse events for which the specificity or severity is not consistent with the 
description in the Package Inserts. For example, under this definition, hepatic necrosis 
would be unexpected if the Package Inserts only referred to elevated hepatic enzymes or 
hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
 
 
Action Taken with Study Treatment 

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Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
 
The study treatment action should be recorded separately for each study treatment. 
• Drug withdrawn 
• Drug interrupted 
• Dose reduced 
• Dose not changed 
• Dose increased 
• Not applicable 
• Unknown 
 
Other specific treatment(s) of adverse events 
• None 
• Remedial drug therapy 
• Other 
 
 
Outcome 
The outcome of the AE is to be documented as follows:  
• Recovered/resolved 
• Recovering/resolving 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Fatal 
• Unknown 
 
 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for 
assessing adverse event severity. Below Table 4.  should be used for assessing severity 
for adverse events that are not specifically listed in the NCI CTCAE. 
 
Table 4: Adverse Event Severity Grading Scale for Events Not Specifically Listed 
in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 

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5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found 
at:  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as 
performed by patients who are not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event  
d. Grade 4 and 5 events must be reported as serious adverse events 
 
8.5. Procedures for Eliciting, Recording and Reporting Adverse Events 
 
 
Eliciting Adverse Events 
 
 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
8.5.2.1. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is acceptable to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
 
8.5.2.2. Progressive Disease 
If progressive disease leads to signs and symptoms that meet the criteria for an SAE (i.e., 
hospitalization, disability, death, or important medical event), the signs and symptoms 
should be reported as an SAE and not the underlying progressive disease. 
 
8.5.2.3. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 8.3), 
regardless of attribution, will be reported to the appropriate parties. When recording a 
death, the event or condition that caused or contributed to the fatal outcome should be 
reported as the single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, report “Unexplained Death”. 
 
8.5.2.4. Pre-Existing Medical Conditions 

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A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
 
8.5.2.5. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the procedure 
itself, should be reported as the SAE. For example, if a subject is hospitalized to undergo 
coronary bypass surgery, record the heart condition that necessitated the bypass as the 
SAE. 
 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met: 
 
• The admission results in a hospital stay of less than 12 hours 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 
• The admission is not associated with an AE. (e.g. social hospitalization for 
purposes of respite care). 
 
8.5.2.6. Laboratory Abnormalities 
An isolated laboratory abnormality that is assigned grade 4, according to CTCAE 
definition, is not reportable as an SAE; unless the investigator assesses that the event 
meets standard ICH criteria for an SAE or Adverse Events of Special Interest (AESIs- 
Section 8.7).  CTCAE grade 4 baseline laboratory abnormalities that are part of the 
disease profile should not be reported as an SAE, specifically when they are allowed or 
not excluded by the protocol inclusion/exclusion criteria. 
 
8.6. Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 30 days 
after the last dose of study drug, or if the female partner of a male study subject becomes 
pregnant while the study subject is receiving the study drug or within 30 days after the 
last dose of study drug, a report should be completed and expeditiously submitted to HRI 
Drug Safety/Bayer/Genentech. Follow-up to obtain the outcome of the pregnancy should 
also occur. Abortion, whether accidental, therapeutic, or spontaneous, should always be 

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classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to the study drug should 
be reported as an SAE. 
 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent.  
 
Female patients of childbearing potential should be advised to use contraception during 
the treatment and at least 30 days after the last dose of study treatment. Women must 
refrain from donating eggs during this same period. 
 
8.7. Adverse Events of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific 
to the product, for which ongoing monitoring and rapid communication by the Investigator 
to the Sponsor is required. Such an event might require further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid 
communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may 
also be warranted. 
 
Adverse events of special interest for this study include the following: 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law: 
o Treatment-emergent ALT or AST > 3 X ULN in combination with total bilirubin 
> 2 X ULN 
o Treatment-emergent ALT or AST > 3 X ULN in combination with clinical 
jaundice 
• Acute Kidney Injury 
• Cutaneous Squamous Cell Carcinomas 
• Non cutaneous Squamous Cell Carcinomas 
• Pancreatitis 
• Liver injury 
• Progression of RAS Mutant Malignancies 
• QT Prolongation 
• Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
o 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may 
be suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 

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8.8. Other Special Situations Reports 
The following other Special Situations Reports should be collected even in the absence 
of an Adverse Event and transmitted to HRI Oncology Drug Safety: 
• Data related to the Product usage during breastfeeding 
• Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
• In addition, reasonable attempts should be made to obtain and submit the age or 
age group of the patient, in order to be able to identify potential safety signals 
specific to a particular population 
 
8.9. Product Complaints 
A Product Complaint is defined as any written or oral information received from a 
complainant that alleges deficiencies related to identity, quality, safety, strength, purity, 
reliability, durability, effectiveness, or performance of a product after it has been released 
and distributed to the commercial market or clinical trial. 
 
8.10. Post-Study Adverse Events 
For studies involving collection of survival data the investigator after the end of the 
adverse event reporting period (defined as 30 days after the last dose of study drug or 
study discontinuation/termination, whichever is earlier) should report all deaths, 
(regardless of cause), and any serious adverse event including development of cancer or 
a congenital anomaly in a subsequently conceived offspring of a female subject including 
pregnancy occurring in the partner of a male study subject who participated in the study 
that is believed to be related to prior exposure to study drug. 
 
Case Transmission Verification will be performed by all parties during this period half 
yearly to ensure successful transmission of single case reports. 
 
8.11. Adverse Event Requiring Expedited Reporting 
HonorHealth will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs), pregnancy reports (including pregnancy occurring 
in the partner of a male study subject), other Special Situation reports, AESIs and Product 
Complaints with an AE where the patient has been exposed to the study drug (Sorafenib 
and Vemurafenib).  
 
The definition of serious adverse events (SAEs) is given in Section 8.2 and Adverse 
Events of Special Interest (AESIs) in Section 8.7. 
 
All SAEs, AESI, and pregnancies must be reported on Medwatch Form 3500A within 
24 hours/ 1 business day of becoming aware of the event, to HonorHealth Oncology 
Drug Safety Team after the Investigator recognizes/classifies the event as a SAE, 
AESI, or pregnancy.  

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The completed MedWatch Form 3500A along with the accompanying SAE Coversheet 
should be sent to the HRI Oncology Drug Safety contacts as specified below. 
Transmission of these reports (initial and follow-up) will be either electronically via email 
or by fax and within the timelines specified below. 
 
MedWatch 3500A (Mandatory Reporting) form is available at: 
https://www.fda.gov/media/69876/download 
 
HonorHealth Drug Safety Team 
Phone: 
480-323-1350 
Fax: 
480-323-1560 
Email: 
OncologyDrugSafety@honorhealth.com 
 
 
HonorHealth will be responsible for reporting SAEs, AESI, and pregnancies to Bayer and 
Genentech as per Section 8.12. 
 
 Medwatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic (Section A) and suspect 
medication information (Section C & D), the report should include the following 
information within the Event Description (Section B.5) of the MedWatch 3500A form: 
• Protocol number and title description  
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics (Section B.6) 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
 Follow-up Information 
Each serious adverse event must be followed up until resolution or stabilization, by 
submission of updated reports.  Additional information may be added to a previously 
submitted report by any of the following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-
up information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 

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8.12. HonorHealth Reporting to Genentech and Bayer 
HonorHealth will forward quarterly listings of non-serious AEs originating from the Study 
to Bayer/Genentech. 
 
HonorHealth will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs), pregnancy reports (including pregnancy occurring 
in the partner of a male study subject), other Special Situation reports, AESIs and Product 
Complaints with an AE where the patient has been exposed to the Product. The 
completed MedWatch form should be sent to the Bayer/Genentech contact specified 
below. Transmission of these reports (initial and follow-up) will be either electronically via 
email or by fax and within the timelines specified below. 
 
Bayer Safety Global Pharmacovigilance – USA 
Bayer Ref #: IRR-US-000177 
Phone: 888-842-2937 
Fax: 973-709-2185 
Email: DrugSafety.GPV.US@bayer.com 
 
Genentech SAE Reporting 
Genentech Ref# ML-42826 
Phone: 800-334-0290 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
Product Complaints without AE should call via PC Hotline Number: 
800-334-0290 (M-F: 5am to 5pm PST) 
 
Transmission of these reports (initial and follow-up) will be either electronically or by fax 
and within the timelines specified below: 
 
Type of Report  
Timelines  
Serious Adverse Events (related and not 
related to the Product) 
 
 
30 calendar days from awareness date 
 
Special Situation Reports (With or without 
AE and pregnancy) 
Product Complaints (With or without AE) 
AESI 
 
Case Transmission Verification of Single Case Reports 
• The parties will verify that all single case reports have been adequately received 
by Bayer and Genentech via HonorHealth emailing Bayer and Genentech a 

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Quarterly line-listing documenting single case reports sent by HonorHealth to 
Bayer and Genentech in the preceding time period.  
• The periodic line-listing will be exchanged within seven (7) calendar days of the 
end of the agreed time period. Confirmation of receipt should be received within 
the time period mutually agreed upon. 
• If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall handle 
the matter on a case-by-case basis until satisfactory resolution.  The sponsor shall 
receive reconciliation guidance documents within the ‘Activation Package’. 
• Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by HonorHealth to Genentech within 
five (5) calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be 
sent to Bayer and Genentech 
 
9. DRUG / TREATMENT INFORMATION 
 
9.1. Vemurafenib  
Package Insert: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202429s019lbl.pdf 
 
Other names for the drug:  
• Zelboraf®;  
• propane-1-sufonic acid {3-[5-(4-chlorphenyl)-1H-pyrrolo[2,3-b]pyridine-3-
carbonyl]-2,4-difluoro-phenyl}-amide  
• C23H18ClF2N3O3S molecular weight 489.9. 
 
Classification - type of agent: A kinase inhibitor 
 
Mode of action: Vemurafenib is a low molecular weight, orally available, inhibitor of some 
mutated forms of BRAF serine-threonine kinase, including BRAF V600E. Vemurafenib 
also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, 
MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including 
V600E result in constitutively activated BRAF proteins, which can cause cell proliferation 
in the absence of growth factors that would normally be required for proliferation. 
Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with 
mutated BRAF V600E. 
 
Storage and stability:  Vemurafenib tablets are to be stored in their original container with 
lids tightly closed at room temperature 20ºC-25 ºC (68 ºF-77 ºF). Storage temperature 
excursions are permitted between 15ºC-30 ºC (59ºF-86 ºF). 
 

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Protocol dose:  480 mg PO (2 x 240mg tablets) BID 
 
Preparation: No preparation required. 
 
Route of administration for this study: Oral 
 
Availability: Provided by Genentech free of charge. 
 
Patient Counseling Information:  
• Advise the patient to read the FDA-approved patient labeling (Medication Guide) 
before starting vemurafenib.  
• Advise the patient to avoid consuming grapefruit and grapefruit juice while take 
vemurafenib during study treatment as this may raise the levels of vemurafenib 
and could make side effects worse. 
• Advise the patient to avoid the use of St. John’s Wort while taking vemurafenib 
during study treatment as this may lower the levels of the drug, which can make it 
less effective. 
• Vemurafenib increases the risk of developing new primary cutaneous 
malignancies. Patients should be advised of the importance of contacting their 
healthcare provider immediately for any changes in their skin. 
• Anaphylaxis and other serious hypersensitivity reactions can occur during 
treatment and upon re-initiation of treatment with vemurafenib. Patients should be 
advised to stop taking vemurafenib and to seek immediate medical attention for 
symptoms of anaphylaxis and hypersensitivity. 
• Severe dermatological reactions can occur in patients receiving vemurafenib. 
Patients should be advised to stop taking vemurafenib and to contact their health-
care provider for severe dermatologic reactions. 
• Vemurafenib can prolong QT interval, which may result in ventricular arrhythmias. 
Patients should be advised of the importance of monitoring their electrolytes and 
the electrical activity of the heart (via and ECG) during treatment with vemurafenib. 
• Liver injury leading to functional hepatic impairment, including coagulopathy or 
other organ dysfunction, can occur with vemurafenib. Patients should be advised 
of the importance of laboratory monitoring of their liver during treatment with 
vemurafenib and to contact their health-care provider for relevant symptoms. 
• Vemurafenib can cause mild to severe photosensitivity. Patients should be advised 
to avoid sun exposure, wear protective clothing, use a broad-spectrum UVA/UVB 
sunscreen and lip balm (SPF≥30) when outdoors to help protect against sunburn. 
• Ophthalmologic reactions can occur in patients treated with vemurafenib. Patients 
should be advised to contact their health care provider immediately for 
ophthalmologic symptoms. 

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• Due to potential risk to a fetus woman of child-bearing potential must use effective 
contraception during treatment with vemurafenib and for 2 weeks after their last 
dose. 
• If a female patient confirms or suspects pregnancy during the study, they should 
contact their healthcare provider immediately. Any confirmed pregnancy is to be 
reported within 24 hours as per Section 8.6. 
• If a male patient’s sexual partner becomes pregnant during the study, they should 
contact their healthcare provider immediately.  Any confirmed pregnancy is to be 
reported within 24 hours as per Section 8.6.  
• Female patients should be advised not to breastfeed during treatment with 
vemurafenib and for 2 weeks following the final dose. 
• Radiation sensitization and recall can occur in patients treated with radiation prior 
to, during, or after treatment with vemurafenib. Patients should be advised to 
inform their health care provider if they have had or are planning to receive 
radiation therapy. Radiotherapy may be allowed while the patient is enrolled in this 
study if given to help palliate a specific symptom (e.g. bone pain, brain metastases, 
etc. 
• Renal failure can occur in patients treated with vemurafenib. Patients should be 
advised of the importance of monitoring serum creatinine prior to and during 
treatment with vemurafenib. 
• Advise patients to contact their health care provider for symptoms of Dupuytren’s 
contracture or plantar fascial fibromatosis 
 
9.2. Sorafenib 
Package Insert: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021923s020lbl.pdf 
 
Other names for the drug(s):  
• Nexavar 
• Sorafenib tosylate 
• 4-(40{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}ogebixt)N2-methylpyridine-2-
carboxamide 4-methylbenzenesulfonate 
• C21H16ClF3N4O3 x C7H8O3S 
 
Classification - type of agent: Kinase inhibitor 
 
Mode of action: Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in 
vitro. Sorafenib was shown to inhibit multiple intracellular (c-CRAF, ARAF and mutant 
BRAF) and cell surface kinases (KIT, FLT-3, RET, RET/PTC, VEGFR-1, VEGFr-2, 
VEGFR-3, and PDGFR-β). Several of these kinases are thought to be involved in tumor 
cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited tumor growth of HCC, 
RCC and DTC human tumor xenografts in immunocompromised mice. Reductions in 

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tumor angiogenesis were seen in models of HCC and RCC upon sorafenib treatment and 
increases in tumor apoptosis were observed in models of HCC, RCC and DTC. 
 
Storage and stability: The tablets should be stored in a dry place at 25 ºC (77 ºF). Storage 
temperature excursions are permitted between 15ºC-30 ºC (59 ºF-86 ºF). 
 
Protocol dose: 200mg (one tablet) PO am and 200mg (one tablet) PO pm 
 
Preparation: No preparation is required 
 
Route of administration for this study: Oral 
 
Availability: Provided by Bayer free of charge. 
 
Patient Counseling Information:  
• Patients should be advised to read the FDA approved patient labelling guide prior 
to starting treatment with sorafenib. 
• Discuss with patients that cardiac ischemia and/or infarction and congestive heart 
failure, have been reported during sorafenib treatment and that they should 
immediately report any episodes of chest pain or other symptoms of cardiac 
ischemia or congestive heart failure. 
• Inform patients with a history of prolonged QT interval that sorafenib can worsen 
the condition. 
• Inform patients that sorafenib can increase the risk of bleeding and that they should 
promptly report any episodes of bleeding. 
• Inform patients that bleeding, or INR elevations have been reported in some 
patients taking warfarin while on sorafenib and that their INR should be monitored 
regularly. 
• Inform patients that hypertension can develop during sorafenib treatment, 
especially during the first six weeks of therapy and that blood pressure should 
monitored regularly during treatment. 
• Patients should be advised of the possible occurrence of hand-foot skin reaction 
and rash during sorafenib treatments and the measures they should take. 
• Patients should be advised that cases of gastrointestinal perforation have been 
reported in patients taking sorafenib. 
• Patients should be informed that temporary interruption of sorafenib is 
recommended in patients undergoing major surgical procedures due to potential 
wound healing complications. 
• Sorafenib can cause hepatitis which may result in hepatic failure and death. 
Patients should be advised that liver function tests should be monitored regularly 
during treatment and that they should report symptoms of hepatitis. 

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• Due to potential risk to a fetus woman of child-bearing potential must use effective 
contraception during treatment and for 6 months after the last dose of sorafenib. 
Male patients with female partners of reproductive potential or who are pregnant 
must use effective contraception during treatment with sorafenib and for 3 months 
after receiving their last dose. 
• If a female patient confirms or suspects pregnancy during the study, they should 
contact their healthcare provider immediately. 
• Patients on sorafenib should not breastfeed while taking the medication and for 2 
weeks after receiving their last dose. 
• If a patient misses a dose of sorafenib, the next dose should be taken at the 
regularly scheduled time; they should not double the dose. Patients should be 
instructed to contact their healthcare provider immediately if they take too much 
sorafenib. 
 
9.3. Return and Retention of Study Drug 
Institutional pharmacy standard operating procedures will be followed for retention, 
storage, and destruction of study drug. 
 
9.4. Drug Accountability 
Patients will be instructed to complete a study drug diary and return along with the study 
medication bottles on Day 1 visit of each cycle for drug accountability.   Drug 
accountability will be completed by delegated study personnel at minimum of once per 
cycle by reviewing both the patient completed drug diary and the returned study 
medication.  Study personnel will document any missed doses in the source documents 
and review this with both the patient and the treating investigator. Study personnel will 
provide additional reinstruction to the patient and implement additional drug accountability 
throughout a cycle as needed.   
 
10. CORRELATIVES / SPECIAL STUDIES 
 
10.1. Trial Specimens 
Blood specimens will be collected for plasma DNA to determine target engagement 
before, during and after treatment.  This will be measured at baseline and just before 
each cycle of treatment.  The site will collect blood samples (3 X 10 mL) at screening, 
Day 1 of each treatment cycle, and at the off treatment study visit. 
 
Please see Laboratory Manual for details on blood collection and processing guidelines. 
 
10.2. Assay Methodology 
Blood samples will be collected and processed for plasma at baseline and just before 
each treatment cycle. Plasma will be used to analyze circulating tumor DNA (ctDNA) to 
give qualitative (mutations) and to some extent quantitative (amount of ctDNA) 
information regarding BRAF and KRAS.  

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Blood samples will be collected and processed for serum at baseline and just before each 
treatment cycle. Serum will be analyzed using the Bio-plex suspension array using 
specific antibodies and flow cytometry as per the methods developed by Takano et al. 
2010 to measure phopho ERK to determine if the treatment has hit the intended target. 
 
Tissue samples 
For those patients that consent to the optional tissue collection for RPPA analysis, tissue 
will be collected from a newly obtained core or excisional biopsy of a tumor lesion if 
performed recently (within 30 days prior to study treatment on Day 1) and during their 
participation in the study should they be scheduled for a biopsy as part of their routine 
care during their participation in the study through the follow-up period. 
 
Tissue samples will be analyzed using Reverse Phase Protein Array (RPPA). 
 
10.3. Specimen Banking 
Any blood samples remaining after the trial specified analyses is completed will be 
transferred to and stored at HonorHealth if the patient consented for use of their remaining 
samples for future research purposes at HonorHealth's discretion. This includes the 
original specimen collected from the patient as well as derivatives created from the 
original specimen (DNA, RNA). 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1. Study Design / Study Endpoints 
This is a phase II open-label, single arm trial, with the identity of the treatment known to 
the patients, Investigators, and Sponsor. 
 
11.2. Sample Size and Accrual 
Between 7 and 12 evaluable patients total will be entered into this study. To obtain that 
number of evaluable patients we estimate up to 24 patients will possibly be enrolled. An 
evaluable patient is defined as one that receives at least one dose of both agents 
(vemurafenib + sorafenib) and has a scan after at least 2 cycles of treatment. We are 
hoping for a disease control rate of ≥40%. Simon’s two-stage design (Simon, 1989) will 
be used. The null hypothesis that the true response rate is 5% will be tested against a 
one-sided alternative. In the first stage, n=7 patients will be accrued. If there are zero 
responses in these 7 patients, the study will be stopped. Otherwise, 5 additional patients 
will be accrued for a total of 12. The null hypothesis will be rejected if 3 or more responses 
are observed in 12 patients. This design yields a type I error rate of 0.0188 and power of 
0.9077 when the true response rate is 40%. (Jung et al, 2004). 
 
11.3. Data Analyses Plans 
 
 Analysis of the Conduct of the Trial 

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Enrollment, major protocol deviations, and discontinuations for the trial will be 
summarized using a CONSORT diagram. 
 
 Patient Disposition 
A detailed description of patient disposition will include: 
• A summary of data on patient discontinuation from treatment. 
• A summary of data on overall qualification status of all patients. 
• An account of all identified protocol deviations. 
 
All patients enrolled in the study will be included in the summation. An evaluable patient 
is any patient who has received any number of doses of both agents (vemurafenib + 
sorafenib) and has a scan after at least 2 cycles of treatment. The number of patients 
who do not qualify for analysis, who die or discontinue before treatment begins, will be 
specified. 
 
 Analysis of Patient Characteristics 
Patient characteristics will include a summary of the following: 
• Patient demographics 
• Baseline disease characteristics 
• Pre-existing conditions 
• Prior therapies 
• Concomitant medications and treatments 
• Other patient characteristics will be summarized as appropriate. 
 
 Statistical Analysis  
The primary efficacy analysis will focus on the disease control rate (CR + PR + SD at 16 
weeks). Secondary endpoints include progression-free survival (PFS) and overall survival 
(OS). The efficacy analysis will only be conducted on patients who have received any 
number of doses of both agents (vemurafenib + sorafenib) and have a scan after at least 
2 cycles of treatment. 
 
Objective responses will be evaluated using the Response Evaluation Criteria In Solid 
Tumors 1.1 (RECIST 1.1). Changes (i.e. improvements) in tumor measurements from 
baseline values will be assigned a status of CR or PR or SD. Objective response 
measurements will comprise the sum of CR plus PR. The overall response rate, as well 
as the rates for the individual categories of response (i.e. CR, PR, SD, and PD), will be 
estimated by the percentage of patients achieving these criteria with exact 95% binomial 
confidence intervals. 
 
Progression-free survival is defined as the interval from the date of study treatment 
initiation (C1/D1) to the earliest date of documented evidence of recurrent or progressive 
disease, or the date of death due to any cause, whichever occurs first. Overall survival 
will be measured from the date of study treatment initiation (C1/D1) to the date of death 

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due to any cause, or the date of last contact (censored observations). For the estimation 
of progression-free and overall survival a Kaplan-Meier analysis will be performed.  
 
Longitudinal measurements of circulating tumor DNA (ctDNA) and phospho ERK will be 
visualized using plots for each evaluable patient.  These measurements will be 
transformed using a logarithmic transformation, if necessary, to remove skewness.  
Significant changes across time will be assessed using linear mixed effects models, to 
account for the correlation among the measurements within an individual.  If the observed 
change is non-linear, nonlinear mixed effects models will be used. 
 
 Safety and Tolerance Analysis 
All patients who received at least one dose of any of the study medications will be included 
in the safety analyses. Vemurafenib + Sorafenib dose administration data will be listed 
and any dose interruptions and dose reductions will be summarized. 
 
The incidence of all AEs (regardless of causality) and all treatment-related AEs (those 
AEs thought to be suspected related to study drug) will be summarized by NCI CTCAE 
version 5.0 term and maximum grade. The incidence of SAEs and AEs that lead to 
discontinuation of study drug will also be summarized. Listings of patients who 
discontinue study drug due to an AE and patients with SAEs and deaths will be presented. 
Narratives will be provided for patients who experience an SAE. 
 
11.4. Stopping Rules 
The study can be stopped early based on the following criteria: 
• Per PI or sponsor discretion 
• If none of the first 7 evaluable patients have disease control (CR+ PR +SD at 16 
weeks) 
 
12. STUDY MANAGEMENT 
 
12.1. Ethics 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), Guidelines of the International Conference on Harmonization (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use, and in full compliance 
with the World Medical Association Declaration of Helsinki and its most recent 
amendments. 
 
 
 
12.2. Institutional Review Board (IRB) Approval 
Before study initiation, this protocol and informed consent form will be submitted for 
review and approval to the IRBs charged with oversight for the clinical sites. In addition, 
any form of proposed advertising and advertising text for patient recruitment must be 

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reviewed and approved by (Sponsor) prior to submission to the IRB. The Investigator will 
forward to (Sponsor) -nominated designee a copy of the IRB’s approval of this protocol, 
any amendments, informed consent form, and any modifications to the informed consent, 
based on the FDA regulations set forth in 21 CFR 56 of the Code of Federal Regulations, 
as well as those of the applicable regulatory bodies in all other participating countries 
outside of the U.S.  
 
In addition, the Investigator will be responsible for forwarding to Sponsor nominated 
designee a description of the IRB board members (including profession and affiliation) or 
a United States (US) Department of Health and Human Services (DHHS) General 
Assurance number and expiration date. If neither of these is available, the chairperson 
must submit a statement indicating that the members of the board responsible for the 
review meet FDA and other appropriate regulatory requirements. In addition, the labeling 
for all approved study drugs should be submitted to the IRB for informational purposes. 
 
12.3. Informed Consent 
Written informed consent of the patient to participate in the study must be obtained and 
documented by the Investigator in accordance with the FDA regulations set forth in 21 
CFR 50 as well as the applicable regulatory bodies in all other participating countries 
outside the United States.  
 
The Investigator must provide the patient with a copy of the informed consent form in a 
language understandable to the patient. Written consent should be obtained before any 
protocol-required procedures are performed, including any procedure not part of normal 
patient care (e.g., withdrawal of current medications). 
 
Changes made by a participating site to the recommended informed consent must be 
forwarded to HRI/Triligent for approval prior to submission to the corresponding IRB. A 
copy of the signed informed consent will be given to the patient or their legal 
representative and a copy must be retained in the Investigator’s study records. 
 
12.4. Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is 
solely responsible for determining whether the trial and its results are patient to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  
Information posted will allow patients to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information. 
 
12.5. Reporting to Regulatory Authorities, Ethics Committees and Investigators 
HonorHealth will be responsible for the expedited reporting of safety reports originating 
from the Study to the Ethics Committees and Institutional Review Boards (IRB), where 

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applicable. 
 
HonorHealth will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
 
12.6. Annual Reports and Study Close-Out 
Any study report submitted to the IRB by the Sponsor-Investigator should be copied to 
Bayer and Genentech. This includes all IRB annual reports and the Clinical Study Report 
(final study report). Additionally, any literature articles that are a result of the study should 
be sent to Bayer and Genentech per the terms detailed in the contract. 
 
12.7. Investigator Obligations 
 
 Form FDA 1572 
The Investigator must provide a fully executed Form FDA 1572. Any additions to the study 
must be provided via a new fully executed Form FDA 1572.  Others should follow FDA 
guidance “Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs”. 
 
 Curriculum Vitae 
The Investigator must provide his/her current signed and dated curriculum vitae and a 
current signed and dated curriculum vitae for each sub-Investigator listed on Form FDA 
1572. Current signed and dated curriculum vitae is defined as updated within 2 years of 
study start up. 
 
 Investigator Protocol Agreement 
The Investigator must sign the Investigator’s Protocol Agreement. The original must be 
kept on file at the Investigator site and a copy provided to HRI. The completed 
Investigator’s Protocol Agreement signifies agreement to comply with all procedures 
outlined by this protocol by the Investigator. An Investigator’s Protocol Agreement must 
be signed if and when a protocol amendment is issued by (Sponsor/CRO). 
 
 Financial Disclosures 
The Investigator and sub-Investigator(s) must complete a Clinical Investigator Financial 
Certification/Disclosure Statement to report financial interests and arrangements that may 
be of concern to FDA per 21 CFR 54. 
 
 Laboratory Certifications and Normal Ranges 
The Investigator will indicate on the Form FDA 1572 the name and location of any local 
laboratories that will be used for laboratory assessments. The Investigator will provide a 
copy of all clinical laboratory certifications, certification numbers, and dates of 
certifications, and. Normal ranges for all laboratory tests will be included with all reported 
results.  Updated versions of these documents must be provided to HRI appropriate. In 
the event the clinical laboratory is changed during the study HRI will be promptly notified, 

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and the Form FDA 1572 will be updated. Appropriate documentation will be submitted to 
HRI to verify the certification of the new laboratory. 
 
All radiology facilities being utilized outside the investigative site must be pre-approved 
by HRI. 
 
 Confidentiality 
The Investigator and any other study personnel involved in this study shall not disclose, 
or use for any purposes (other than for the performance of this study), any data, records, 
or other information (hereinafter collectively “information”) disclosed to the Investigator or 
other study personnel. Such information shall remain the confidential and proprietary 
property of HRI and shall be disclosed only to the Investigator or other designated study 
personnel.  
 
The obligation of non-disclosure shall not apply to the following: 
• Relevant disclosure to potential study participants for the purpose of obtaining 
informed consent; 
• Information after such time that it is or becomes publicly available through no fault 
of the Investigator or other study personnel; and, 
• Information after such time that it is disclosed to the Investigator by a third party 
entitled to disclose such information. 
• If the study site is a ‘covered site’ under the definitions of the Health Insurance 
Portability and Accounting Act (HIPAA), the Investigator will ensure that the patient 
consents to the use of data by HRI/Bayer/Genentech and its designees for the 
purposes of regulatory submissions, study publications, and drug approval. 
 
12.8. Source Documentation 
Source documents serve as the evidence of the existence of the patient and the data 
collected for this trial.  Source documents will be the responsibility of the Investigator and 
will be filed at the site and available as needed by the Sponsor or assigned clinical 
monitor. 
 
Data captured on the eCRFs is to be transcribed from source document and must be 
consistent with any discrepancies explained and documented. 
 
12.9. Case Report Forms 
All the clinical data will be captured by the site on electronic case report forms (eCRFs).   
The eCRFs will be used for all consented patients. The investigator and trained trial 
personnel will enter and edit the data via a secure network, with secure identification and 
password requirement.  A complete electronic audit trial will be maintained.  The 
investigator will be required to provide approval of all data to confirm accuracy.   Copies 
of the eCRFs will be provided to the investigator at the conclusion of the trial.    
 

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HRI will monitor the study to verify study data, medical records, and eCRFs in accordance 
with current ICH GCP guidelines as well as other applicable regulations and guidelines. 
 
12.10. Data Management and Monitoring / Auditing 
Data monitoring procedures will be carried out by an HRI appointed monitor and will be 
performed on a regular basis to comply with Good Clinical Practice guidelines.  
 
Review of the case report forms, cross-reference with source documentation (including 
radiology review), review of study related regulatory documents and logs (e.g., 
enrollment, study site staff training and delegation) and review of drug infusion records 
will be monitored on an ongoing basis during monitoring sessions. The monitor will ensure 
that the investigation is conducted according to protocol design and regulatory 
requirements.  At the conclusion of the monitoring visit, the site monitor will meet with the 
site staff to discuss and request specific corrections to the case report forms, and/or 
request clarification, and/or additional source documentation. The Principal Investigator 
and Clinical Research Coordinator responsible for the study will be provided with a follow-
up letter for resolution of the findings.  
 
The HRI monitor will complete a written monitoring report.  The report will include a 
summary of what the site monitor reviewed and the site monitor’s statements concerning 
the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to 
be taken, and/or actions recommended to ensure compliance. The Principal Investigator 
will be expected to submit any Corrective Action Plans, in writing. 
 
 Data Safety and Monitoring 
An independent Data Safety and Monitoring Committee (DSMC) will be formed to 
evaluate the safety and effectiveness of the study medication for each subject. The DSMC 
will also review all SAEs and AESIs reported by each site. The DSMC will review study 
data to determine if endpoints are being met and if the study can continue with or without 
changes to the protocol or if the study should be terminated immediately due to safety 
concerns or lack of data to support study endpoints.  Findings and recommendations of 
the DSMC will be reported to the Sponsor after each meeting. 
 
12.11. Record Retention 
In accordance with applicable regulatory requirements, following closure of the study, the 
Investigator will maintain a copy of all site study records in a safe and secure location.  
HRI will inform the Investigator of the time period for retaining these records in order to 
comply with applicable regulatory requirements. 
 
HRI reserves the right to terminate the study for refusal of the Investigator and/or 
investigational site to comply with any requirements stated in this study protocol. 
 
 

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13. REFERENCES 
 
1. Cascinu S, Berardi R, Labianca R, et al. Cetuximab plus gemcitabine and cisplatin 
compared with gemcitabine and cisplatin alone in patients with advanced 
pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 
2008;9(1):39-44. doi:10.1016/S1470-2045(07)70383-2. 
 
2. Calvin, K. AACR Annual Meeting 2012 (Special Session – New Drugs on the 
Horizon). 
 
3. Chouitar, J., Zhang, J., et al. (2012). MLN2480, a RAF kinase investigational agent 
with preclinical activity in BRAF mutant and wild-type tumor models. Pigment Cell 
& Melanoma Research, 25(6):848-849. 
 
4. Elenbaas, B., Singh, L., et al. (2010). 105 BIIB024, a potent pan-Raf kinase 
inhibitor for melanoma and solid tumors. EJC Supplements - EJC SUPPL 8, 40-
41. 
 
5. Gulmann C, Sheehan KM, Conroy RM, Wulfkuhle JD, Espina V, Mullarkey MJ, 
Kay EW, Liotta LA, Petricoin EF 3rd. Quantitative cell signaling analysis reveals 
down-regulation of MAPK pathway activation in colorectal cancer. J Pathol. 2009 
Aug;218(4):514-9. doi: 10.1002/path.2561. PMID: 19396842. 
 
6. Jung SH, Lee T, Kim K, George SL. Admissible two-stage designs for phase II 
cancer clinical trials. Stat Med. 2004;23(4):561-569. doi:10.1002/sim.1600. 
 
7. Kato, S., Naing, A., Falchook, G., Holley, V. R., Velez-Bravo, V. M., Patel, S., 
Zinner, R. G., Piha-Paul, S. A., Tsimberidou, A. M., Hong, D. S., et al. (2015). 
Abstract 2689: Overcoming BRAF/MEK resistance using vemurafenib with 
crizotinib or sorafenib in patients with BRAF-mutant advanced cancers: phase I 
study. Cancer Research 75, 2689. 
 
8. Kholodenko, B. N. (2015). Drug Resistance Resulting from Kinase Dimerization Is 
Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects. 
Cell Rep 12, 1939-1949. 
 
9. Kindler HL, Wroblewski K, Wallace JA, et al. Gemcitabine plus sorafenib in patients 
with advanced pancreatic cancer: a phase II trial of the University of Chicago 
Phase 
II 
Consortium. 
Invest 
New 
Drugs. 
2012;30(1):382-386. 
doi:10.1007/s10637-010-9526-z. 
 
10. Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, Neale RE, 
Tempero M, Tuveson DA, Hruban RH, Neoptolemos JP. Pancreatic cancer. Nat 

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Page 63 of 94 
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Rev Dis Primers. 2016 Apr 21;2:16022. doi: 10.1038/nrdp.2016.22. PMID: 
27158978. 
 
11. Kufareva I, Abagyan R. Type-II kinase inhibitor docking, screening, and profiling 
using modified structures of active kinase states. J Med Chem. 2008;51(24):7921-
7932. doi:10.1021/jm8010299. 
 
 
12. Olszanski, A.J., Gonzalez, R., et al. (2017). Phase I study of the investigational, 
oral pan-RAF kinase inhibitor TAK-580 (MLN2480) in patients with advanced solid 
tumors (ST) or melanoma (MEL): Final analysis. Annals of Oncology (2017) 28 
(supp15): v122-v141. 
 
13. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. 
Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, 
liver, and pancreas cancers in the United States. Cancer Res. 2014 Jun 
1;74(11):2913-21. doi: 10.1158/0008-5472. 
 
14. Rasco, D. W., Middleton, M. R., et al. (2015). Phase I study of two dosing 
schedules of the investigational oral pan-RAF kinase inhibitor MLN2480 in patients 
(pts) with advanced solid tumors or melanoma. European Journal of Cancer 51, 
S53-S54. 
 
15. Roskoski R Jr. Classification of small molecule protein kinase inhibitors based 
upon the structures of their drug-enzyme complexes. Pharmacol Res. 
2016;103:26-48. doi:10.1016/j.phrs.2015.10.021. 
 
16. Rukhlenko, O.S., Khorsand, F., et al. (2018). Dissecting RAF Inhibitor Resistance 
by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS 
Signaling. Cell Systems 7, 161-179.e114. 
 
17. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J 
Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12. 
 
18. Simon, R. (1989). Optimal two-stage designs for phase II clinical trials. Controlled 
Clinical Trials 10, 1-10.       
 
19. Srivastava A, Moorthy A. Sorafenib induces synergistic effect on inhibition of 
vemurafenib resistant melanoma growth. Front Biosci (Schol Ed). 2019;11:193-
202. Published 2019 Mar. 
 

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20. Strobel O, Neoptolemos J, Jäger D, Büchler MW. Optimizing the outcomes of 
pancreatic cancer surgery. Nat Rev Clin Oncol. 2019 Jan;16(1):11-26. doi: 
10.1038/s41571-018-0112-1. PMID: 30341417. 
 
21. Sun, Y., Alberta, J. A., et al (2017). A brain-penetrant RAF dimer antagonist for the 
noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro 
Oncol 19, 774-785. 
 
22. Takano, S., Sogawa, K., Yoshitomi, H. et al. Increased circulating cell signalling 
phosphoproteins in sera are useful for the detection of pancreatic cancer. Br J 
Cancer 103, 223–231 (2010). https://doi.org/10.1038/sj.bjc.6605734 
 
 

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APPENDICES 
 
Appendix A: Schedule of Events 
 
Assessment 
Screening 
Within  
28 Days 
Cycle 1 
Cycle 2 + 
Prior to 
Cycles 
3, 5, 7, 
etc. 
Off 
Treatment 
Visit 11 
Follow-up 
Day  
1 
 
Day  
8 
Day  
15 
Day  
22 
Day  
1 
 
 
 
Window 
 
 
 
 
 
 
 
 
 
 
 
14-28 ( ± 
2 days) of 
last dose 
30 days of 
last dose, 
then every 
3 months 
Signed informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Direct Physical 
Exam 
 
X2 
 
X3 
X 
X 
X3 
 
 
 
 
X 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X2 
 
 
 
 
X3 
 
 
 
 
X 
 
BSA calculation 
 
X2 
 
 
 
 
X 
 
 
 
 
 
 
Vital signs4 
X 
X2 
 
X3 
X 
X 
X3 
 
 
 
 
X 
 
ECOG PS 
X 
X2 
 
X3 
X 
X 
X3 
 
 
 
 
X 
 
CT/ MRI scan / 
tumor 
measurements5 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG6 
X 
X 
 
 
X 
 
X6 
 
 
 
 
 
 
CBC w/differential 
& PLTs 
X 
X2 
 
X3 
X 
X 
X 
 
 
 
 
X 
 
Serum chemistries7 
X 
X2 
 
X3 
X 
X 
X 
 
 
 
 
X 
 
PT/INR 
X 
X2, 8 
 
 
 
 
X8 
 
 
 
 
X8 
 
CA 19-9 (or CA 
125, or CEA if not 
expressers of CA 
19-9) 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Serum pregnancy  
X 
X2 
 
 
 
 
X 
 
 
 
 
X 
 
Confirm KRAS, 
BRAF Mutation 
Status 13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
correlative analysis 
(3 X 10 mL) 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Optional Tumor 
Tissue 15 
X 
<----------------------------------------------------------------------------------X----------------------------------------------------------------------------------> 
Concomitant 
medications9 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
X 
 
Adverse events10 
 
X 
 
X 
X 
X 
X 
 
 
 
 
X 
 
Contact Information 
Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Telephone follow-
up12 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Drug 
Accountability-
(Section 9.4) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
TREATMENT 
Vemurafenib14 
 
X ---------------------------------------------------------> 
X --------------------------------------------> 
 
 
 
Sorafenib14 
 
X ---------------------------------------------------------> 
X --------------------------------------------> 
 
 
 
 
Schedule of Events footnotes: 
1. To include concurrent baseline conditions (using NCI CTCAE, version 5.0), prior cancer therapy 
(including documentation of prior surgery, adjuvant or neoadjuvant chemotherapy and 
radiotherapy). 
2. Should be performed < 24 hours prior to the initiating study treatment day on C1/D1. 
3. Should be performed within 72 hours prior to treatment on day 1 of each cycle beyond cycle 1.  
4. Vitals signed include blood pressure, pulse, respiratory rate and temperature. 
5. Computed tomography (CT) / magnetic resonance imaging (MRI) scan to document disease 
status (including chest, abdomen, pelvis, and other regions as clinically indicated.  In addition, a 
brain scan is required to exclude brain metastases if clinically indicated only.  If a CT scan was 
taken within 28 days prior to first dose, a new scan is not necessary. (see RECIST 1.1 criteria in 
Section 7.1). Follow-up scans are due every 2 cycles (prior to cycle 3, 5, 7, etc.) 
6. ECG (Cycles 1 through 3, then every 3 cycles 6, 9, 12 etc.)  
7. To include glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline phosphatase albumin, 
LDH, total protein, and electrolytes (sodium, potassium, phosphorus, chloride, C02, magnesium, 
calcium).   In patients with known Gilbert’s syndrome, it is recommended to perform a direct 
bilirubin and indirect bilirubin. Calculate creatinine clearance (Cockcroft-Gault equation) 
8. PT/INR required only for patients on warfarin. 
9. To include all medications and supplements taken within 30 days prior to study enrollment. The 
use of grapefruit juice and St. John’s Wort (hyperforin) is prohibited during study treatment.  The 
treating investigator is to discuss this with the patient prior to initiating study treatment and will 
review list of all medications and supplements during the course of the study. 
10. Patient will be followed until resolution of any drug-related AE or SAE occurring during the study, 
including, within 30 days of last administration of study medication, or when the patient begins 
alternative therapy; whichever is sooner.  
11. Off Treatment -Early Termination assessments can be completed 14-28 (+/- 2) days from the last 
dose of study treatment.  
12. Follow-up assessments for survival in person or by telephone will be conducted in all patients 30 
days after the last dose of study treatment and then every 3 months until study completion (may 
be done through medical record review or follow up phone calls).  Receipt of second line therapy 
will be recorded. 
13. Confirm KRAS and BRAF mutation status.  For those patients in which the mutation status of 
KRAS and BRAF kinases has not previously been determined, the patient must have an archival 
tumor specimen (primary or metastatic site) available to submit to confirm KRAS and BRAF 
status.  The results of the mutation status are required for determining patients eligibility for this 
trial 
14. Patients will be asked to take the specified number of tablets for their prescribed dose on an 
empty stomach at a regular time each day with water. Doses should be taken either one hour 
prior or two hours after a meal. Approximately 12 hours should elapse between doses. 
15. For those patients that consent to the optional tissue collection for RPPA analysis, tissue will be 
collected from a newly obtained core or excisional biopsy of a tumor lesion if performed recently 
(within 30 days prior to study treatment on Day 1) and during their participation in the study 
should they be scheduled for a biopsy as part of their routine care during their participation in the 
study through the follow-up period 

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Appendix B: ECOG Performance Status 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours 
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 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am 
J Clin Oncol. 1982;5:649-655. 
 
 

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Appendix C: Revised National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), version 5.0 
 (PUBLISHED 27 NOVEMBER 2017) 
The National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) 
Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 can be viewed 
on-line at the following NCI web site: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf    
 

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Appendix D: New York Heart Association (NYHA) 
 
 
Class Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases. 
Class Objective Assessment 
A 
No objective evidence of cardiovascular disease. No symptoms and no limitation 
in ordinary physical activity. 
B 
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight 
limitation during ordinary activity. Comfortable at rest. 
C 
Objective evidence of moderately severe cardiovascular disease. Marked 
limitation in activity due to symptoms, even during less-than-ordinary activity. 
Comfortable only at rest. 
D 
Objective evidence of severe cardiovascular disease. Severe limitations. 
Experiences symptoms even while at rest. 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart 
Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the 
heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 
1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart 
and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, 
Brown and Co. 1964, p 114. 
 

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Appendix E: Medications with Risk of QT Prolongation and TdP (Torsades de 
Pointes) 
 
Data obtained from CredibleMeds https://crediblemeds.org/new-drug-list/ 
 
Table E1 - Medications with a KNOWN risk of TdP 
Table E2 - Medications with a POSSIBLE risk of TdP 
Table E3 - Medications with a CONDITIONAL risk of TdP 
 
Table F1-Medications with a known risk of TdP 
(These drugs prolong the QT interval AND are clearly associated with a known 
risk of TdP, even when taken as recommended) 
Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Aclarubicin 
(Only on Non US 
Market) 
Aclacin, 
Aclacinomycine, 
Aclacinon, 
Aclaplastin, 
Jaclacin 
Anti-cancer 
Cancer 
Amiodarone 
Cordarone, 
Pacerone, 
Nexterone 
Antiarrhythmic 
Arrhythmia 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 
3 inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox 
Anti-cancer 
Cancer (leukemia) 
Astemizole 
(Removed from US 
Market) 
Hismanal 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
Bepridil 
Vascor 
Antianginal 
Angina Pectoris 
(heart pain) 
Cesium Chloride 
Energy Catalyst 
Toxin 
Alternative therapy 
cancer 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
Chlorpromazine 
Thorazine, 
Largactil, 
Megaphen 
Antipsychotic / 
Antiemetic 
Nausea, 
Schizophrenia, many 
others 
Chlorprothixene 
(Only on Non US 
Market) 
Truxal 
Antipsychotic 
Schizophrenia 
Cilostazol 
Pletal 
Phosphodiesterase 
3 inhibitor 
Intermittent 
claudication 
Ciprofloxacin 
Cipro, Cipro-XR, 
Neofloxin 
Antibiotic 
Bacterial infection 

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Cisapride 
(Removed from US 
Market) 
Propulsid 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, 
SSRI 
Depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic 
Arrhythmia 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Arrhythmia 
Domperidone 
(Only on Non US 
Market) 
Motilium, 
Motillium, 
Motinorm Costi, 
Nomit 
Antiemetic 
Nausea, vomiting 
Donepezil 
Aricept 
Cholinesterase 
inhibitor 
Dementia 
(Alzheimer's 
Disease) 
Dronedarone 
Multaq 
Antiarrhythmic 
Arrhythmia 
Droperidol 
Inapsine, 
Droleptan, 
Dridol, Xomolix 
Antipsychotic / 
Antiemetic 
Anesthesia (adjunct), 
nausea 
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 
Bacterial infection, 
increase GI motility 
Escitalopram 
Cipralex, 
Lexapro, Nexito, 
Anxiset-E, 
Exodus, Esto, 
Seroplex, Elicea, 
Lexamil, Lexam, 
Antidepressant, 
SSRI 
Depression (major), 
anxiety disorders 

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Entact, Losita, 
Reposil, 
Animaxen, 
Esitalo, Lexamil 
Flecainide 
Tambocor, 
Almarytm, 
Apocard, Ecrinal, 
Flécaine 
Antiarrhythmic 
Arrhythmia 
Fluconazole 
Diflucan, Trican 
Antifungal 
Fungal infection 
Gatifloxacin 
(Removed from US 
Market) 
Tequin 
Antibiotic 
Bacterial infection 
Grepafloxacin 
(Removed from US 
Market) 
Raxar 
Antibiotic 
Bacterial infection 
Halofantrine 
(Only on Non US 
Market) 
Halfan 
Antimalarial 
Malaria 
Haloperidol 
Haldol, 
Aloperidin, 
Bioperidolo, 
Brotopon, Dozic, 
Duraperidol, 
Einalon S, 
Eukystol, 
Halosten, 
Keselan, Linton, 
Peluces, 
Serenace, 
Serenase, 
Sigaperidol 
Antipsychotic 
Schizophrenia, 
agitation 
Hydroquinidine 
(Dihydroquinidine) 
(Only on Non US 
Market) 
Serecor 
Antiarrhythmic 
Arrhythmia 
Hydroxychloroquine 
Plaquenil, 
Quineprox 
Antimalarial, Anti-
inflammatory 
Malaria, SLE, 
rheumatoid arthritis 
Ibogaine 
(Only on Non US 
Market) 
Psychedelic 
Narcotic addiction, 
unproven 
Ibutilide 
Corvert 
Antiarrhythmic 
Arrhythmia 
Levofloxacin 
Levaquin, 
Tavanic 
Antibiotic 
Bacterial infection 
Levomepromazine 
(Methotrimeprazine) 
Nosinan, 
Nozinan, 
Levoprome 
Antipsychotic 
Schizophrenia 

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(Only on Non US 
Market) 
Levomethadyl 
acetate 
(Removed from US 
Market) 
Orlaam 
Opioid agonist 
Narcotic dependence 
Levosulpiride 
(Only on Non US 
Market) 
Lesuride, 
Levazeo, Enliva 
Antipsychotic 
Schizophrenia 
Meglumine 
antimoniate 
(Only on Non US 
Market) 
Glucantime 
Antiparasitic 
Leishmaniasis 
Mesoridazine 
(Removed from US 
Market) 
Serentil 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine, 
Symoron, 
Amidone, 
Methadose, 
Physeptone, 
Heptadon 
Opioid agonist 
Narcotic 
dependence, pain 
Moxifloxacin 
Avelox, Avalox, 
Avelon 
Antibiotic 
Bacterial infection 
Nifekalant 
(Only on Non US 
Market) 
Shinbit 
Antiarrhythmic 
Arrhythmia 
Ondansetron 
Zofran, Anset, 
Ondemet, 
Zuplenz, 
Emetron, 
Ondavell, 
Emeset, 
Ondisolv, 
Setronax 
Antiemetic 
Nausea, vomiting 
Oxaliplatin 
Eloxatin 
Anti-cancer 
Cancer 
Papaverine HCl 
(Intra-coronary) 
Vasodilator, 
Coronary 
Diagnostic adjunct 
Pentamidine 
Pentam 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 
Pimozide 
Orap 
Antipsychotic 
Tourette's Disorder 
Probucol 
(Removed from US 
Market) 
Lorelco 
Antilipemic 
Hypercholesterolemia 

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CONFIDENTIAL 
Procainamide 
Pronestyl, 
Procan 
Antiarrhythmic 
Arrhythmia 
Propofol 
Diprivan, 
Propoven 
Anesthetic, general Anesthesia 
Quinidine 
Quinaglute, 
Duraquin, 
Quinact, 
Quinidex, Cin-
Quin, Quinora 
Antiarrhythmic 
Arrhythmia 
Roxithromycin 
(Only on Non US 
Market) 
Rulide, Xthrocin, 
Roxl-150, Roxo, 
Surlid, Rulide, 
Biaxsig, Roxar, 
Roximycinv, 
Roxomycin, 
Rulid, Tirabicin, 
Coroxin 
Antibiotic 
Bacterial infection 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general Anesthesia 
Sotalol 
Betapace, 
Sotalex, Sotacor 
Antiarrhythmic 
Arrhythmia 
Sparfloxacin 
(Removed from US 
Market) 
Zagam 
Antibiotic 
Bacterial infection 
Sulpiride 
(Only on Non US 
Market) 
Dogmatil, 
Dolmatil, 
Eglonyl, 
Espiride, Modal, 
Sulpor 
Antipsychotic, 
atypical 
Schizophrenia 
Sultopride 
(Only on Non US 
Market) 
Barnetil, Barnotil, 
Topral 
Antipsychotic, 
atypical 
Schizophrenia 
Terfenadine 
(Removed from US 
Market) 
Seldane 
Antihistamine 
Allergic rhinitis 
Terlipressin 
(Only on Non US 
Market) 
Teripress, 
Glypressin, 
Terlipin, 
Remestyp, 
Tresil, Teriss 
Vasoconstrictor 
Septic shock 
Terodiline 
(Only on Non US 
Market) 
Micturin, Mictrol 
Muscle relaxant 
Bladder spasm 
Thioridazine 
Mellaril, 
Novoridazine, 
Thioril 
Antipsychotic 
Schizophrenia 
Vandetanib 
Caprelsa 
Anti-cancer 
Cancer (thyroid) 

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Table F2. Medications with a possible risk of TdP 
These drugs can cause QT prolongation BUT currently lack evidence for a risk 
of TdP when taken as recommended. 
Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Abarelix 
(Only on Non US Market) 
Plenaxis 
GnRH Antagonist 
Cancer (prostate) 
Alfuzosin 
Uroxatral 
Alpha-1 
adrenergic 
blocker 
Benign prostatic 
hyperplasia 
Alimemazine 
(Trimeprazine) 
(Only on Non US Market) 
Nedeltran, 
Panectyl, 
Repeltin, 
Therafene, 
Theraligene, 
Theralen, 
Theralene, 
Vallergan, 
Vanectyl, 
Temaril 
Antihistamine 
Allergy 
Apalutamide 
Erleada 
Nonsteroidal 
antiandrogen 
Cancer (prostate) 
Apomorphine 
Apokyn, 
Ixense, 
Spontane, 
Uprima 
Dopamine 
agonist 
Parkinson's 
disease 
Aripiprazole 
Abilify, 
Aripiprex 
Antipsychotic, 
atypical 
Schizophrenia, 
depression 
(adjunct) 
Artemether/Lumefantrine 
Coartem 
Anti-malarial 
Marlaria 
Artenimol/piperaquine 
(Only on Non US Market) 
Eurartesim 
Antimalarial 
Malaria 
Asenapine 
Saphris, 
Sycrest 
Antipsychotic, 
atypical 
Schizophrenia 
Atomoxetine 
Strattera 
CNS stimulant 
ADHD 
Bedaquiline 
Sirturo 
Antibiotic 
Tuberculosis, 
Multi-drug 
resistant 
Bendamustine 
Treanda, 
Treakisym, 
Ribomustin, 
Levact 
Anti-cancer 
Cancer 
(Leukemia, 
lymphoma) 

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CONFIDENTIAL 
Benperidol 
(Only on Non US Market) 
Anquil, 
Glianimon 
Antipsychotic 
Schizophrenia 
Betrixaban 
Bevyxxa 
Anticoagulant 
Anticoagulant 
Bortezomib 
Velcade, 
Bortecad 
Proteasome 
inhibitor 
Cancer (multiple 
myeloma,lympho
ma) 
Bosutinib 
Bosulif 
Anti-cancer 
Cancer (leukemia) 
Buprenorphine 
Butrans, 
Belbuca, 
Bunavail, 
Buprenex, 
Subutex, 
Suboxone, 
Zubsolv 
Opioid agonist 
Narcotic addiction 
and pain 
Cabozantinib 
Cometriq 
Anti-cancer 
Cancer (renal cell) 
Capecitabine 
Xeloda 
Anti-cancer 
Cancer (GI, 
Breast) 
Carbetocin 
(Only on Non US Market) 
Pabal, 
Lonactene, 
Duratocin 
Uterotonic 
Uterine atony 
Ceritinib 
Zykadia 
Anti-cancer 
Cancer (Lung) 
Clofazimine 
(Only on Non US Market) 
Lamprene 
Antibiotic 
Leprosy 
Clotiapine 
(Only on Non US Market) 
Entumine 
Antipsychotic, 
atypical 
Psychosis 
Clozapine 
Clozaril, 
Fazaclo, 
Versacloz 
Antipsychotic, 
atypical 
Schizophrenia 
Cobimetinib 
Cotellic 
Anti-cancer 
Cancer 
(Melanoma) 
Crizotinib 
Xalkori 
Anti-cancer 
Cancer (Non-
small cell lung 
cancer, 
metastatic) 
Cyamemazine 
(Cyamepromazine) 
(Only on Non US Market) 
Tercian 
Antipsychotic 
Schizophrenia, 
sedation 
Dabrafenib 
Tafinlar 
Anti-cancer 
Cancer 
(melanoma) 
Dasatinib 
Sprycel 
Anti-cancer 
Cancer (leukemia) 
Degarelix 
Firmagon, 
Ferring 
Anti-androgen 
Cancer (prostate) 
Delamanid 
(Only on Non US Market) 
Deltyba 
Antibiotic 
Tuberculosis, 
Multi-drug 
resistant 

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CONFIDENTIAL 
Desipramine 
Pertofrane, 
Norpramine 
Antidepressant, 
Tricyclic 
Depression 
Deutetrabenazine 
Austedo 
Vesicular 
monamine 
transporter 2 
inhibitor 
Chorea 
(Huntington's 
disease) 
Dexmedetomidine 
Precedex, 
Dexdor, 
Dexdomitor 
Sedative 
Sedation 
Dextromethorphan/Quinidi
ne 
Nuedexta 
Unknown 
Pseudobulbar 
affect 
Dolasetron 
Anzemet 
Antiemetic 
Nausea, vomiting 
Efavirenz 
Sustiva 
Antiviral 
HIV/AIDS 
Eliglustat 
Cerdelga 
Glucosylceramide 
synthase inhibitor 
Gaucher's 
disease 
Encorafenib 
Braftovi 
BRAF inhibitor 
Cancer 
(Melanoma) 
Entrectinib 
Rozlytrek 
Anti-cancer 
Cancer (Lung) 
Epirubicin 
Ellence, 
Pharmorubici
n, Epirubicin 
Ebewe 
Anti-cancer 
Cancer 
Eribulin mesylate 
Halaven 
Anti-cancer 
Cancer (breast, 
metastatic) 
Ezogabine (Retigabine) 
Potiga, 
Trobalt 
Anticonvulsant 
Seizures, Partial 
Felbamate 
Felbatol 
Anticonvulsant 
Seizures 
Fingolimod 
Gilenya 
Sphingosine 
phospate 
receptor 
modulator 
Multiple Sclerosis 
Fluorouracil (5-FU) 
Adrucil, 
Carac, 
Efudex, 
Efudix 
Anti-cancer 
Cancer 
Flupentixol 
(Only on Non US Market) 
Depixol, 
Fluanxol 
Antipsychotic 
Schizophrenia 
Gemifloxacin 
Factive 
Antibiotic 
Bacterial infection 
Gilteritinib 
Xospata 
Antineoplastic 
Cancer (Acute 
Myeloid 
Leukemia) 
Glasdegib 
Daurismo 
Anti-cancer 
Cancer (Acute 
myeloid leukemia) 

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CONFIDENTIAL 
Granisetron 
Kytril, 
Sancuso, 
Granisol 
Antiemetic 
Nausea, vomiting 
Hydrocodone - ER 
Hysingla™ 
ER, Zohydro 
ER 
Analgesic 
Pain, severe 
Iloperidone 
Fanapt, 
Fanapta, 
Zomaril 
Antipsychotic, 
atypical 
Schizophrenia 
Imipramine (Melipramine) 
Tofranil 
Antidepressant, 
Tricyclic 
Depression 
Inotuzumab ozogamicin 
Besponsa 
Anti-cancer 
Cancer (acute 
lymphocytic 
leukemia} 
Isradipine 
Dynacirc 
Antihypertensive 
Hypertension 
Ivosidenib 
Tibsovo 
IDH1 inhibitor 
Cancer (Acute 
myeloid leukemia) 
Ketanserin 
(Only on Non US Market) 
Sufrexal 
Antihypertensive 
Hypertension 
Lacidipine 
(Only on Non US Market) 
Lacipil, 
Motens 
Calcium channel 
blocker 
Hypertension 
Lapatinib 
Tykerb, 
Tyverb 
Anti-cancer 
Cancer (breast, 
metastatic) 
Lefamulin 
Xenleta 
Antibiotic 
Community 
acquired 
pneumonia 
Lenvatinib 
Lenvima 
Anti-cancer 
Cancer (Thyroid) 
Leuprolide (Leuprorelin) 
Lupron, 
Eligard, 
Viadur, 
Carcinil, 
Enanton, 
Leuplin, 
Lucrin, 
Procren, 
Prostap 
Anti-androgen 
Cancer (prostate) 
Levetiracetam 
Keppra 
Anti-seizure 
Epilepsy 
Levomethadone 
(levamethadone) 
(Only on Non US Market) 
Opioid 
Opiate withdrawal 
syndrome 
Lithium 
Eskalith, 
Lithobid 
Antimanic 
Bipolar disorder 
Lofexidine 
Lucemyra 
Alpha-2-
adrenergic 
agonist, central 
Opioid withdrawal 
syndrome 

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CONFIDENTIAL 
Lopinavir/Ritonavir 
Kaletra, 
Aluvia 
Antiviral 
HIV/AIDS 
Lumateperone 
Caplyta 
Antipsychotic, 
atypical 
Schizophrenia 
Lurasidone 
Latuda 
Antipsychotic, 
atypical 
Schizophrenia, 
biopolar disorder 
and others 
Maprotiline 
Ludiomil 
Anti-depressant, 
Tetracyclic 
Depression 
Melperone 
(Only on Non US Market) 
Bunil, Buronil, 
Eunerpan 
Antipsychotic, 
atypical 
Schizophrenia 
Memantine 
Namenda XR 
NMDA receptor 
antagonist 
Alzheimer's 
disease 
Mianserin 
(Only on Non US Market) 
Tolvon 
Anti-depressant 
Depression 
Midostaurin 
Rydapt 
Anti-cancer 
Cancer (Acute 
myeloid leukemia) 
Mifepristone 
Korlym, 
Mifeprex 
Progesterone 
antagonist 
Pregnancy 
termination 
Mirabegron 
Myrbetriq 
Beta3 adrenergic 
antagonist 
Bladder spasm 
Mirtazapine 
Remeron 
Antidepressant, 
Tetracyclic 
Depression 
Moexipril/Hydrochlorothia
zide 
Uniretic, 
Univasc 
Antihypertensive 
Hypertension, 
diuresis 
Necitumumab 
Portrazza 
Anti-cancer 
Cancer (Lung) 
Nicardipine 
Cardene 
Antihypertensive 
Hypertension 
Nilotinib 
Tasigna 
Anti-cancer 
Cancer (leukemia) 
Norfloxacin 
Noroxin, 
Ambigram 
Antibiotic 
Bacterial infection 
Nortriptyline 
Pamelor, 
Sensoval, 
Aventyl, 
Norpress, 
Allegron, 
Noritren, 
Nortrilen 
Antidepressant, 
Tricyclic 
Depression 
Nusinersen 
Spinraza 
Antisense 
oligonucleotide 
Spinal Muscular 
Atrophy 
Ofloxacin 
Floxin 
Antibiotic 
Bacterial infection 
Oliceridine 
Olinvyk 
Analgesia 
Pain 
Osilodrostat 
Isturisa 
Aldosterone 
synthase inhibitor 
Cushing's 
Disease 

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CONFIDENTIAL 
Osimertinib 
Tagrisso 
Anti-cancer 
Cancer (EGFR 
pos. NSC Lung 
cancer) 
Oxytocin 
Pitocin, 
Syntocinon 
Oxytocic 
Labor stimulation 
Ozanimod 
Zeposia 
Immunomodulatio
n 
Multiple Sclerosis 
Paliperidone 
Invega, 
Xepilon 
Antipsychotic, 
atypical 
Schizophrenia 
Palonosetron 
Aloxi 
Antiemetic 
Nausea, vomiting 
Panobinostat 
Farydak 
Histone 
deacetylase 
inhibitor 
Cancer, Multiple 
myeloma 
Pasireotide 
Signifor 
Somatostatin 
analog 
Cushings Disease 
Pazopanib 
Votrient 
Anti-cancer 
Cancer (renal cell, 
sarcoma) 
Perflutren lipid 
microspheres 
Definity, 
Optison 
Imaging contrast 
agent 
Diagnostic adjunct 
Perphenazine 
Trilafon, 
Etrafon/Triavil
, Decentan 
Antipsychotic 
Schizophrenia 
Pilsicainide 
(Only on Non US Market) 
Sunrythm 
Anti-arrhythmic 
Arrhythmia 
Pimavanserin 
Nuplazid 
Antipsychotic, 
atypical 
Psychosis, 
Parkinson's 
Disease 
Pipamperone 
(Only on Non US Market) 
Dipiperon, 
Propitan, 
Dipiperal, 
Piperonil, 
Piperonyl 
Antipsychotic 
Schizophrenia 
Pitolisant (Tiprolisant) 
Wakix 
Histamine 3 
antagonist/invers
e agonist 
Narcolepsy 
Pretomanid 
Antitubercular 
Tuberculosis, 
extensively drug 
resistant 
Primaquine phosphate 
Antimalarial 
Malaria 
Promethazine 
Phenergan 
Antipsychotic / 
Antiemetic 
Nausea, vomiting 
Prothipendyl 
(Only on Non US Market) 
Dominal, 
Largophren, 
Timoval, 
Antipsychotic 
Schizophrenia 

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CONFIDENTIAL 
Timovan, 
Tumovan 
Remimazolam 
Byfavo 
Sedative 
Sedation 
Ribociclib 
Kisqali 
Anti-cancer 
Cancer (breast) 
Rilpivirine 
Edurant, 
Complera, 
Eviplera, 
Juluca 
Antiviral 
Viral infection 
(HIV/AIDS) 
Romidepsin 
Istodax 
Histone 
deacetylase 
inhibitor 
Cancer 
(lymphoma) 
Rucaparib 
Rubraca 
PARP inhibitor 
Cancer 
Saquinavir 
Invirase(comb
o) 
Antiviral 
Viral infection 
(HIV/AIDS) 
Selpercatinib 
Retevmo 
Kinase inhibitor 
Lung cancer 
Sertindole 
(Only on Non US Market) 
Serdolect, 
Serlect 
Antipsychotic, 
atypical 
Schizophrenia, 
anxiety 
Siponimod 
Mayzent 
Multiple Sclerosis 
Sorafenib 
Nexavar 
Anti-cancer 
Cancer (liver, 
renal cell, 
metastatic thyroid) 
Sunitinib 
Sutent 
Anti-cancer 
Cancer (GIST, 
renal cell, pNET) 
Tacrolimus 
Prograf, 
Prograf, 
Advagraf, 
Protopic 
Immunosuppress
ant 
Immune 
suppression 
Tamoxifen 
Nolvadex, 
Istubal 
Anti-cancer 
Cancer (breast) 
Tazemetostat 
Tazverik 
Anti-cancer 
Epithelioid 
sarcoma 
Telavancin 
Vibativ 
Antibiotic 
Bacterial infection 
Telithromycin 
Ketek 
Antibiotic 
Bacterial infection 
Tetrabenazine 
Nitoman, 
Xenazine 
Vesicular 
Monoamine 
Transporter 2 
Inhibitor 
Chorea 
(Huntington's 
disease) 
Tiapride 
(Only on Non US Market) 
Tiapridal, 
Italprid, 
Sereprile, 
Tialaread, 
Tiaryl, 
Tiaprim, 
Tiaprizal, 
Selective D2, D3 
dopamine 
antagonist 
Alcoholism, 
withdrawal 

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CONFIDENTIAL 
Sereprid, 
Tiapridex 
Tipiracil/Trifluridine 
Lonsurf 
Anti-cancer 
Cancer 
(Metastatic 
colorectal) 
Tizanidine 
Zanaflex, 
Sirdalud 
Muscle relaxant 
Muscle spasticity 
Tolterodine 
Detrol, 
Detrusitol 
Muscle relaxant 
Bladder spasm 
Toremifene 
Fareston 
Estrogen 
agonist/antagonis
t 
Cancer (breast, 
metastatic) 
Tramadol 
Crispin, 
Ralivia ER, 
Ralivia 
Flashtab, 
Tramadolum, 
Tramal, 
Tramodol, 
Tridural, 
Ultram, 
Ultram ER, 
Zydol, Ixprim, 
Zaldiar, 
Topalgic 
Analgesic 
Pain 
Trimipramine 
Surmontil, 
Rhotrimine, 
Stangyl 
Antidepressant, 
Tricyclic 
Depression 
Tropisetron 
(Only on Non US Market) 
Navoban, 
Setrovel 
Antiemetic 
Nausea, vomiting 
Valbenazine 
Ingrezza 
Vesicular 
monamine 
transporter 2 
inhibitor 
Tardive 
Dyskinesia 
Vardenafil 
Levitra 
Phosphodiesteras
e 5 inhibitor 
Erectile 
dysfunction 
Vemurafenib 
Zelboraf 
Anti-cancer 
Cancer 
(melanoma) 
Venlafaxine 
Effexor, 
Efexor 
Antidepressant, 
SNRI 
Depression 
Vorinostat 
Zolinza 
Histone 
deacetylase 
inhibitor 
Cancer 
(lymphoma) 
Zotepine 
(Only on Non US Market) 
Losizopilon, 
Lodopin, 
Antipsychotic, 
atypical 
Schizophrenia 

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CONFIDENTIAL 
Setous, 
Zoleptil 
Zuclopenthixol 
(Zuclopentixol) 
(Only on Non US Market) 
Cisordinol, 
Clopixol, 
Acuphase 
Antipsychotic 
Psychosis 
 
 
Table F3. Medications with a possible risk of TdP 
These drugs can cause QT prolongation BUT currently lack evidence for a risk 
of TdP when taken as recommended. 
Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Abarelix 
(Only on Non US Market) 
Plenaxis 
GnRH Antagonist 
Cancer (prostate) 
Alfuzosin 
Uroxatral 
Alpha-1 
adrenergic 
blocker 
Benign prostatic 
hyperplasia 
Alimemazine 
(Trimeprazine) 
(Only on Non US Market) 
Nedeltran, 
Panectyl, 
Repeltin, 
Therafene, 
Theraligene, 
Theralen, 
Theralene, 
Vallergan, 
Vanectyl, 
Temaril 
Antihistamine 
Allergy 
Apalutamide 
Erleada 
Nonsteroidal 
antiandrogen 
Cancer (prostate) 
Apomorphine 
Apokyn, 
Ixense, 
Spontane, 
Uprima 
Dopamine 
agonist 
Parkinson's 
disease 
Aripiprazole 
Abilify, 
Aripiprex 
Antipsychotic, 
atypical 
Schizophrenia, 
depression 
(adjunct) 
Artemether/Lumefantrine 
Coartem 
Anti-malarial 
Marlaria 
Artenimol/piperaquine 
(Only on Non US Market) 
Eurartesim 
Antimalarial 
Malaria 
Asenapine 
Saphris, 
Sycrest 
Antipsychotic, 
atypical 
Schizophrenia 
Atomoxetine 
Strattera 
CNS stimulant 
ADHD 
Bedaquiline 
Sirturo 
Antibiotic 
Tuberculosis, 
Multi-drug 
resistant 

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CONFIDENTIAL 
Bendamustine 
Treanda, 
Treakisym, 
Ribomustin, 
Levact 
Anti-cancer 
Cancer 
(Leukemia, 
lymphoma) 
Benperidol 
(Only on Non US Market) 
Anquil, 
Glianimon 
Antipsychotic 
Schizophrenia 
Betrixaban 
Bevyxxa 
Anticoagulant 
Anticoagulant 
Bortezomib 
Velcade, 
Bortecad 
Proteasome 
inhibitor 
Cancer (multiple 
myeloma,lympho
ma) 
Bosutinib 
Bosulif 
Anti-cancer 
Cancer (leukemia) 
Buprenorphine 
Butrans, 
Belbuca, 
Bunavail, 
Buprenex, 
Subutex, 
Suboxone, 
Zubsolv 
Opioid agonist 
Narcotic addiction 
and pain 
Cabozantinib 
Cometriq 
Anti-cancer 
Cancer (renal cell) 
Capecitabine 
Xeloda 
Anti-cancer 
Cancer (GI, 
Breast) 
Carbetocin 
(Only on Non US Market) 
Pabal, 
Lonactene, 
Duratocin 
Uterotonic 
Uterine atony 
Ceritinib 
Zykadia 
Anti-cancer 
Cancer (Lung) 
Clofazimine 
(Only on Non US Market) 
Lamprene 
Antibiotic 
Leprosy 
Clotiapine 
(Only on Non US Market) 
Entumine 
Antipsychotic, 
atypical 
Psychosis 
Clozapine 
Clozaril, 
Fazaclo, 
Versacloz 
Antipsychotic, 
atypical 
Schizophrenia 
Cobimetinib 
Cotellic 
Anti-cancer 
Cancer 
(Melanoma) 
Crizotinib 
Xalkori 
Anti-cancer 
Cancer (Non-
small cell lung 
cancer, 
metastatic) 
Cyamemazine 
(Cyamepromazine) 
(Only on Non US Market) 
Tercian 
Antipsychotic 
Schizophrenia, 
sedation 
Dabrafenib 
Tafinlar 
Anti-cancer 
Cancer 
(melanoma) 
Dasatinib 
Sprycel 
Anti-cancer 
Cancer (leukemia) 

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CONFIDENTIAL 
Degarelix 
Firmagon, 
Ferring 
Anti-androgen 
Cancer (prostate) 
Delamanid 
(Only on Non US Market) 
Deltyba 
Antibiotic 
Tuberculosis, 
Multi-drug 
resistant 
Desipramine 
Pertofrane, 
Norpramine 
Antidepressant, 
Tricyclic 
Depression 
Deutetrabenazine 
Austedo 
Vesicular 
monamine 
transporter 2 
inhibitor 
Chorea 
(Huntington's 
disease) 
Dexmedetomidine 
Precedex, 
Dexdor, 
Dexdomitor 
Sedative 
Sedation 
Dextromethorphan/Quinidi
ne 
Nuedexta 
Unknown 
Pseudobulbar 
affect 
Dolasetron 
Anzemet 
Antiemetic 
Nausea, vomiting 
Efavirenz 
Sustiva 
Antiviral 
HIV/AIDS 
Eliglustat 
Cerdelga 
Glucosylceramide 
synthase inhibitor 
Gaucher's 
disease 
Encorafenib 
Braftovi 
BRAF inhibitor 
Cancer 
(Melanoma) 
Entrectinib 
Rozlytrek 
Anti-cancer 
Cancer (Lung) 
Epirubicin 
Ellence, 
Pharmorubici
n, Epirubicin 
Ebewe 
Anti-cancer 
Cancer 
Eribulin mesylate 
Halaven 
Anti-cancer 
Cancer (breast, 
metastatic) 
Ezogabine (Retigabine) 
Potiga, 
Trobalt 
Anticonvulsant 
Seizures, Partial 
Felbamate 
Felbatol 
Anticonvulsant 
Seizures 
Fingolimod 
Gilenya 
Sphingosine 
phospate 
receptor 
modulator 
Multiple Sclerosis 
Fluorouracil (5-FU) 
Adrucil, 
Carac, 
Efudex, 
Efudix 
Anti-cancer 
Cancer 
Flupentixol 
(Only on Non US Market) 
Depixol, 
Fluanxol 
Antipsychotic 
Schizophrenia 
Gemifloxacin 
Factive 
Antibiotic 
Bacterial infection 

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CONFIDENTIAL 
Gilteritinib 
Xospata 
Antineoplastic 
Cancer (Acute 
Myeloid 
Leukemia) 
Glasdegib 
Daurismo 
Anti-cancer 
Cancer (Acute 
myeloid leukemia) 
Granisetron 
Kytril, 
Sancuso, 
Granisol 
Antiemetic 
Nausea, vomiting 
Hydrocodone - ER 
Hysingla™ 
ER, Zohydro 
ER 
Analgesic 
Pain, severe 
Iloperidone 
Fanapt, 
Fanapta, 
Zomaril 
Antipsychotic, 
atypical 
Schizophrenia 
Imipramine (Melipramine) 
Tofranil 
Antidepressant, 
Tricyclic 
Depression 
Inotuzumab ozogamicin 
Besponsa 
Anti-cancer 
Cancer (acute 
lymphocytic 
leukemia} 
Isradipine 
Dynacirc 
Antihypertensive 
Hypertension 
Ivosidenib 
Tibsovo 
IDH1 inhibitor 
Cancer (Acute 
myeloid leukemia) 
Ketanserin 
(Only on Non US Market) 
Sufrexal 
Antihypertensive 
Hypertension 
Lacidipine 
(Only on Non US Market) 
Lacipil, 
Motens 
Calcium channel 
blocker 
Hypertension 
Lapatinib 
Tykerb, 
Tyverb 
Anti-cancer 
Cancer (breast, 
metastatic) 
Lefamulin 
Xenleta 
Antibiotic 
Community 
acquired 
pneumonia 
Lenvatinib 
Lenvima 
Anti-cancer 
Cancer (Thyroid) 
Leuprolide (Leuprorelin) 
Lupron, 
Eligard, 
Viadur, 
Carcinil, 
Enanton, 
Leuplin, 
Lucrin, 
Procren, 
Prostap 
Anti-androgen 
Cancer (prostate) 
Levetiracetam 
Keppra 
Anti-seizure 
Epilepsy 
Levomethadone 
(levamethadone) 
(Only on Non US Market) 
Opioid 
Opiate withdrawal 
syndrome 

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Lithium 
Eskalith, 
Lithobid 
Antimanic 
Bipolar disorder 
Lofexidine 
Lucemyra 
Alpha-2-
adrenergic 
agonist, central 
Opioid withdrawal 
syndrome 
Lopinavir/Ritonavir 
Kaletra, 
Aluvia 
Antiviral 
HIV/AIDS 
Lumateperone 
Caplyta 
Antipsychotic, 
atypical 
Schizophrenia 
Lurasidone 
Latuda 
Antipsychotic, 
atypical 
Schizophrenia, 
biopolar disorder 
and others 
Maprotiline 
Ludiomil 
Anti-depressant, 
Tetracyclic 
Depression 
Melperone 
(Only on Non US Market) 
Bunil, Buronil, 
Eunerpan 
Antipsychotic, 
atypical 
Schizophrenia 
Memantine 
Namenda XR 
NMDA receptor 
antagonist 
Alzheimer's 
disease 
Mianserin 
(Only on Non US Market) 
Tolvon 
Anti-depressant 
Depression 
Midostaurin 
Rydapt 
Anti-cancer 
Cancer (Acute 
myeloid leukemia) 
Mifepristone 
Korlym, 
Mifeprex 
Progesterone 
antagonist 
Pregnancy 
termination 
Mirabegron 
Myrbetriq 
Beta3 adrenergic 
antagonist 
Bladder spasm 
Mirtazapine 
Remeron 
Antidepressant, 
Tetracyclic 
Depression 
Moexipril/Hydrochlorothia
zide 
Uniretic, 
Univasc 
Antihypertensive 
Hypertension, 
diuresis 
Necitumumab 
Portrazza 
Anti-cancer 
Cancer (Lung) 
Nicardipine 
Cardene 
Antihypertensive 
Hypertension 
Nilotinib 
Tasigna 
Anti-cancer 
Cancer (leukemia) 
Norfloxacin 
Noroxin, 
Ambigram 
Antibiotic 
Bacterial infection 
Nortriptyline 
Pamelor, 
Sensoval, 
Aventyl, 
Norpress, 
Allegron, 
Noritren, 
Nortrilen 
Antidepressant, 
Tricyclic 
Depression 
Nusinersen 
Spinraza 
Antisense 
oligonucleotide 
Spinal Muscular 
Atrophy 
Ofloxacin 
Floxin 
Antibiotic 
Bacterial infection 

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Oliceridine 
Olinvyk 
Analgesia 
Pain 
Osilodrostat 
Isturisa 
Aldosterone 
synthase inhibitor 
Cushing's 
Disease 
Osimertinib 
Tagrisso 
Anti-cancer 
Cancer (EGFR 
pos. NSC Lung 
cancer) 
Oxytocin 
Pitocin, 
Syntocinon 
Oxytocic 
Labor stimulation 
Ozanimod 
Zeposia 
Immunomodulatio
n 
Multiple Sclerosis 
Paliperidone 
Invega, 
Xepilon 
Antipsychotic, 
atypical 
Schizophrenia 
Palonosetron 
Aloxi 
Antiemetic 
Nausea, vomiting 
Panobinostat 
Farydak 
Histone 
deacetylase 
inhibitor 
Cancer, Multiple 
myeloma 
Pasireotide 
Signifor 
Somatostatin 
analog 
Cushings Disease 
Pazopanib 
Votrient 
Anti-cancer 
Cancer (renal cell, 
sarcoma) 
Perflutren lipid 
microspheres 
Definity, 
Optison 
Imaging contrast 
agent 
Diagnostic adjunct 
Perphenazine 
Trilafon, 
Etrafon/Triavil
, Decentan 
Antipsychotic 
Schizophrenia 
Pilsicainide 
(Only on Non US Market) 
Sunrythm 
Anti-arrhythmic 
Arrhythmia 
Pimavanserin 
Nuplazid 
Antipsychotic, 
atypical 
Psychosis, 
Parkinson's 
Disease 
Pipamperone 
(Only on Non US Market) 
Dipiperon, 
Propitan, 
Dipiperal, 
Piperonil, 
Piperonyl 
Antipsychotic 
Schizophrenia 
Pitolisant (Tiprolisant) 
Wakix 
Histamine 3 
antagonist/invers
e agonist 
Narcolepsy 
Pretomanid 
Antitubercular 
Tuberculosis, 
extensively drug 
resistant 
Primaquine phosphate 
 
Antimalarial 
Malaria 
Promethazine 
Phenergan 
Antipsychotic / 
Antiemetic 
Nausea, vomiting 

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Prothipendyl 
(Only on Non US Market) 
Dominal, 
Largophren, 
Timoval, 
Timovan, 
Tumovan 
Antipsychotic 
Schizophrenia 
Remimazolam 
Byfavo 
Sedative 
Sedation 
Ribociclib 
Kisqali 
Anti-cancer 
Cancer (breast) 
Rilpivirine 
Edurant, 
Complera, 
Eviplera, 
Juluca 
Antiviral 
Viral infection 
(HIV/AIDS) 
Romidepsin 
Istodax 
Histone 
deacetylase 
inhibitor 
Cancer 
(lymphoma) 
Rucaparib 
Rubraca 
PARP inhibitor 
Cancer 
Saquinavir 
Invirase(comb
o) 
Antiviral 
Viral infection 
(HIV/AIDS) 
Selpercatinib 
Retevmo 
Kinase inhibitor 
Lung cancer 
Sertindole 
(Only on Non US Market) 
Serdolect, 
Serlect 
Antipsychotic, 
atypical 
Schizophrenia, 
anxiety 
Siponimod 
Mayzent 
Multiple Sclerosis 
Sorafenib 
Nexavar 
Anti-cancer 
Cancer (liver, 
renal cell, 
metastatic thyroid) 
Sunitinib 
Sutent 
Anti-cancer 
Cancer (GIST, 
renal cell, pNET) 
Tacrolimus 
Prograf, 
Prograf, 
Advagraf, 
Protopic 
Immunosuppress
ant 
Immune 
suppression 
Tamoxifen 
Nolvadex, 
Istubal 
Anti-cancer 
Cancer (breast) 
Tazemetostat 
Tazverik 
Anti-cancer 
Epithelioid 
sarcoma 
Telavancin 
Vibativ 
Antibiotic 
Bacterial infection 
Telithromycin 
Ketek 
Antibiotic 
Bacterial infection 
Tetrabenazine 
Nitoman, 
Xenazine 
Vesicular 
Monoamine 
Transporter 2 
Inhibitor 
Chorea 
(Huntington's 
disease) 
Tiapride 
(Only on Non US Market) 
Tiapridal, 
Italprid, 
Sereprile, 
Tialaread, 
Tiaryl, 
Selective D2, D3 
dopamine 
antagonist 
Alcoholism, 
withdrawal 

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Tiaprim, 
Tiaprizal, 
Sereprid, 
Tiapridex 
Tipiracil/Trifluridine 
Lonsurf 
Anti-cancer 
Cancer 
(Metastatic 
colorectal) 
Tizanidine 
Zanaflex, 
Sirdalud 
Muscle relaxant 
Muscle spasticity 
Tolterodine 
Detrol, 
Detrusitol 
Muscle relaxant 
Bladder spasm 
Toremifene 
Fareston 
Estrogen 
agonist/antagonis
t 
Cancer (breast, 
metastatic) 
Tramadol 
Crispin, 
Ralivia ER, 
Ralivia 
Flashtab, 
Tramadolum, 
Tramal, 
Tramodol, 
Tridural, 
Ultram, 
Ultram ER, 
Zydol, Ixprim, 
Zaldiar, 
Topalgic 
Analgesic 
Pain 
Trimipramine 
Surmontil, 
Rhotrimine, 
Stangyl 
Antidepressant, 
Tricyclic 
Depression 
Tropisetron 
(Only on Non US Market) 
Navoban, 
Setrovel 
Antiemetic 
Nausea, vomiting 
Valbenazine 
Ingrezza 
Vesicular 
monamine 
transporter 2 
inhibitor 
Tardive 
Dyskinesia 
Vardenafil 
Levitra 
Phosphodiesteras
e 5 inhibitor 
Erectile 
dysfunction 
Vemurafenib 
Zelboraf 
Anti-cancer 
Cancer 
(melanoma) 
Venlafaxine 
Effexor, 
Efexor 
Antidepressant, 
SNRI 
Depression 
Vorinostat 
Zolinza 
Histone 
deacetylase 
inhibitor 
Cancer 
(lymphoma) 

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Zotepine 
(Only on Non US Market) 
Losizopilon, 
Lodopin, 
Setous, 
Zoleptil 
Antipsychotic, 
atypical 
Schizophrenia 
Zuclopenthixol 
(Zuclopentixol) 
(Only on Non US Market) 
Cisordinol, 
Clopixol, 
Acuphase 
Antipsychotic 
Psychosis 
 
 
 

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Appendix F: Table 1.Compiled list CYP3A4 inhibitors [US FDA (2019);Flockhart 
(2007)] 
This table is prepared to provide examples of clinical index inducers and is not intended 
to be an exhaustive list. 
 
  
Strong inhibitors 
Moderate inhibitors 
Weak inhibitors 
Inhibitor Strength TBD 
CYP3A4 
boceprevir, 
clarithromycin 
cobicistat, danoprevir 
and ritonavir(c), 
elvitegravir and 
ritonavir(c), grapefruit 
juice(a), idelalisib, 
indinavir and ritonavir(c), 
itraconazole, 
ketoconazole, lopinavir, 
nefazadone, nelfinavir, 
ribociclib, ritonavir, 
paritaprevir and ritonavir 
and (ombitasvir and/or 
dasabuvir) (c), 
posaconazole, 
ritonavir(c), saquinavir 
and ritonavir(c), 
telaprevir, tipranavir and 
ritonavir(c), telithromycin,  
troleandomycin, 
voriconazole 
aprepitant, ciprofloxacin,  
conivaptan(b), crizotinib, 
cyclosporine, diltiazem(d), 
dronedarone, 
erythromycin, 
fluconazole, fluvoxamine, 
grapefruit juice, imatinib, 
netupitant/palonosetron, 
tofisopam(e), verapamil 
atomoxetine, 
chlorzoxazone, 
cilostazol, cimetidine, 
clotrimazole, 
esomeprazole, 
fosaprepitant, lesinurad, 
istradefylline, ivacaftor, 
lomitapide, omeprazole, 
pantoprazole, ranitidine, 
ranolazine, ticagrelor 
amiodarone, 
chloramphenicol, 
delaviridine, diethyl-
dithiocarbamate 
(DDTC), gestodene(e), 
mibefradil(e), 
mifepristone, 
norfloxacin, star fruit 
 
(a) The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have 
shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) 
or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength). 
(b) The classification is based on studies conducted with intravenously administered conivaptan. 
(c) Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should be used when 
extrapolating the observed effect of ritonavir alone to the effect of combination regimens on CYP3A activities. 
(d) Diltiazem increased AUC of certain sensitive CYP3A substrates (e.g., buspirone) more than 5-fold.” [US FDA (2019)] 
(e) Off the US market; not approved in US 
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic 
pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with 
strong index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive substrates of CYP3A with ≥10-fold increase in 
AUC by co-administration of strong index inhibitors are shown above the dashed line. Other elimination pathways may also 
contribute to the elimination of the substrates listed in the table above and should be considered when assessing the drug 
interaction potential.”[US FDA (2019)]  
 
 

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Appendix G continued: Table 2. Compiled list of CYP3A4 inducers [US FDA 
(2019); Flockhart (2007)] 
 
This table is prepared to provide examples of clinical index inducers and is not intended to be 
an exhaustive list. 
 
  
Strong inducers 
Moderate inducers 
Weak inducers 
Inhibitor Strength TBD 
CYP3A 
apalutamide, 
carbamazepine, 
enzalutamide, 
mitotane, phenytoin, 
rifampin, St. John’s 
wort(a) 
bosentan, efavirenz, 
etravirine, nafcillin, 
phenobarbital, 
primidone, rifabutin 
armodafinil, 
modafinil, 
rufinamide, 
oxcarbazepine 
brigatinib, nevirapine, 
pioglitazone 
 
 (a) The effect of St. John’s wort varies widely and is preparation dependent. 
 
Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic 
pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively.” [US FDA (2019)] 
 
References: 
 
1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. 
Indiana University School of Medicine (2007). https://drug-
interactions.medicine.iu.edu. Accessed 11/04/20. 
 
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table 
of Substrates, Inhibitors and Inducers 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/DrugInteractionsLabeling/ucm093664.htm. Accessed 11/04/20. 
 
 
 
 
 
 
 
 

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